Evaluating Exercise as a Therapeutic Intervention for Methamphetamine Addiction-Like Behavior 1

Abstract

The need for effective treatments for addiction and dependence to the illicit stimulant methamphetamine in primary care settings is increasing, yet no effective medications have been FDA approved to reduce dependence [1]. This is partially attributed to the complex and dynamic neurobiology underlying the various stages of addiction [2]. Therapeutic strategies to treat methamphetamine addiction, particularly the relapse stage of addiction, could revolutionize methamphetamine addiction treatment. In this context, preclinical studies demonstrate that voluntary exercise (sustained physical activity) could be used as an intervention to reduce methamphetamine addiction. Therefore, it appears that methamphetamine disrupts normal functioning in the brain and this disruption is prevented or reduced by engaging in exercise. This review discusses animal models of methamphetamine addiction and sustained physical activity and the interactions between exercise and methamphetamine behaviors. The review highlights how methamphetamine and exercise affect neuronal plasticity and neurotoxicity in the adult mammalian striatum, hippocampus, and prefrontal cortex, and presents the emerging mechanisms of exercise in attenuating intake and in preventing relapse to methamphetamine seeking in preclinical models of methamphetamine addiction.

Keywords

Exercise methamphetamine addiction animal models reward relapse neurogenesis neurotoxicity syndromes neuronal plasticity

INTRODUCTION

For centuries, there has been widespread interest to understand the importance of physical activity on the overall quality of life of an individual. The idea that stress and mental states have adverse effects on physical health is well accepted, and conversely, it is suggested that a healthy body will espouse a healthy mind [3]. Thus, an emerging area of interest focuses on the mechanisms by which exercise (sustained physical activity) affects the mammalian brain, particularly on cognitive function. One way to conduct research in this field involves the use animal models to delve more deeply into cortical connectivity and molecular and cellular mechanisms involved in exercise and brain function. This micro-view allows us to see major benefits (and minor pitfalls) of exercise that may otherwise be easily overlooked.

Addiction or substance dependence is a mental disorder that involves the loss of behavioral control over drug taking and drug seeking which involves impulsivity and compulsivity. The impulsive and compulsive features of addiction can be grouped into three stages: [1] binge/prolonged intoxication, [2] withdrawal neutral/negative affect, and [3] preoccupation/anticipation (craving); these stages comprise the cycle of addiction. The limited (often recreational) use of drugs with abuse potential is distinct from the pattern of escalated drug use and the materialization of a chronic drug-dependent state [4]. Furthermore, the last stage of the addiction cycle describes a key element of addiction in humans which defines addiction as a chronic relapsing disorder [2]. Understanding the neurobiology of addiction is critical for identifying therapeutic strategies, and in this regard animal models of addiction have proved to be an immensely valuable tool for parsing out the neurobiological adaptations that contribute to the progression of addiction through these various stages [2, 5, 6].

A recent review detailed the value of exercise as a potential therapeutic strategy for intervention during the various stages of addiction for several drugs of abuse [7]. The therapeutic value of exercise could be due to its natural reinforcing effects and it may contribute to reward interaction, whereby, the presence of two reinforcing agents (e.g. illicit drug and exercise) could devalue the alternate reinforcer [8, 9]. The current review focuses on methamphetamine, a psychostimulant illicit drug with high abuse potential, with the objective to understand where the interaction between methamphetamine and exercise may be beneficial. This review discusses the neurobiological adaptations produced by exercise which contribute to reversing the negative effects of methamphetamine, in addition to exploring the theory of exercise itself eliciting addictive behavior.

METHAMPHETAMINE ADDICTION: IMPACT ON SOCIETY

The burden of methamphetamine abuse is increasing in the United States; available SAMHSA reports show 8% of all drug and alcohol treatment admissions involve methamphetamine and treatment studies report frequent relapses to methamphetamine seeking among those that are trying to quit [10]. Furthermore, methamphetamine abuse takes emotional and financial tolls on society, cutting across ages, races, ethnicities, and genders. It increases mortality, morbidity, and economic costs. Therefore, successfully reducing risk-taking behaviors, such as methamphetamine abuse, can potentially result in large public health gains [11, 12].

According to the recent reports from the National Institutes on Drug abuse (NIDA) and others, there are a few treatment options for methamphetamine addiction [1, 13–15]. For example, the best therapy currently available is the behavioral treatment approach (Matrix model, an outpatient treatment using psychosocial protocols, [16]); however, behavioral therapies are associated with lower beneficial effects on maintaining an individual’s abstinence as well as reducing drug craving elicited by drug-related context and cues [17]. Therefore, NIDA is currently conducting research to seek improved treatment options, including investigating the efficacy of non-traditional and non-pharmaceutical options that may treat methamphetamine addiction.

PHYSICAL FITNESS VIA EXERCISE: IMPACT ON SOCIETY

In the world we live in today, almost everything we need is available at the click of a mouse. As an unfortunate consequence, it has become too easy to avoid physical activity and slip into a sedentary lifestyle, which has been associated with obesity, diabetes mellitus, increased risk of cardiovascular disease, and direct and indirect socioeconomic costs [18–21]. In recent years, the benefits of exercise on health and wellness have become increasingly well known. Exercise has been found to reduce the severity and even reverse the previously stated medical conditions associated with physical inactivity, which in turn reduces the cost of medical needs and other indirect socioeconomic costs [18, 22, 23]. Perhaps more relevant to this review, exercise can improve mental health by offering relief from the symptoms of depression and anxiety, and by improving mood [24–26]; these effects make exercise a valuable tool in disrupting the vicious feed-forward loop between mental illness and substance abuse [27–29].

While regular and regimented physical activity may be therapeutic, clinical cases of exercise eliciting addiction-like behavior have been reported with many sports activities including running, martial arts, weight lifting and body-building, and have been summarized in The Exercise Paradox [30]. The latter study used the Exercise Dependence Scale and the Exercise Addiction Inventory and reported that between 3.4% and 13.4% of a sample of university students were at high risk for “exercise addiction” [30]. Clinical cases have reported loss of control over exercise behavior and compulsivity or ‘obligation’ to perform exercise [30], both of which are hallmarks of addictive disorders [31]. Salience, withdrawal, emotional dysregulation, negative physical and psychosocial consequences, tolerance to the quantity and/or intensity, and relapse to abuse behavior are other phenotypes that support the notion that exercise may be an addictive behavior [30, 32–34]. However, because exercise is considered a sociologically normative behavior, addiction to exercise may be difficult to detect. Thus, partially due to the paucity of peer-reviewed evidence, “exercise addiction” is not yet categorized in Diagnostic and Statistical Manual of Mental Diseases or International Classification of Diseases [31, 35]. Furthermore, excessive preoccupation with exercise has been observed with other disorders, including eating disorders and body dysmorphic disorders [33, 34, 36, 37]. This begs the question whether addiction-like exercise behavior is manifested due to vulnerability of specific personality types, or caused by excessive exposure to exercise. Animal models are more useful at parsing out such causalities.

EXERCISE AS A TREATMENT OPTION FOR METHAMPHETAMINE ADDICTION

In the context of substance abuse disorders, such as methamphetamine addiction, a single pharmacological intervention may not be sufficient or useful throughout the progression of addiction because the underlying neurobiology of addiction is continually changing between the different stages of addiction [2, 38]. Exercise is reported to have negative relationships with the extent, duration and frequency of drug use throughout the stages of initiation, prolonged intoxication, withdrawal, and relapse [7], and thus, has been sought out as a potential non-pharmacological treatment. Moderate exercise in methamphetamine dependent individuals significantly reduced depression symptom scores; in fact, “individuals with the most severe medical, psychiatric and addiction disease burden at baseline showed the most significant improvement in depressive symptoms by study endpoint” [39]. Similarly, group exercise for substance use disorder patients was found to significantly improve the physical health and psychological health domains of quality of life questionnaire; this intervention was beneficial even to patients with the most severe health problems [40]. Since depression and poor mental health are risk factors for relapse to drug seeking [27–29], these studies suggest that exercise is a useful strategy for reducing relapse in methamphetamine dependent individuals. Most importantly, the low cost and ease-of-implementation make exercise therapy all the more lucrative as a potential intervention. Therefore, clinical studies suggest that exercise can be used as a therapeutic intervention that may treat methamphetamine addiction, particularly during the relapse stage of addiction. The rest of the review will focus on the preclinical models of methamphetamine addiction and of exercise eliciting addiction like behavior. Furthermore, we hope to provide a brief overview on the neuroprotective effects of exercise on methamphetamine addiction in the context of inhibition of intake.

ANIMAL MODELS OF ADDICTION TO ILLICIT DRUGS

Drug-taking behavior has been demonstrated in rodent models of intravenous drug self-administration, in which rodents are trained to self-administer drugs by pressing a lever for an intravenous drug infusion in an operant conditioning chamber [41]. As mentioned previously, addiction is distinct from limited or recreational drug use. An increase in drug availability or a history of drug intake has been shown to accelerate the development of dependence in humans [42, 43]. Thus, animal models of addiction should highlight dependence-like behaviors, such as escalation of drug intake over time and withdrawal symptoms when the drug is withheld [41]. In that regard, intravenous methamphetamine self-administration with intermittent (1 h biweekly), limited (1 h daily), or long (extended; >4 h daily) access has significant clinical relevance by illustrating a range of different methamphetamine seeking behaviors in rats [44]. Extended access to methamphetamine produces an escalation of methamphetamine self-administration, suggesting compulsive drug intake and reflecting dependence-like behavior. Therefore, the escalation model may provide a useful approach to understand the neurobiological mechanisms responsible for the transition from limited methamphetamine use to compulsive intake. The escalation model may be particularly suitable for testing the hypothesis that alterations in adult brain plasticity induced by the methamphetamine are partially responsible for addictive behavior [41].

The reinstatement of drug-seeking behavior in rats is widely used as a model of craving that mimics the relapse stage of addiction often observed in the clinic [45], and is used extensively to uncover the key brain regions, brain circuitry, neurotransmitters, and neuromodulators associated with reinstatement behavior. The paradigm extinguishes learned self-administration behavior by explicitly not rewarding (e.g. withholding intravenous methamphetamine infusion) the animal after the correct response is emitted (e.g. a correct lever press) and tests the ability of a priming stimulus to reinstate drug-seeking response [46]. The stimuli can be cues previously paired with drug self-administration (cue priming) or acute noncontingent exposure to the drug (experimenter delivered; i.e., drug priming) or context (spatial location) where the drug was self-administered. The drug seeking reinstatement model has been used to mimic an addict’s drug-response pattern [47], and mimic high rates of relapse [47, 48].

An alternative approach for assessing drug reward involves conditioned place preference (CPP), which determines the Pavlovian associations between rewarding effects of a drug and a contiguously presented stimulus, i.e. the context in which the rewarding effects of the drug are experienced [49, 50]. This conditioning approach is different from operant behavior, as it does not involve the animal ‘working’ for the drug reward (e.g. no lever responses), but rather, it examines the preference for the context following the development of the association [51]. Furthermore, in this model animals receive passive administration of the drug (i.e. experimenter delivered), and are tested (cue/context) in a drug-free state [50, 52]. Although the operant self-administration and CPP models have face validity, the operant model of drug reward and reinstatement is more advantageous. For example, while CPP behavior fails to demonstrate drug dose-dependency, the self-administration model is useful for eliciting distinct drug intake patterns (limited vs. compulsive intake of the drug) to mimic recreational use vs. dependent use, and to model an addict’s drug-response pattern, and high relapse rates. Thus, the intravenous self-administration model of drug exposure appears to be the best suited for studying the neural mechanisms of drug reward and relapse.

ANIMAL MODELS OF SUSTAINED PHYSICAL ACTIVITY

Various animal models of exercise have been utilized which can be broadly classified as either voluntary or as forced exercise [53]. One of the most commonly used exercise paradigms involves the use of running wheels. In a voluntary wheel running paradigm, a wheel is placed in the home cage of the animal and the animal has ad libitum access to the wheel. In contrast, forced wheel running isolates the animal with the wheel and partitions off access to any other area; rotation of the wheel can be controlled remotely (using a computer or other mechanism) to ensure that the animal is forced to run while on the wheel [53]. Another forced exercise animal model is treadmill running, where the animal is forced to run on a motor-driven treadmill for a controlled amount of time [53]. Swimming has also been used as an exercise model where the animal was forced to swim in a tank with access to a platform for resting (optional) without leaving the water [54, 55]. Both voluntary and forced exercise paradigms have proven effective animal models; while voluntary exercise is typically chosen to simulate human choices for physical activity, forced exercise is suggested to more closely resemble human exercise regiments [56]. Environmental enrichment is another technique that provides greater opportunity for physical activity compared to standard housing conditions [53], but is a more complex paradigm with social and cognitive stimulation additionally involved; thus, environmental enrichment will not be discussed in the present review.

Utilizing these models of sustained physical activity, there is emerging evidence from animal studies that exercise is addictive and the behavioral outcomes can be compared with other drugs of abuse [8]. For example, the binge/intoxication phase of addiction is characterized by escalation of drug intake; in voluntary wheel running paradigms, escalation of running activity over days of access has been reported by several groups [57–60]. Such behavior indicates that exercise is reinforcing and can induce increased use over time. Additionally, using the CPP task, rats were reported to prefer the chamber previously paired with running wheels (wheel-paired context) compared to the chamber without wheel-pairing history [57], suggesting that access to running wheel is rewarding. Interestingly, physical exercise has been shown to activate the same mesolimbic reward pathway as illicit drugs; like methamphetamine, exercise can increase extracellular dopamine in the ventral striatum (Fig. 1), thus further identifying the neuronal mechanism underlying the rewarding and reinforcing effects of exercise [57, 61]. Combined, this body of research suggests that exercise is rewarding, and can illicit behaviors that correspond to the binge/intoxication phase ofaddiction.

The negative affect and withdrawal symptoms that are typical to drug dependence have also been observed in humans when experiencing a withdrawal from physical exercise [30]; some of these behavioral and physical aspects can also be found in animal models. For example, in mice that were selectively bred for high wheel running activity, providing access to running wheels and subsequently removing wheels access (withdrawal) lead to reduction of systolic and diastolic blood pressure, and of body temperatures, when compared with inbred mice with continued access to wheels or to control mice [62]. Evidence for the negative affect in animal models of drug addiction include behavioral symptoms such as depression and anxiety [63, 64]. Similar observations were made in exercise-preferring inbred mice that were withdrawn from running wheel activity, in whom behavioral despair or depression, assessed using the forced swim test, was elevated compared to control mice [65]. Taken together, animals that are genetically predisposed for high levels of physical activity and are then not permitted to engage in such activity, showed classical signs of withdrawal similar to those seen in drug dependent animals. However, these effects are not restricted to animals that are selectively bred for high wheel running. Outbred rats that were given free access to running wheels for 30 days and then prevented access to wheels for 24 hours were more likely to ‘relapse’ or binge on running after the wheels were reintroduced [60]. Because drug-addiction is a chronic relapsing disorder, the latter study provides strong evidence that, like drugs of abuse, running wheels can elicit relapse behavior. In conclusion, exercise does elicit addictive behavior, and this effect is enhanced in the genetically vulnerable strain.

CONVERGENCE BETWEEN EXERCISE AND METHAMPHETAMINE ADDICTION IN ANIMAL MODELS

There is an extensive amount of preclinical research supporting exercise as a treatment for drug addiction where exercise has been repeatedly shown to reduce the amount of drug intake during self-administration sessions (for review [7]). With respect to methamphetamine, exercise regimens have reduced self-administration during acquisition [58, 66] and during escalation of intake [58]. Research conducted in our laboratory also shows that access to exercise (voluntary wheel running) during protracted withdrawal from methamphetamine self-administration improved the rate of extinction and reduced both context- and cue-induced reinstatement of methamphetamine seeking [59]. Exercise also inhibits amphetamine reward as evidenced by inhibition of CPP for amphetamine following forced treadmill running [67]. However, withdrawal from access to running wheels was found to increase methamphetamine intake during acquisition compared to rats with continued access to wheels as well as compared to exercise naïve rats [58]. Furthermore, escalation of methamphetamine intake did not differ between exercise-withdrawn rats and exercise-naïve rats [58], suggesting that the protective effect of exercise in methamphetamine addiction may be contingent on continued availability of the running wheel. This lends further credence to the hypothesis that the efficacy of exercise depends on its ability to serve as a strong alternate rewarding and reinforcing agent. The neurobiological bases underlying the effects of exercise in methamphetamine addiction as well as the adaptations underlying the addictive effects of exercise will be explored in the subsequent sections.

NEURAL CIRCUITRY UNDERLYING METHAMPHETAMINE AND EXERCISE ADDICTION

The reward and relapse circuitry in the adult mammalian brain has been delineated based on multiple groundbreaking studies performed in rodent models of acute and chronic reinforcement schedules and reinstatement to drug-seeking behavior [45, 68]. The acute reinforcing actions of stimulants, like methamphetamine, has been attributed to the mesolimbic dopamine pathway that initiates in the ventral tegmental area and terminates in the nucleus accumbens (ventral striatum; the brain reward center); however, it is important to note that for sedative/hypnotics and opiates, such as ethanol and heroin, these regions are not critical for the acute reinforcing effects [2]. Furthermore, there is evidence that neurotransmitters other than dopamine may also play a significant role in the rewarding effects of stimulants. For example, the nucleus accumbens receives inputs from several other brain regions, including the medial prefrontal cortex and hippocampal regions [2], and notably, the neurotransmitter glutamate from these regions regulates dopamine release from the nucleus accumbens and ventral tegmental area [69–71]. These results suggest that illicit drugs dysregulate prefrontocortical and hippocampal neurocircuitry, and thereby, contribute to the enhanced dopamine release from the mesolimbic dopamine pathway, and all of these regions play critical roles in the acute reinforcing effects of stimulant drugs [2].

The key brain regions implicated in the reinstatement of drug-seeking behavior include, but are not limited to, the medial prefrontal cortex, nucleus accumbens, bed nucleus of the stria terminalis, central nucleus of the amygdala, basolateral amygdala, hippocampal regions, and ventral tegmental area [2, 45, 68]. The dorsal striatum, that receives efferent projections from the mesocortical (the ventral tegmental area to prefrontal cortex) dopamine pathway, and the ventral striatum (nucleus accumbens) are considered the two focal points for reinstatement of drug-seeking behavior, or relapse centers of the brain [2, 68]. Most importantly, it is believed that the release of the neurotransmitters dopamine, glutamate, and corticotropin-releasing factor in these key brain regions are essential for the behavioral effects of the drug during the withdrawal and craving stages of addiction that contribute to relapse [72, 73]. The overlapping effects of exercise and methamphetamine on this neurocircuitry has been elegantly detailed in a recent review [7]; this overlap is briefly touched upon here from the perspectives of exercise addiction and of exercise therapy for methamphetamine addiction (Table 1).

To add to the existing theories on addiction, one recent discovery that is potentially important for addiction research is the ability of the adult mammalian brain to continuously generate new progenitors throughout adulthood. Broadly defined, progenitors are a progeny of stem cells that are characterized by limited self-renewal and can mature into differentiating cells, such as neurons and glia in the brain. The discovery [74–76] and eventual acceptance [77, 78] that adult-generated progenitors that can mature into neurons or glial cells in numerous mammalian species, including humans (for review [79]) has spurred substantial investigation of the proliferative capacity of brain regions such as thehippocampus. The role of adult neurogenesis in the hippocampus in methamphetamine addiction andthe influence of exercise on these neural progenitors will be discussed in the subsequent sections.

NEURAL PROGENITORS AND NEUROGENESIS IN THE HIPPOCAMPUS IS AFFECTED BY METHAMPHETAMINE AND EXERCISE

Adult neurogenesis in the adult mammalian brain occurs in only one region of the hippocampus, namely the subgranular zone, situated on the border of the granule cell layer and hilus of the dentate gyrus. Stem-like precursor cells are mitotically active and divide into preneuronal progenitors (while simultaneously maintaining the stem-like population) which then differentiate into mature granule cells [80–82]. There is strong evidence that these cells not only functionally integrate into the hippocampal network [82–89], but also regulate hippocampal-sensitive cognitive function [90–100]. Further, the neurogenic properties of the dentate gyrus can be modulated by multiple factors, including physical activity and drugs of abuse [101, 102].

REGULATION OF HIPPOCAMPAL NEUROGENESIS BY METHAMPHETAMINE

The ability of methamphetamine to modulate proliferation and survival of hippocampal neural progenitors has not been as prolific of a research focus. Of the few studies investigating the deleterious impact of methamphetamine on dentate gyrus neuronal generation, both acute administrations [103, 104] and chronic exposures [105] reduce proliferation and survival of neural progenitors, although intermittent access to the drug appears to be unique in its enhancement of proliferation of progenitors [105, 106]. Further, findings from a recent cell cycle kinetic study (where newly born proliferating cells were sequentially labeled with mitotic markers to calculate the rate of movement of progenitors through the cell cycle) determined that the impairment of proliferation following chronic methamphetamine self-administration was the result of a reduction in number of S-phase progenitors (as opposed to a change in the length of S-phase of the cell cycle) [106]. With regards to hippocampal cognitive performance following methamphetamine self-administration, evidence demonstrates that performance on spatial and working memory tasks are inversely correlated to the quantity of methamphetamine consumed (operant self-administration) which also negatively correlates with hippocampal proliferation [107]. Interestingly, the survival of progenitors birth-dated at the start of the abstinent period was increased and positively correlated with reinstatement of methamphetamine seeking, thus implying a relationship between the survival of neural progenitors and the severity of relapse to the drug [107]. One potential mechanism for the impairments in hippocampal granule cell proliferation is the observed dysregulation of the trophic factor brain derived neurotrophic factor (BDNF) and its receptor Tropomyosin receptor kinase B (TrkB), along with compromised glutamatergic signaling [108]. Taken together, these findings serve to support the theory that the neurogenic dysregulation caused by methamphetamine is an additional source of vulnerability to dependence on the drug [109–111].

REGULATION OF HIPPOCAMPAL NEUROGENESIS BY EXERCISE

Exercise exerts beneficial effects on hippocampal function and neurogenesis. Extensive evidence has demonstrated that exercise in animals is correlated with increases in both the number of neural progenitors as well as the number of surviving neurons in the hippocampus (for review, [56]). One of the mechanisms suggested for this increased neurogenesis is exercise-mediated increases in hippocampal trophic factors that are generally believed to support neuronal proliferation and survival, including BDNF and its receptor TrkB [112–128]. Other factors underlying the increased neurogenesis in the granule cell layer include increased stimulation and network activity in the surrounding hippocampus [115, 117, 119, 122, 124, 129–132], immune system regulation [133–136], and modulation of stress hormones [116, 137–140]. Furthermore, these increases in granule cell production correspond to improvements in hippocampal sensitive tasks including spatial navigation, pattern separation, and contextual fear conditioning (for review, [141]). Interestingly, evidence suggests that while the proliferative stimulation following exercise is lost relatively soon following cessation of activity, the increase in survival of granule cells continues for an extended duration, including into advanced age [58, 142]. Taken together, physical activity clearly enhances hippocampal neurogenesis and subsequently, hippocampal dependent cognition.

EXERCISE-INDUCED REDUCTION OF METHAMPHETAMINE TAKING AND SEEKING IS NOT ASSOCIATED WITH EXERCISE-INDUCED ENHANCEMENT OF HIPPOCAMPAL PROGENITORS AND NEUROGENESIS

It has been hypothesized that exercise-induced upregulation of hippocampal neurogenesis may underlie exercise-mediated reduction in the vulnerability to relapse in methamphetamine addicted animals [101]. However, recent findings demonstrate that wheel running-induced reduction in escalation of methamphetamine self-administration and reduction in reinstatement of methamphetamine seeking triggered by drug context and drug cues occurred independent of alterations in the number of neural progenitors and neurogenesis in the hippocampus [58, 59]. Therefore, while exercise and methamphetamine exert seemingly opposite effects on hippocampal neurogenesis (Fig. 1), the ability of exercise to regulate methamphetamine seeking appears to be dissociated from their effects of neurogenic events. Nevertheless, these studies have demonstrated that running activity during methamphetamine-self administration and during withdrawal prevented other measures of toxicity produced by methamphetamine (discussed below) to inhibit methamphetamine seeking behaviors [59].

METHAMPHETAMINE PRODUCES TOXICITY IN THE BRAIN

Studies over the past four decades have conceptualized that methamphetamine produces significant toxicity in the striatum, and that the neurotoxicity is responsible for the addictive effects of the drug. Briefly, methamphetamine reduces the function of dopamine transporters, vesicular monoamine transporters, tyrosine hydroxylase and MAO-B, to produce excessive dopamine release [143, 144] which leads to striatal neurotoxicity via enhanced reactive oxygen species (ROS) and reactive nitrogen species [145–157], and via compromised mitochondrial function [158, 159]. Methamphetamine also increases mitochondria-dependent pro-apoptotic proteins, decreases mitochondria-dependent anti-apoptotic proteins, and damages the endoplasmic reticulum, all of which contribute to increased neuronal cell death [159, 160]. Taken together, increased methamphetamine intake during extended access schedules of reinforcement leads to striatal neurotoxicity, which may be critical for the transition to compulsive use [161].

Non-striatal mechanisms have also been suggested for the emergence of the relapse/preoccupation anticipation stage of methamphetamine addiction [2]. Human imaging studies and postmortem studies provide converging evidence suggesting that chronic methamphetamine use produces neurotoxicity in the hippocampus [162, 163], and reduces frontal cortical, amygdalar, as well as hippocampal gray matter volumes [164–170], all of which may underlie the profound deficits in executive function, declarative memory, and impulsivity in methamphetamine addicts [170–172]. The behavioral deficits observed in methamphetamine addicts have been demonstrated in preclinical models of binge methamphetamine exposure and extended access methamphetamine self-administration, where methamphetamine exposure produces cognitive dysfunction and memory impairments dependent on the hippocampus [48, 107, 173–176]. Neurodegeneration and neurotoxicity in the hippocampus is also observed, and positively correlated with methamphetamine-induced behavioral deficits [105, 177–179]. Additional mechanistic studies show that repeated methamphetamine exposure (via experimenter delivered paradigms) reduced the long-term potentiation of hippocampal CA1 pyramidal neurons [180, 181], increases excitability of dentate gyrus neurons [182], demonstrating that methamphetamine exposure produces synaptic maladaptation in the hippocampus that may mediate some of the addiction-dependent behaviors. Since long-term potentiation in CA1 and dentate gyrus regions positively and bi-directionally interacts with hippocampal neurogenesis [122, 130, 132, 183–185], methamphetamine-mediated altered plasticity in these regions may contribute to methamphetamine’s effects on neurogenesis detailed in the section above.

Inflammation is another mechanism involved in methamphetamine-induced neurotoxicity, and its effects are considerably potentiated by oxidative stress [150]. Methamphetamine releases pro-inflammatory cytokines via activation of microglia and astroglia [186–188], which contribute to neuronal damage as well as behavioral deficits observed with chronic methamphetamine use [162, 189, 190]. Reduction in glial cell activation as well as administration of anti-inflammatory glial modulators have been found to reduce the sensitization to methamphetamine and methamphetamine self-administration in rodent models [191–194]. In conclusion, oxidative stress and associated mechanisms play a critical role in methamphetamine induced neurotoxicity and behavioral changes, which in turn further perpetuates maladaptive methamphetamine taking behavior.

PHYSICAL ACTIVITY REDUCES TOXICITY IN THE BRAIN

The previous sections have focused on the detrimental effects of ROS, however, it is important to understand that moderate levels of reactive species are in fact, beneficial and essential for cellular signaling, and epigenetic regulation [195]. Moderate levels of exercise regulates the body’s redox homeostasis by improving metabolism and blood flow throughout the body, and that contributes to the several health promoting effects of exercise (for review [195]). Specifically, moderate exercise increases both antioxidant capacity and resistance against oxidative stress throughout the body, thus increasing resistance and tolerance to oxidative stress. Interestingly, the brain appears to be particularly protected against the adverse oxidative effects of over (or exhaustive)-exercise [196–199]. Specifically, the brain remained protected while skeletal muscles, liver and kidney showed oxidative damage following a single bout of exhaustive exercise; where the exercise paradigm involved treadmill running at 24 meters/min until the rat lost its righting reflex [196, 197]. Also, chronic exercise did not increase lipid peroxidation in the rat brain [198], although these effects are modulated by dietary vitamin intake [200, 201]. Compared to moderate training (swimming1 hr/day for 8 weeks), very hard training (progressively increasing swim-time to 4.5 hr/day) and over-training (abruptly increasing swim-time from 1 hr/day to4.5 hr/day) decreased brain protein oxidation products and improved performance in an associated rat memory task [199]; however, this tolerance has its limits as others report increased ROS and lipid peroxidation and impaired memory following intense or exhaustive exercise [202–204]. Exercise has been shown to exert beneficial effects in rodent models of several brain disorders including, but not limited to, models of ischemic stroke, stroke-prone spontaneously hypertensive rats and N-methyl-D-aspartate (NMDA) lesion models for Alzheimer’s disease [205–207].

Several sub-cellular mechanisms are suggested to underlie the effects of exercise on brain function. These include increased expression of brain anti-oxidants including several superoxide dismutases, glutathione peroxidase and peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) in the striatum and the hippocampus [208, 209]. The latter transcription factor, PGC-1α, is doubly beneficial as it can further upregulate other antioxidant enzymes, and more importantly, increase biogenesis of mitochondria to improve the efficiency of ATP generation, and thereby, reduce oxidative neurodegeneration in the substantia nigra and the hippocampus [210]. Exercise is also reported to increase the activity of proteasome complex in the brain [198], which is a putative mechanism for improved cognition and reduced neurodegeneration in Alzheimer’s Disease and Parkinson’s Disease [211, 212].

Exercise, via modulation of oxidative pathways as well as through independent mechanisms, has been shown to modulate trophic factor signaling in the brain to promote brain plasticity (for review, [3, 213]). Specifically, exercise increases hippocampal BDNF expression, activates its downstream signaling pathways, and increases cAMP response element binding protein (CREB), that subsequently upregulates other inducible transcription factors [214–216]. These molecular changes could manifest themselves as beneficial neuroplasticity changes such as increasing cell survival [217, 218], formation of new synapses (synaptogenesis; [219]), and neurogenesis [220, 221]. Furthermore, because ROS is known to dose-dependently modulate proliferation of neuronal progenitor cells in the hippocampus [217, 222], exercise may modulate neurogenesis by regulating ROS in the dentate gyrus. Modulating the levels of trophic factors and ROS in regions other than the dentate gyrus may alter the generation of new glia (gliogenesis), such as astroglia and oligodendroglia that may contribute to functional plasticity [222–225]. The medial prefrontal cortex, a brain region involved in executive and impulse control [38, 226, 227], is one region where this mechanism has been investigated [44]. Specifically, voluntary wheel running in rats was also shown to increase in proliferation and survival of progenitor cells medial prefrontal cortex, and these new cells matured into new astroglia (∼33% ) and new oligodendroglia (∼55% ) [44]. Thus, exercise-induced gliogenesis may be a mechanism underlying exercise-induced improvement in cognition and executive function observed in several disease conditions [228, 229].

EXERCISE-INDUCED REDUCTION OF METHAMPHETAMINE TAKING AND SEEKING IS ASSOCIATED WITH EXERCISE-INDUCED REDUCTION OF METHAMPHETAMINE-INDUCED BRAIN TOXICITY

As discussed previously, exercise reduces methamphetamine intake when both the reinforcers are concurrently available, in part, because exercise serves as an alternative reinforcer ([7]; also see Table 1). However, the above sections demonstrate that the potential for overlap between exercise and methamphetamine extends much deeper and is more complicated than simply modulating neurotransmission in the brain reward and reinstatement centers (Fig. 1). Exercise improves brain function via changes in redox homeostasis and contributes to increased resistance and tolerance to oxidative challenge, and thereby promotes cell survival. Notably, swimming exercise was found to attenuate amphetamine-induced CPP and anxiety, which corresponded with exercise-induced reduction in ROS and protein oxidation products in hippocampal homogenates [54]. Studies conducted by our group and others revealed that rats with continued access to voluntary wheel running attenuated acquisition and escalation of methamphetamine self-administration compared to rats without access to running wheels [58, 66]. Furthermore, access to running wheels during protracted abstinence from methamphetamine accelerated extinction and attenuated reinstatement of methamphetamine seeking [59]. Indeed, voluntary running attenuated methamphetamine-induced damage to dopamine and serotonin terminals in the striatum, potentially, by promoting repair of the damaged terminals [230, 231]. Further, attenuated methamphetamine self-administration in rats with continued access to voluntary wheel running was associated with attenuation of neuronal apoptosis and decreased neuronal nitric oxide synthase expression in the nucleus accumbens [58], suggesting that regulation of oxidative stress mechanisms may be an alternate or concomitant mechanism which contributes to the beneficial effects of exercise in methamphetamine addiction. Future studies should include empirical validation of these mechanisms in exercise-mediated modulation of methamphetamine seeking.

Interestingly, withdrawal from wheel running during methamphetamine self-administration enhanced consumption of methamphetamine compared to exercise-naïve rats [58], suggesting that deprivation from chronic exercise may render subjects vulnerable to methamphetamine. The latter observation further contributes to the idea that exercise itself is addictive, however, very little is known about the mechanism underlying this increased addiction vulnerability. Evidence from studies in mice selectively bred for increased voluntary wheel running suggests dopamine is increased in the nucleus accumbens and the dorsal striatum (the reward and reinforcement centers of the brain), but is negatively correlated with running suggesting attenuation of sensitivity to reinforcing effects of running [232]. Furthermore, the dorsal striatum and substantia nigra were hypo-dopaminergic [233] thus providing a conducive environment for mechanisms that can compensate for this reduced dopamine tone (for example, methamphetamine-induced dopaminerelease; Table 1). Finally, running correlated with hippocampal activation (increased Fos) in controls but this correlation was lost in mice selectively bred for high wheel running activity [234]. Instead, the high runners showed increased activation (Fos) of the motivation circuitry, i.e. prefrontal cortex, striatum and lateral hypothalamus along with increased BDNF in the hippocampus [234, 235]. Taken together, a blunted dopamine reward system, a hypo-dopaminergic response in the nigro-striatal pathway (relapse circuitry) together with the activation of neurons in the brain regions involved in motivation in the exercise-withdrawn animal, may contribute to the addictive effects of exercise and may provide the ideal environment for cross-sensitization to other powerful reinforcers such as methamphetamine. However, these speculations need to be empirically validated using animal models.

FUTURE DIRECTIONS AND CONCLUSION

While some information is available regarding the associated neurobiological changes underlying the interactions of exercise with methamphetamine taking and seeking, a lot of the potential mechanisms have not been empirically evaluated. An example, is the opposite effects of methamphetamine and chronic exercise on astrocytes and inflammatory markers in the brain [186, 187, 236, 237], and yet their interaction in these avenues remains unexplored. Furthermore, there is a gap in our understanding of the neurobiological adaptations following exercise withdrawal and neurobehavioral effects of excessive exercise. An emerging direction in drug abuse research investigates epigenetic modifications of the chromatin structure that results in activation or repression of gene expression in altering the vulnerability to drug addiction [238, 239]. Epigenetic modification not only alters the rewarding effects of methamphetamine, chronic methamphetamine also produces epigenetic changes that are permissive for progressing through the different phases of addiction [240, 241]. Particularly, modifications in the genes regulating BDNF expression and signaling have been implicated in the initiation-binge/intoxication stage as well as the relapse-preoccupation/anticipation stage of psychostimulant addiction (for review, [242]). Exercise is known to increase BDNF expression in the hippocampus [243], and epigenetic modifications have been shown to be a part of the underlying mechanism [244]. It would be interesting to see how epigenetic modifications by exercise lead to long-term adaptations that promote/inhibit methamphetamine taking and seeking.

In sum, the identification of the neuroplastic and neuromodulatory effects of exercise over the past few decades has shed new light on the therapeutic and, more recently, the protective effects that are associated with exercise. Future studies aimed at understanding the potential link between correlative decreases in illicit drug use and addiction and increase in exercise output in animal models will allow researchers to determine whether decreases in neurotoxicity by exercise is behaviorally relevant to the prevention of addiction to illicit drugs. This may pave the way for future therapeutic possibilities for treating drug addiction disorders.

Footnotes

ACKNOWLEDGMENTS

Preparation of this review was supported by funds from the National Institute on Drug Abuse (DA034140 to CDM) and the National Institute on Alcohol Abuse and Alcoholism (AA020098 and AA006420 to CDM, and T32AA00747 to MCS). We appreciate the assistance of Janet Hightower from Biomedical Graphics Department at Scripps for assistance with the schematic presentation. This is publication number 29064 from the Scripps Research Institute.

References

NIDA. Topics in brief: Methamphetamine addiction: Progress, but need to remain vigilant. The Science of Drug Abuse and Addiction. 2011

Koob

Volkow

2010

Neurocircuitry of addiction

Neuropsychopharmacology 35 1 217 238

Phillips

Baktir

Srivatsan

Salehi

2014

Neuroprotective effects of physical activity on the brain: A closer look at trophic factor signaling

Frontiers in Cellular Neuroscience 8 170

Koob

Le Moal

1997

Drug abuse: Hedonic homeostatic dysregulation

Science 278 5335 52 58

Crews

Boettiger

2009

Impulsivity, frontal lobes and risk for addiction

Pharmacol Biochem Behav 93 3 237 247

Feltenstein

See

2008

The neurocircuitry of addiction: An overview

Br J Pharmacol 154 2 261 274

Lynch

Peterson

Sanchez

Abel

Smith

2013

Exercise as a novel treatment for drug addiction: A neurobiological and stage-dependent hypothesis

Neurosci Biobehav Rev 37 8 1622 1644

Kanarek

D’Anci

Jurdak

Mathes

2009

Running and addiction: Precipitated withdrawal in a rat model of activity-based anorexia

Behav Neurosci 123 4 905 912

Carroll

Boe

1982

Increased intravenous drug self-administration during deprivation of other reinforcers

Pharmacol Biochem Behav 17 3 563 567

10.

SAMHSA. Results from the 2007 National Survey on Drug Use and Health: Detailed Tables. Substance Abuse and Mental Health Services Administration, Office of Applied Studies. 2008

11.

(USPSTF) USPSTF. Screening for illicit drug use. 2008

12.

(WHO) WHO. 1980

13.

NIDA. Research reports: Methamphetamine abuse and addiction. The Science of Drug Abuse and Addiction. 2006

14.

NIDA. Drug Facts: Methamphetamine. The Science of Drug Abuse and Addiction. 2010

15.

Gonzales

Mooney

Rawson

2010

The methamphetamine problem in the United States

Annu Rev Public Health 31 385 398

16.

Rawson

Shoptaw

Obert

McCann

Hasson

Marinelli-Casey

1995

An intensive outpatient approach for cocaine abuse treatment. The Matrix model

J Subst Abuse Treat 12 2 117 127

17.

Gettig

Grady

Nowosadzka

2006

Methamphetamine: Putting the brakes on speed

J Sch Nurs 22 2 66 73

18.

Barrett

Hayney

Muller

Rakel

Ward

Obasi

2012

Meditation or exercise for preventing acute respiratory infection: A randomized controlled trial

Annals of family medicine 10 4 337 346

19.

Wang

Pratt

Macera

Zheng

Heath

2004

Physical activity, cardiovascular disease, and medical expenditures in U.S. adults

Annals of behavioral medicine: A publication of the Society of Behavioral Medicine 28 2 88 94

20.

Pratt

Macera

Wang

2000

Higher direct medical costs associated with physical inactivity

The Physician and sportsmedicine 28 10 63 70

21.

Patel

Bernstein

Deka

Feigelson

Campbell

Gapstur

2010

Leisure time spent sitting in relation to total mortality in a prospective cohort of US adults

Am J Epidemiol 172 4 419 429

22.

United States. Department of Health and Human Services. 2008 physical activity guidelines for Americans: Be active, healthy, and happy! Washington, DC: U.S. Dept. of Health and Human Services; 2008. ix, pp. 61

23.

Mekary

Feskanich

Willett

Field

2010

Physical activity in relation to long-term weight maintenance after intentional weight loss in premenopausal women

Obesity (Silver Spring) 18 1 167 174

24.

DiLorenzo

Bargman

Stucky-Ropp

Brassington

Frensch

LaFontaine

1999

Long-term effects of aerobic exercise on psychological outcomes

Prev Med 28 1 75 85

25.

Blumenthal

Babyak

Moore

Craighead

Herman

Khatri

1999

Effects of exercise training on older patients with major depression

Arch Intern Med 159 19 2349 2356

26.

Peluso

Guerra de Andrade

2005

Physical activity and mental health: The association between exercise and mood

Clinics 60 1 61 70

27.

Koob

2013

Addiction is a Reward Deficit and Stress Surfeit Disorder

Frontiers in Psychiatry 4 72

28.

Jones

Knutson

Haines

2003

Common problems in patients recovering from chemical dependency

American Family Physician 68 10 1971 1978

29.

Polter

Kauer

2014

Stress and VTA synapses: Implications for addiction and depression

Eur J Neurosci 39 7 1179 1188

30.

Egorov

Szabo

2013

The exercise paradox: An interactional model for a clearer conceptualization of exercise addiction

Journal of Behavioral Addictions 2 4 199 208

31.

American Psychiatric Association., American Psychiatric Association. DSM-5 Task Force. Diagnostic and statistical manual of mental disorders: DSM-5. 5th ed. Washington, D.C.: American Psychiatric Publishing; 2013. xliv, pp. 947

32.

Sabzo

2010

Addiction to Exercise: A Symptom or a Disorder?

New York

Nova Science Publishers Inc

33.

Bruno

Quattrone

Scimeca

Cicciarelli

Romeo

Pandolfo

2014

Unraveling exercise addiction: The role of narcissism and self-esteem

Journal of Addiction 2014 987841

34.

Meulemans

Pribis

Grajales

Krivak

2014

Gender differences in exercise dependence and eating disorders in young adults: A path analysis of a conceptual model

Nutrients 6 11 4895 4905

35.

Council on Clinical Classifications., National Center for Health Statistics (U.S.), World Health Organization., Commission on Professional and Hospital Activities. The International classification of diseases, clinical modifications, ICD-9-CM. 9th revision. ed. Ann Arbor: CPHA; 1978

36.

Pope

Jr Gruber

Choi

Olivardia

Phillips

1997

Muscle dysmorphia. An underrecognized form of body dysmorphic disorder

Psychosomatics 38 6 548 557

37.

Lichtenstein

Andries

Hansen

Frystyk

Stoving

2015

Exercise addiction in men is associated with lower fat-adjusted leptin levels

Clinical Journal of Sport Medicine: Official Journal of the Canadian Academy of Sport Medicine 25 2 138 143

38.

Kalivas

Volkow

2005

The neural basis of addiction: A pathology of motivation and choice

Am J Psychiatry 162 8 1403 1413

39.

Haglund

Ang

Mooney

Gonzales

Chudzynski

Cooper

2014

Predictors of depression outcomes among abstinent methamphetamine-dependent individuals exposed to an exercise intervention

Am J Addict

40.

Muller

Clausen

2014

Group exercise to improve quality of life among substance use disorder patients

Scandinavian Journal of Public Health

41.

Ahmed

Koob

1998

Transition from moderate to excessive drug intake: Change in hedonic set point

Science 282 5387 298 300

42.

Gawin

Ellinwood

1989

Cocaine dependence

Annu Rev Med 40 149 161

43.

Kramer

Fischman

Littlefield

1967

Amphetamine abuse. Pattern and effects of high doses taken intravenously

Jama 201 5 305 309

44.

Mandyam

Wee

Eisch

Richardson

Koob

2007

Methamphetamine self-administration and voluntary exercise have opposing effects on medial prefrontal cortex gliogenesis

J Neurosci 27 42 11442 11450

45.

Shaham

Shalev

De Wit

Stewart

2003

The reinstatement model of drug relapse: History, methodology and major findings

Psychopharmacology (Berl) 168 1-2 3 20

46.

Shalev

Grimm

Shaham

2002

Neurobiology of relapse to heroin and cocaine seeking: A review

Pharmacol Rev 54 1 1 42

47.

McFarland

Kalivas

2001

The circuitry mediating cocaine-induced reinstatement of drug-seeking behavior

J Neurosci 21 21 8655 8663

48.

Rogers

De Santis

See

2008

Extended methamphetamine self-administration enhances reinstatement of drug seeking and impairs novel object recognition in rats

Psychopharmacology (Berl) 199 4 615 624

49.

Spragg

SDS

1940

Morphine addiction in chimpanzees

Comparative Psychology Monographs 15 1 132

50.

Bardo

Bevins

2000

Conditioned place preference: What does it add to our preclinical understanding of drug reward? Psychopharmacology (Berl)

153 1 31 43

51.

Advokat

1985

Evidence of place conditioning after chronic intrathecal morphine in rats

Pharmacol Biochem Behav 22 2 271 277

52.

Bardo

Miller

Neisewander

1984

Conditioned place preference with morphine: The effect of extinction training on the reinforcing CR

Pharmacol Biochem Behav 21 4 545 549

53.

Arida

Scorza

Gomes da Silva

Cysneiros

Cavalheiro

2011

Exercise paradigms to study brain injury recovery in rodents

American Journal of Physical Medicine & Rehabilitation / Association of Academic Physiatrists 90 6 452 465

54.

Segat

Kronbauer

Roversi

Schuster

Vey

Roversi

2014

Exercise modifies amphetamine relapse: Behavioral and oxidative markers in rats

Behav Brain Res 262 94 100

55.

Rupp

Wahl

1990

Influence of thyroid hormones and catecholamines on myosin of swim-exercised rats

Journal of Applied Physiology 68 3 973 978

56.

Voss

Vivar

Kramer

van Praag

2013

Bridging animal and human models of exercise-induced brain plasticity

Trends in Cognitive Sciences 17 10 525 544

57.

Greenwood

Foley

Strong

Loughridge

Day

2011

Long-term voluntary wheel running is rewarding and produces plasticity in the mesolimbic reward pathway

Behavioural Brain Research 217 2 354 362

58.

Engelmann

Aparicio

Kim

Sobieraj

Yuan

Grant

2014

Chronic wheel running reduces maladaptive patterns of methamphetamine intake: Regulation by attenuation of methamphetamine-induced neuronal nitric oxide synthase

Brain Struct Funct 219 2 657 672

59.

Sobieraj

Kim

Fannon

Mandyam

2014

Chronic wheel running-induced reduction of extinction and reinstatement of methamphetamine seeking in methamphetamine dependent rats is associated with reduced number of periaqueductal gray dopamine neurons

Brain Struct Funct

60.

Ferreira

Lamarque

Boyer

Perez-Diaz

Jouvent

Cohen-Salmon

2006

Spontaneous appetence for wheel-running: A model of dependency on physical activity in rat

Eur Psychiatry 21 8 580 588

61.

Brene

Bjornebekk

Aberg

Mathe

Olson

Werme

2007

Running is rewarding and antidepressive

Physiol Behav 92 1-2 136 140

62.

Kolb

Kelly

Garland

2013

Mice from lines selectively bred for high voluntary wheel running exhibit lower blood pressure during withdrawal from wheel access

Physiology & Behavior 112-113 49 55

63.

Perrine

Sheikh

Nwaneshiudu

Schroeder

Unterwald

2008

Withdrawal from chronic administration of cocaine decreases delta opioid receptor signaling and increases anxiety- and depression-like behaviors in the rat

Neuropharmacology 54 2 355 364

64.

Anraku

Ikegaya

Matsuki

Nishiyama

2001

Withdrawal from chronic morphine administration causes prolonged enhancement of immobility in rat forced swimming test

Psychopharmacology 157 2 217 220

65.

Malisch

Breuner

Kolb

Wada

Hannon

Chappell

2009

Behavioral despair and home-cage activity in mice with chronically elevated baseline corticosterone concentrations

Behavior Genetics 39 2 192 201

66.

Miller

Vaillancourt

Wright

Jr Aarde

Vandewater

Creehan

2012

Reciprocal inhibitory effects of intravenous d-methamphetamine self-administration and wheel activity in rats

Drug Alcohol Depend 121 1-2 90 96

67.

Fontes-Ribeiro

Marques

Pereira

Silva

Macedo

2011

May exercise prevent addiction?

Curr Neuropharmacol 9 1 45 48

68.

Crombag

Bossert

Koya

Shaham

2008

Review. Context-induced relapse to drug seeking: A review

Philos Trans R Soc Lond B Biol Sci 363 1507 3233 3243

69.

Floresco

Todd

Grace

2001

Glutamatergic afferents from the hippocampus to the nucleus accumbens regulate activity of ventral tegmental area dopamine neurons

J Neurosci 21 13 4915 4922

70.

Floresco

Blaha

Yang

Phillips

2001

Modulation of hippocampal and amygdalar-evoked activity of nucleus accumbens neurons by dopamine: Cellular mechanisms of input selection

J Neurosci 21 8 2851 2860

71.

Taepavarapruk

Floresco

Phillips

2000

Hyperlocomotion and increased dopamine efflux in the rat nucleus accumbens evoked by electrical stimulation of the ventral subiculum: Role of ionotropic glutamate and dopamine D1 receptors

Psychopharmacology (Berl) 151 2-3 242 251

72.

Koob

1999

Stress, corticotropin-releasing factor, and drug addiction

Ann N Y Acad Sci 897 27 45

73.

Knackstedt

Kalivas

2009

Glutamate and reinstatement

Curr Opin Pharmacol 9 1 59 64

74.

Messier

Leblond

1960

Cell proliferation and migration as revealed by radioautography after injection of thymidine-H3 into male rats and mice

Am J Anat 106 247 285

75.

Altman

1969

Autoradiographic and histological studies of postnatal neurogenesis. 3. Dating the time of production and onset of differentiation of cerebellar microneurons in rats

J Comp Neurol 136 3 269 293

76.

Altman

Das

1965

Autoradiographic and histological evidence of postnatal hippocampal neurogenesis in rats

J Comp Neurol 124 3 319 335

77.

Eriksson

Perfilieva

Bjork-Eriksson

Alborn

Nordborg

Peterson

1998

Neurogenesis in the adult human hippocampus

Nat Med 4 11 1313 1317

78.

Manganas

Zhang

Hazel

Smith

Wagshul

2007

Magnetic resonance spectroscopy identifies neural progenitor cells in the live human brain

Science 318 5852 980 985

79.

Bonfanti

Peretto

2011

Adult neurogenesis in mammals–a theme with many variations

Eur J Neurosci 34 6 930 950

80.

Kempermann

Jessberger

Steiner

Kronenberg

2004

Milestones of neuronal development in the adult hippocampus

Trends Neurosci 27 8 447 452

81.

Abrous

Koehl

Le Moal

2005

Adult neurogenesis: From precursors to network and physiology

Physiol Rev 85 2 523 569

82.

Toni

Laplagne

Zhao

Lombardi

Ribak

Gage

2008

Neurons born in the adult dentate gyrus form functional synapses with target cells

Nat Neurosci 11 8 901 907

83.

Gould

Reeves

Fallah

Tanapat

Gross

Fuchs

1999

Hippocampal neurogenesis in adult Old World primates

Proceedings of the National Academy of Sciences of the United States of America 96 9 5263 5267

84.

Gould

Reeves

Graziano

Gross

1999

Neurogenesis in the neocortex of adult primates

Science 286 5439 548 552

85.

Shors

Townsend

Zhao

Kozorovitskiy

Gould

2002

Neurogenesis may relate to some but not all types of hippocampal-dependent learning

Hippocampus 12 5 578 584

86.

Aimone

Wiles

Gage

2006

Potential role for adult neurogenesis in the encoding of time in new memories

Nat Neurosci 9 6 723 727

87.

Clark

Bhattacharya

Miller

Kohman

DeYoung

Rhodes

2012

New neurons generated from running are broadly recruited into neuronal activation associated with three different hippocampus-involved tasks

Hippocampus 22 9 1860 1867

88.

Lacefield

Itskov

Reardon

Hen

Gordon

2012

Effects of adult-generated granule cells on coordinated network activity in the dentate gyrus

Hippocampus 22 1 106 116

89.

Gould

Beylin

Tanapat

Reeves

Shors

1999

Learning enhances adult neurogenesis in the hippocampal formation

Nat Neurosci 2 3 260 265

90.

Shors

Miesegaes

Beylin

Zhao

Rydel

Gould

2001

Neurogenesis in the adult is involved in the formation of trace memories

Nature 410 6826 372 376

91.

Feng

Rampon

Tang

Shrom

Jin

Kyin

2001

Deficient neurogenesis in forebrain-specific presenilin-1 knockout mice is associated with reduced clearance of hippocampal memory traces

Neuron 32 5 911 926

92.

Deisseroth

Singla

Toda

Monje

Palmer

Malenka

2004

Excitation-neurogenesis coupling in adult neural stem/progenitor cells

Neuron 42 4 535 552

93.

Schmidt-Hieber

Jonas

Bischofberger

2004

Enhanced synaptic plasticity in newly generated granule cells of the adult hippocampus

Nature 429 6988 184 187

94.

Kim

Christian

Ming

Song

2012

Time-dependent involvement of adult-born dentate granule cells in behavior

Behavioural Brain Research 227 2 470 479

95.

Bakker

Kirwan

Miller

Stark

2008

Pattern separation in the human hippocampal CA3 and dentate gyrus

Science 319 5870 1640 1642

96.

Clelland

Choi

Romberg

Clemenson

Jr Fragniere

Tyers

2009

A functional role for adult hippocampal neurogenesis in spatial pattern separation

Science 325 5937 210 213

97.

Sahay

Scobie

Hill

O’Carroll

Kheirbek

Burghardt

2011

Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation

Nature 472 7344 466 470

98.

Sahay

Wilson

Hen

2011

Pattern separation: A common function for new neurons in hippocampus and olfactory bulb

Neuron 70 4 582 588

99.

McHugh

Jones

Quinn

Balthasar

Coppari

Elmquist

2007

Dentate gyrus NMDA receptors mediate rapid pattern separation in the hippocampal network

Science 317 5834 94 99

100.

Aimone

Deng

Gage

2011

Resolving new memories: A critical look at the dentate gyrus, adult neurogenesis, and pattern separation

Neuron 70 4 589 596

101.

Mandyam

Koob

2012

The addicted brain craves new neurons: Putative role for adult-born progenitors in promoting recovery

Trends Neurosci 35 4 250 260

102.

van Praag

2008

Neurogenesis and exercise: Past and future directions

Neuromolecular Med 10 2 128 140

103.

Teuchert-Noodt

Dawirs

Hildebrandt

2000

Adult treatment with methamphetamine transiently decreases dentate granule cell proliferation in the gerbil hippocampus

J Neural Transm 107 2 133 143

104.

Kochman

Fornal

Jacobs

2009

Suppression of hippocampal cell proliferation by short-term stimulant drug administration in adult rats

Eur J Neurosci 29 11 2157 2165

105.

Mandyam

Wee

Crawford

Eisch

Richardson

Koob

2008

Varied access to intravenous methamphetamine self-administration differentially alters adult hippocampal neurogenesis

Biol Psychiatry 64 11 958 965

106.

Yuan

Quiocho

Kim

Wee

Mandyam

2011

Extended access methamphetamine decreases immature neurons in the hippocampus which results from loss and altered development of neural progenitors without altered dynamics of the S-phase of the cell cycle

Pharmacol Biochem Behav 100 1 98 108

107.

Recinto

Samant

Chavez

Kim

Yuan

Soleiman

2012

Levels of neural progenitors in the hippocampus predict memory impairment and relapse to drug seeking as a function of excessive methamphetamine self-administration

Neuropsychopharmacology 37 5 1275 1287

108.

Galinato

Orio

Mandyam

2014

Methamphetamine differentially affects BDNF and cell death factors in anatomically defined regions of the hippocampus

Neuroscience 286c 97 108

109.

Canales

2007

Adult neurogenesis and the memories of drug addiction

Eur Arch Psychiatry Clin Neurosci 257 5 261 270

110.

Canales

2010

Comparative neuroscience of stimulant-induced memory dysfunction: Role for neurogenesis in the adult hippocampus

Behav Pharmacol 21 5-6 379 393

111.

Chambers

2013

Adult hippocampal neurogenesis in the pathogenesis of addiction and dual diagnosis disorders

Drug and alcohol dependence 130 1-3 1 12

112.

Neeper

Gomez-Pinilla

Choi

Cotman

1995

Exercise and brain neurotrophins

Nature 373 6510 109

113.

Neeper

Gomez-Pinilla

Choi

Cotman

1996

Physical activity increases mRNA for brain-derived neurotrophic factor and nerve growth factor in rat brain

Brain Research 726 1-2 49 56

114.

Berchtold

Chinn

Chou

Kesslak

Cotman

2005

Exercise primes a molecular memory for brain-derived neurotrophic factor protein induction in the rat hippocampus

Neuroscience 133 3 853 861

115.

Molteni

Ying

Gomez-Pinilla

2002

Differential effects of acute and chronic exercise on plasticity-related genes in the rat hippocampus revealed by microarray

The European Journal of Neuroscience 16 6 1107 1116

116.

Uysal

Kiray

Sisman

Camsari

Gencoglu

Baykara

2015

Effects of voluntary and involuntary exercise on cognitive functions, and VEGF and BDNF levels in adolescent rats

Biotechnic & Histochemistry: Official publication of the Biological Stain Commission 90 1 55 68

117.

Ding

Ying

Gomez-Pinilla

2011

Exercise influences hippocampal plasticity by modulating brain-derived neurotrophic factor processing

Neuroscience 192 773 780

118.

Sartori

Vieira

Ferrari

Langone

Tongiorgi

Parada

2011

The antidepressive effect of the physical exercise correlates with increased levels of mature BDNF, and proBDNF proteolytic cleavage-related genes, p11 and tPA

Neuroscience 180 9 18

119.

Vaynman

Ying

Gomez-Pinilla

2003

Interplay between brain-derived neurotrophic factor and signal transduction modulators in the regulation of the effects of exercise on synaptic-plasticity

Neuroscience 122 3 647 657

120.

Hopkins

Nitecki

Bucci

2011

Physical exercise during adolescence versus adulthood: Differential effects on object recognition memory and brain-derived neurotrophic factor levels

Neuroscience 194 84 94

121.

Marlatt

Potter

Lucassen

van Praag

2012

Running throughout middle-age improves memory function, hippocampal neurogenesis, and BDNF levels in female C57BL/6J mice

Developmental Neurobiology 72 6 943 952

122.

Farmer

Zhao

van Praag

Wodtke

Gage

Christie

2004

Effects of voluntary exercise on synaptic plasticity and gene expression in the dentate gyrus of adult male Sprague-Dawley rats in vivo

Neuroscience 124 1 71 79

123.

Berchtold

Castello

Cotman

2010

Exercise and time-dependent benefits to learning and memory

Neuroscience 167 3 588 597

124.

Liu

Chen

Kuo

Huang

2009

Differential effects of treadmill running and wheel running on spatial or aversive learning and memory: Roles of amygdalar brain-derived neurotrophic factor and synaptotagmin I

J Physiol 587 Pt 13 3221 3231

125.

Vaynman

Ying

Gomez-Pinilla

2004

Exercise induces BDNF and synapsin I to specific hippocampal subfields

Journal of Neuroscience Research 76 3 356 362

126.

Griffin

Bechara

Birch

Kelly

2009

Exercise enhances hippocampal-dependent learning in the rat: Evidence for a BDNF-related mechanism

Hippocampus 19 10 973 980

127.

O’Callaghan

Griffin

Kelly

2009

Long-term treadmill exposure protects against age-related neurodegenerative change in the rat hippocampus

Hippocampus 19 10 1019 1029

128.

Chang

Chen

Jen

2008

Exercise enhances the proliferation of neural stem cells and neurite growth and survival of neuronal progenitor cells in dentate gyrus of middle-aged mice

Journal of Applied Physiology (Bethesda, Md: 1985) 105 5 1585 1594

129.

O’Callaghan

Ohle

Kelly

2007

The effects of forced exercise on hippocampal plasticity in the rat: A comparison of LTP, spatial- and non-spatial learning

Behavioural Brain Research 176 2 362 366

130.

van Praag

Christie

Sejnowski

Gage

1999

Running enhances neurogenesis, learning, and long-term potentiation in mice

Proc Natl Acad Sci U S A 96 23 13427 13431

131.

Vasuta

Caunt

James

Samadi

Schibuk

Kannangara

2007

Effects of exercise on NMDA receptor subunit contributions to bidirectional synaptic plasticity in the mouse dentate gyrus

Hippocampus 17 12 1201 1208

132.

Snyder

Kee

Wojtowicz

2001

Effects of adult neurogenesis on synaptic plasticity in the rat dentate gyrus

J Neurophysiol 85 6 2423 2431

133.

Speisman

Kumar

Rani

Foster

Ormerod

2013

Daily exercise improves memory, stimulates hippocampal neurogenesis and modulates immune and neuroimmune cytokines in aging rats

Brain, Behavior, and Immunity 28 25 43

134.

Moon

Kim

Yang

Song

Park

2012

Macrophage migration inhibitory factor mediates the antidepressant actions of voluntary exercise

Proceedings of the National Academy of Sciences of the United States of America 109 32 13094 13099

135.

Walton

Sutter

Laywell

Levkoff

Kearns

Marshall

2nd

2006

Microglia instruct subventricular zone neurogenesis

Glia 54 8 815 825

136.

Ziv

Ron

Butovsky

Landa

Sudai

Greenberg

2006

Immune cells contribute to the maintenance of neurogenesis and spatial learning abilities in adulthood

Nat Neurosci 9 2 268 275

137.

Yau

Zhang

Christie

Lee

2014

Sustained running in rats administered corticosterone prevents the development of depressive behaviors and enhances hippocampal neurogenesis and synaptic plasticity without increasing neurotrophic factor levels

Cell Transplantation 23 4-5 481 492

138.

Gregoire

Bonenfant

Le Nguyen

Aumont

Fernandes

2014

Untangling the influences of voluntary running, environmental complexity, social housing and stress on adult hippocampal neurogenesis

PloS One 9 1 e86237

139.

Kwon

Kim

Chang

Kim

Leem

2013

Exercise ameliorates cognition impairment due to restraint stress-induced oxidative insult and reduced BDNF level

Biochemical and Biophysical Research Communications 434 2 245 251

140.

Liang

Guan

Fan

Chi

Yang

2013

Regular treadmill running improves spatial learning and memory performance in young mice through increased hippocampal neurogenesis and decreased stress

Brain Research 1531 1 8

141.

Yau

Gil-Mohapel

2014

Physical exercise-induced adult neurogenesis: A good strategy to prevent cognitive decline in neurodegenerative diseases?

2014 403120

142.

Merkley

Jian

Mosa

Tan

Wojtowicz

2014

Homeostatic regulation of adult hippocampal neurogenesis in aging rats: Long-term effects of early exercise

Frontiers in Neuroscience 8 174

143.

Ares-Santos

Granado

Moratalla

2013

The role of dopamine receptors in the neurotoxicity of methamphetamine

J Intern Med 273 5 437 453

144.

Fleckenstein

Volz

Riddle

Gibb

Hanson

2007

New insights into the mechanism of action of amphetamines

Annu Rev Pharmacol Toxicol 47 681 698

145.

Itzhak

1997

Modulation of cocaine- and methamphetamine-induced behavioral sensitization by inhibition of brain nitric oxide synthase

J Pharmacol Exp Ther 282 2 521 527

146.

Itzhak

Anderson

Ali

2004

Differential response of nNOS knockout mice to MDMA ("ecstasy")- and methamphetamine-induced psychomotor sensitization and neurotoxicity

Ann N Y Acad Sci 1025 119 128

147.

Itzhak

Gandia

Huang

Ali

1998

Resistance of neuronal nitric oxide synthase-deficient mice to methamphetamine-induced dopaminergic neurotoxicity

J Pharmacol Exp Ther 284 3 1040 1047

148.

Itzhak

Martin

Ali

1999

Methamphetamine- and 1-methyl-4-phenyl- 1,2,3, 6-tetrahydropyridine-induced dopaminergic neurotoxicity in inducible nitric oxide synthase-deficient mice

Synapse 34 4 305 312

149.

Itzhak

Martin

Ali

2000

Comparison between the role of the neuronal and inducible nitric oxide synthase in methamphetamine-induced neurotoxicity and sensitization

Ann N Y Acad Sci 914 104 111

150.

Yamamoto

Bankson

2005

Amphetamine neurotoxicity: Cause and consequence of oxidative stress

Crit Rev Neurobiol 17 2 87 117

151.

Wang

Ali

Angulo

1139

Connection between the striatal neurokinin-1 receptor and nitric oxide formation during methamphetamine exposure

Ann N Y Acad Sci 164 171

152.

Eyerman

Yamamoto

2007

A rapid oxidation and persistent decrease in the vesicular monoamine transporter 2 after methamphetamine

J Neurochem 103 3 1219 1227

153.

Wang

Angulo

2011

Synergism between methamphetamine and the neuropeptide substance P on the production of nitric oxide in the striatum of mice

Brain Res 1369 131 139

154.

Zhu

Wang

Ali

Angulo

2009

The neurokinin-1 receptor modulates the methamphetamine-induced striatal apoptosis and nitric oxide formation in mice

J Neurochem 111 3 656 668

155.

Fleckenstein

Hanson

2003

Impact of psychostimulants on vesicular monoamine transporter function

Eur J Pharmacol 479 1-3 283 289

156.

Fleckenstein

Gibb

Hanson

2000

Differential effects of stimulants on monoaminergic transporters: Pharmacological consequences and implications for neurotoxicity

Eur J Pharmacol 406 1 1 13

157.

Shiba

Yamato

Kudo

Watanabe

Utsumi

Yamada

2011

In vivo imaging of mitochondrial function in methamphetamine-treated rats

Neuroimage 57 3 866 872

158.

Burrows

Gudelsky

Yamamoto

2000

Rapidand transient inhibition of mitochondrial functionfollowing methamphetamine or 3,4-methylenedioxy-methamphetamine administration

Eur J Pharmacol 398 1 11 18

159.

Deng

Cai

McCoy

Chen

Trush

Cadet

2002

Methamphetamine induces apoptosis in an immortalized rat striatal cell line by activating the mitochondrial cell death pathway

Neuropharmacology 42 6 837 845

160.

Jayanthi

Deng

Noailles

Ladenheim

Cadet

2004

Methamphetamine induces neuronal apoptosis via cross-talks between endoplasmic reticulum and mitochondria-dependent death cascades

FASEB J 18 2 238 251

161.

Everitt

Belin

Economidou

Pelloux

Dalley

Robbins

2008

Review. Neural mechanisms underlying the vulnerability to develop compulsive drug-seeking habits and addiction

Philos Trans R Soc Lond B Biol Sci 363 1507 3125 3135

162.

Kitamura

Takeichi

Wang

Tokunaga

Ishigami

Kubo

2010

Microglial and astrocytic changes in the striatum of methamphetamine abusers

Leg Med (Tokyo) 12 2 57 62

163.

Kitamura

2009

Detection of methamphetamine neurotoxicity in forensic autopsy cases

Leg Med (Tokyo) 11 Suppl1 S63 S65

164.

Morales

Lee

Hellemann

O’Neill

London

2012

Gray-matter volume in methamphetamine dependence: Cigarette smoking and changes with abstinence from methamphetamine

Drug Alcohol Depend 125 3 230 238

165.

Orikabe

Yamasue

Inoue

Takayanagi

Mozue

Sudo

2011

Reduced amygdala and hippocampal volumes in patients with methamphetamine psychosis

Schizophr Res 132 2-3 183 189

166.

Nakama

Chang

Fein

Shimotsu

Jiang

Ernst

2011

Methamphetamine users show greater than normal age-related cortical gray matter loss

Addiction 106 8 1474 1483

167.

Daumann

Koester

Becker

Wagner

Imperati

Gouzoulis-Mayfrank

2011

Medial prefrontal gray matter volume reductions in users of amphetamine-type stimulants revealed by combined tract-based spatial statistics and voxel-based morphometry

Neuroimage 54 2 794 801

168.

Schwartz

Mitchell

Lahna

Luber

Huckans

Mitchell

2010

Global and local morphometric differences in recently abstinent methamphetamine-dependent individuals

Neuroimage 50 4 1392 1401

169.

Kim

Lee

Song

Kim

Kwon

Kim

2010

Alterations in cortical activity of male methamphetamine abusers performing an empathy task: fMRI study

Hum Psychopharmacol 25 1 63 70

170.

Thompson

Hayashi

Simon

Geaga

Hong

Sui

2004

Structural abnormalities in the brains of human subjects who use methamphetamine

J Neurosci 24 26 6028 6036

171.

Price

DeSantis

Simpson

Tolliver

McRae-Clark

Saladin

2011

The impact of clinical and demographic variables on cognitive performance in methamphetamine-dependent individuals in rural South Carolina

Am J Addict 20 5 447 455

172.

Weber

Blackstone

Iudicello

Morgan

Grant

Moore

2012

Neurocognitive deficits are associated with unemployment in chronic methamphetamine users

Drug Alcohol Depend 125 1-2 146 153

173.

Itoh

Fukumori

Suzuki

1984

Effect of methamphetamine on the locomotor activity in the 6-OHDA dorsal hippocampus lesioned rat

Life Sci 34 9 827 833

174.

Yoshikawa

Shibuya

Kaneno

Toru

1991

Blockade of behavioral sensitization to methamphetamine by lesion of hippocampo-accumbal pathway

Life Sci 48 13 1325 1332

175.

Yamamoto

1997

Cortical and hippocampal EEG power spectra in animal models of schizophrenia produced with methamphetamine, cocaine, and phencyclidine

Psychopharmacology (Berl) 131 4 379 387

176.

Friedman

Castaneda

Hodge

1998

Long-term monoamine depletion, differential recovery, and subtle behavioral impairment following methamphetamine-induced neurotoxicity

Pharmacol Biochem Behav 61 1 35 44

177.

Commins

Seiden

1986

Alpha-Methyltyrosine blocks methylamphetamine-induced degeneration in the rat somatosensory cortex

Brain Res 365 1 15 20

178.

Eisch

O’Dell

Marshall

1996

Striatal and cortical NMDA receptors are altered by a neurotoxic regimen of methamphetamine

Synapse 22 3 217 225

179.

Schmued

Bowyer

1997

Methamphetamine exposure can produce neuronal degeneration in mouse hippocampal remnants

Brain Res 759 1 135 140

180.

Swant

Chirwa

Stanwood

Khoshbouei

2010

Methamphetamine reduces LTP and increases baseline synaptic transmission in the CA1 region of mouse hippocampus

PLoS ONE 5 6 e11382

181.

Onaivi

Ali

Chirwa

Zwiller

Thiriet

Akinshola

2002

Ibogaine signals addiction genes and methamphetamine alteration of long-term potentiation

Ann N Y Acad Sci 965 28 46

182.

Criado

Gombart

Huitron-Resendiz

Henriksen

2000

Neuroadaptations in dentate gyrus function followingrepeated methamphetamine administration

Synapse 37 2 163 166

183.

Derrick

York

Martinez

2000

Increased granule cell neurogenesis in the adult dentate gyrus following mossy fiber stimulation sufficient to induce long-term potentiation

Brain Res 857 1-2 300 307

184.

Chun

Sun

Jung

2009

LTD induction suppresses LTP-induced hippocampal adult neurogenesis

Neuroreport 20 14 1279 1283

185.

Chun

Sun

Park

Jung

2006

Enhanced proliferation of progenitor cells following long-term potentiation induction in the rat dentate gyrus

Neurobiol Learn Mem 86 3 322 329

186.

Goncalves

Martins

Ferreira

Milhazes

Borges

Ribeiro

2008

Methamphetamine-induced early increase of IL-6 and TNF-alpha mRNA expression in the mouse brain

Ann N Y Acad Sci 1139 103 111

187.

Yamaguchi

Kuraishi

Minami

Nakai

Hirai

Satoh

1991

Methamphetamine-induced expression of interleukin-1 beta mRNA in the rat hypothalamus

Neurosci Lett 128 1 90 92

188.

Nakajima

Yamada

Nagai

Uchiyama

Miyamoto

Mamiya

2004

Role of tumor necrosis factor-alpha in methamphetamine-induced drug dependence and neurotoxicity

J Neurosci 24 9 2212 2225

189.

Clark

Wiley

Bradberry

2013

Psychostimulant Abuse and Neuroinflammation: Emerging Evidence of Their Interconnection

Neurotoxicity Research 23 2 174 188

190.

Miguel-Hidalgo

2009

The role of glial cells in drug abuse

Current Drug Abuse Reviews 2 1 72 82

191.

Boger

Middaugh

Granholm

McGinty

2009

Minocycline restores striatal tyrosine hydroxylase in GDNF heterozygous mice but not in methamphetamine-treated mice

Neurobiol Dis 33 3 459 466

192.

Zhang

Kitaichi

Fujimoto

Nakayama

Shimizu

Iyo

2006

Protective effects of minocycline on behavioral changes and neurotoxicity in mice after administration of methamphetamine

Prog Neuropsychopharmacol Biol Psychiatry 30 8 1381 1393

193.

Snider

Vunck

van den Oord

Adkins

McClay

Beardsley

2012

The glial cell modulators, ibudilast and its amino analog, AVattenuate methamphetamine locomotor activity and its sensitization in mice

Eur J Pharmacol 679 1-3 75 80

194.

Snider

Hendrick

Beardsley

2013

Glial cell modulators attenuate methamphetamine self-administration in the rat

Eur J Pharmacol 701 1-3 124 130

195.

Radak

Zhao

Koltai

Ohno

Atalay

2013

Oxygen consumption and usage during physical exercise: The balance between oxidative stress and ROS-dependent adaptive signaling

Antioxidants & Redox Signaling 18 10 1208 1246

196.

Radak

Asano

Inoue

Kizaki

Oh-Ishi

Suzuki

1995

Superoxide dismutase derivative reduces oxidative damage in skeletal muscle of rats during exhaustive exercise

Journal of applied physiology 79 1 129 135

197.

Radak

Asano

Inoue

Kizaki

Oh-Ishi

Suzuki

1996

Superoxide dismutase derivative prevents oxidative damage in liver and kidney of rats induced by exhausting exercise

European Journal of Applied Physiology and Occupational Physiology 72 3 189 194

198.

Radak

Kaneko

Tahara

Nakamoto

Pucsok

Sasvari

2001

Regular exercise improves cognitive function and decreases oxidative damage in rat brain

Neurochem Int 38 1 17 23

199.

Ogonovszky

Berkes

Kumagai

Kaneko

Tahara

Goto

2005

The effects of moderate-, strenuous- and over-training on oxidative stress markers, DNA repair, and memory, in rat brain

Neurochem Int 46 8 635 640

200.

Coskun

Gonul

Guzel

Balabanli

2005

The effects of vitamin C supplementation on oxidative stress and antioxidant content in the brains of chronically exercised rats

Molecular and Cellular Biochemistry 280 1-2 135 138

201.

Suzuki

Katamine

Tatsumi

1983

Exercise-induced enhancement of lipid peroxide metabolism in tissues and their transference into the brain in rat

Journal of Nutritional Science and Vitaminology 29 2 141 151

202.

Somani

Husain

1996

Exercise training alters kinetics of antioxidant enzymes in rat tissues

Biochemistry and Molecular Biology International 38 3 587 595

203.

Rosa

Takahashi

Aboulafia

Nouailhetas

Oliveira

2007

Oxidative stress induced by intense and exhaustive exercise impairs murine cognitive function

J Neurophysiol 98 3 1820 1826

204.

Tsakiris

Angelogianni

Tesseromatis

Tsakiris

Tsopanakis

2006

Alterations in antioxidant status, protein concentration, acetylcholinesterase, Na+, K+-ATPase, and Mg2+-ATPase activities in rat brain after forced swimming

Int J Sports Med 27 1 19 24

205.

Kishi

Hirooka

Katsuki

Ogawa

Shinohara

Isegawa

2012

Exercise training causes sympathoinhibition through antioxidant effect in the rostral ventrolateral medulla of hypertensive rats

Clinical and Experimental Hypertension 34 4 278 283

206.

Zhang

Sha

Jia

2012

Exercise induces mitochondrial biogenesis after brain ischemia in rats

Neuroscience 205 10 17

207.

Toldy

Atalay

Stadler

Sasvari

Jakus

Jung

2009

The beneficial effects of nettle supplementation and exercise on brain lesion and memory in rat

The Journal of Nutritional Biochemistry 20 12 974 981

208.

Somani

Ravi

Rybak

1995

Effect of exercise training on antioxidant system in brain regions of rat

Pharmacol Biochem Behav 50 4 635 639

209.

Marosi

Bori

Hart

Sarga

Koltai

Radak

2012

Long-term exercise treatment reduces oxidative stress in the hippocampus of aging rats

Neuroscience 226 21 28

210.

St-Pierre

Drori

Uldry

Silvaggi

Rhee

Jager

2006

Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators

Cell 127 2 397 408

211.

Matsui

Ito

Taniguchi

Inoue

Takeda

Takahashi

2010

Proteasome inhibition in medaka brain induces the features of Parkinson’s disease

J Neurochem 115 1 178 187

212.

Cecarini

Bonfili

Cuccioloni

Mozzicafreddo

Rossi

Buizza

1822

Crosstalk between the ubiquitin-proteasome system and autophagy in a human cellular model of Alzheimer’s disease

Biochim Biophys Acta 11 1741 1751

213.

Radak

Ihasz

Koltai

Goto

Taylor

Boldogh

2014

The redox-associated adaptive response of brain to physical exercise

Free Radical Research 48 1 84 92

214.

Perez-Gomez

Tasker

2013

Transient domoic acid excitotoxicity increases BDNF expression and activates both MEK- and PKA-dependent neurogenesis in organotypic hippocampal slices

BMC Neurosci 14 72

215.

Bechara

Lyne

Kelly

2014

BDNF-stimulated intracellular signalling mechanisms underlie exercise-induced improvement in spatial memory in the male Wistar rat

Behav Brain Res 275 297 306

216.

Sun

Zhang

2014

Forced running exercise attenuates hippocampal neurogenesis impairment and the neurocognitive deficits induced by whole-brain irradiation via the BDNF-mediated pathway

Biochem Biophys Res Commun 443 2 646 651

217.

Novaes Gomes

Fernandes

Vannucci Campos

Cassilhas

Viana

D’Almeida

2014

The beneficial effects of strength exercise on hippocampal cell proliferation and apoptotic signaling is impaired by anabolic androgenic steroids

Psychoneuroendocrinology 50 106 117

218.

Ploughman

Austin

Glynn

Corbett

2014

The effects of poststroke aerobic exercise on neuroplasticity: A systematic review of animal and clinical studies

Translational stroke research

219.

Murphy

Segal

1997

Morphological plasticity of dendritic spines in central neurons is mediated by activation of cAMP response element binding protein

Proc Natl Acad Sci U S A 94 4 1482 1487

220.

Holmes

Galea

Mistlberger

Kempermann

2004

Adult hippocampal neurogenesis and voluntary running activity: Circadian and dose-dependent effects

J Neurosci Res 76 2 216 222

221.

van Praag

Shubert

Zhao

Gage

2005

Exercise enhances learning and hippocampal neurogenesis in aged mice

J Neurosci 25 38 8680 8685

222.

Noble

Mayer-Proschel

Proschel

2005

Redox regulation of precursor cell function: Insights and paradoxes

Antioxidants & Redox Signaling 7 11-12 1456 1467

223.

Tonchev

2011

Brain ischemia, neurogenesis, and neurotrophic receptor expression in primates

Archives Italiennes de Biologie 149 2 225 231

224.

Cheng

Coksaygan

Tang

Khatri

Balice-Gordon

Rao

2007

Truncated tyrosine kinase B brain-derived neurotrophic factor receptor directs cortical neural stem cells to a glial cell fate by a novel signaling mechanism

J Neurochem 100 6 1515 1530

225.

Somkuwar

Staples

Galinato

Fannon

Mandyam

2014

Role of NG2 expressing cells in addiction: A new approach for an old problem

Frontiers in Pharmacology 5 279

226.

Balodis

Molina

Kober

Worhunsky

White

Rajita

2013

Divergent neural substrates of inhibitory control in binge eating disorder relative to other manifestations of obesity

Obesity (Silver Spring) 21 2 367 377

227.

Dalley

Cardinal

Robbins

2004

Prefrontal executive and cognitive functions in rodents: Neural and neurochemical substrates

Neurosci Biobehav Rev 28 7 771 784

228.

Pinilla

2006

The impact of diet and exercise on brain plasticity and disease

Nutr Health 18 3 277 284

229.

Kolanowski

Strumpf

Eslinger

2006

Improving cognition and function through exercise intervention in Alzheimer’s disease

J Nurs Scholarsh 38 4 358 365

230.

O’Dell

Galvez

Ball

Marshall

2012

Running wheel exercise ameliorates methamphetamine-induced damage to dopamine and serotonin terminals

Synapse 66 1 71 80

231.

O’Dell

Marshall

2014

Running wheel exercise before a binge regimen of methamphetamine does not protect against striatal dopaminergic damage

Synapse 68 9 419 425

232.

Mathes

Nehrenberg

Gordon

Hua

Garland

Jr Pomp

2010

Dopaminergic dysregulation in mice selectively bred for excessive exercise or obesity

Behav Brain Res 210 2 155 163

233.

Waters

Pringle

Forster

Renner

Malisch

Garland

1508

Selection for increased voluntary wheel-running affects behavior and brain monoamines in mice

Brain Res 9 22

234.

Rhodes

Garland

Jr Gammie

2003

Patterns of brain activity associated with variation in voluntary wheel-running behavior

Behav Neurosci 117 6 1243 1256

235.

Johnson

Rhodes

Jeffrey

Garland

Jr Mitchell

2003

Hippocampal brain-derived neurotrophic factor but not neurotrophin-3 increases more in mice selected for increased voluntary wheel running

Neuroscience 121 1 1 7

236.

Hamer

Endrighi

Poole

2012

Physical activity, stress reduction, and mood: Insight into immunological mechanisms

Methods Mol Biol 934 89 102

237.

Bernardi

Tramontina

Nardin

Biasibetti

Costa

Vizueti

2013

Treadmill exercise induces hippocampal astroglial alterations in rats

Neural Plast 709732

238.

Nielsen

Utrankar

Reyes

Simons

Kosten

2012

Epigenetics of drug abuse: Predisposition or response

Pharmacogenomics 13 10 1149 1160

239.

Nestler

2014

Epigenetic mechanisms of drug addiction

Neuropharmacology 76 Pt B 259 268

240.

Aguilar-Valles

Vaissiere

Griggs

Mikaelsson

Takacs

Young

2014

Methamphetamine-associated memory is regulated by a writer and an eraser of permissive histone methylation

Biol Psychiatry 76 1 57 65

241.

Cadet

Jayanthi

2013

Epigenetics of methamphetamine-induced changes in glutamate function

Neuropsychopharmacology 38 1 248 249

242.

Schmidt

McGinty

West

Sadri-Vakili

2013

Epigenetics and psychostimulant addiction

Cold Spring Harbor perspectives in medicine 3 3 a012047

243.

Zoladz

Pilc

2010

The effect of physical activity on the brain derived neurotrophic factor: From animal to human studies

Journal of Physiology and Pharmacology: An Official Journal of the Polish Physiological Society 61 5 533 541

244.

Gomez-Pinilla

Zhuang

Feng

Ying

Fan

2011

Exercise impacts brain-derived neurotrophic factor plasticity by engaging mechanisms of epigenetic regulation

Eur JNeurosci 33 3 383 390

245.

Foley

Fleshner

2008

Neuroplasticity of dopamine circuits after exercise: Implications for central fatigue

Neuromolecular Med 10 2 67 80

246.

Loweth

Tseng

Wolf

2013

Using metabotropic glutamate receptors to modulate cocaine’s synaptic and behavioral effects: mGluR1 finds a niche

Curr OpinNeurobiol 23 4 500 506

247.

Pickens

Airavaara

Theberge

Fanous

Hope

Shaham

2011

Neurobiology of the incubation of drug craving

Trends Neurosci 34 8 411 420

248.

Rothman

Baumann

2003

Monoamine transporters and psychostimulant drugs

Eur J Pharmacol 479 1-3 23 40

249.

Kish

2008

Pharmacologic mechanisms of crystal meth

CMAJ: Canadian Medical Association Journal = Journal de l’Association Medicale Canadienne 178 13 1679 1682

250.

Chen

Kuo

Liao

Jen

Huang

Cherng

2008

Long-term compulsive exercisereduces the rewarding efficacy of 3,4-methylenedioxy-methamphetamine

Behav Brain Res 187 1 185 189

251.

Marques

Vasconcelos

Rolo

Pereira

Silva

Macedo

2008

Influence of chronic exercise on the amphetamine-induced dopamine release and neurodegeneration in the striatum of the rat

Ann N Y Acad Sci 1139 222 231

252.

Sutoo

Akiyama

1996

The mechanism by which exercise modifies brain function

Physiol Behav 60 1 177 181

253.

Droste

Schweizer

Ulbricht

Reul

2006

Long-term voluntary exercise and the mouse hypothalamic-pituitary-adrenocortical axis: Impact of concurrent treatment with the antidepressant drug tianeptine

J Neuroendocrinol 18 12 915 925

254.

Kolb

Rezende

Holness

Radtke

Lee

Obenaus

2013

Mice selectively bred for high voluntary wheel running have larger midbrains: Support for the mosaic model of brain evolution

J Exp Biol 216 Pt 3 515 523

255.

O’Neil

Kuczenski

Segal

Cho

Lacan

Melega

2006

Escalating dose pretreatment induces pharmacodynamic and not pharmacokinetic tolerance to a subsequent high-dose methamphetamine binge

Synapse 60 6 465 473

256.

Zhang

Loonam

Noailles

Angulo

2001

Comparison of cocaine- and methamphetamine-evoked dopamine and glutamate overflow in somatodendritic and terminal field regions of the rat brain during acute, chronic, and early withdrawal conditions

Ann N Y Acad Sci 937 93 120

257.

Real

Ferreira

Hernandes

Britto

Pires

1363

Exercise-induced plasticity of AMPA-type glutamate receptor subunits in the rat brain

Brain Res 63 71

258.

Biedermann

Fuss

Zheng

Sartorius

Falfan-Melgoza

Demirakca

2012

In vivo voxel based morphometry: Detection of increased hippocampal volume and decreased glutamate levels in exercising mice

Neuroimage 61 4 1206 1212

259.

Guezennec

Abdelmalki

Serrurier

Merino

Bigard

Berthelot

1998

Effects of prolonged exercise on brain ammonia and amino acids

Int J Sports Med 19 5 323 327

260.

Crawford

Roberts

Beveridge

2013

The group II metabotropic glutamate receptor agonist, LY68, decreases methamphetamine self-administration in rats

Drug Alcohol Depend 132 3 414 419

261.

Schwendt

Reichel

See

2012

Extinction-dependent alterations in corticostriatal mGluR2/3 and mGluR7 receptors following chronic methamphetamine self-administration in rats

PLoS ONE 7 3 e34299

262.

Kufahl

Watterson

Nemirovsky

Hood

Villa

Halstengard

2013

Attenuation of methamphetamine seeking by the mGluR2/3 agonist LY68 in rats with histories of restricted and escalated self-administration

Neuropharmacology 66 290 301

263.

Nestler

2001

Molecular neurobiology of addiction

Am J Addict 10 3 201 217

264.

Werme

Thoren

Olson

Brene

2000

Running and cocaine both upregulate dynorphin mRNA in medial caudate putamen

Eur J Neurosci 12 8 2967 2974

265.

Werme

Messer

Olson

Gilden

Thoren

Nestler

2002

Delta FosB regulates wheel running

J Neurosci 22 18 8133 8138

266.

Smith

Yancey

2003

Sensitivity to the effects of opioids in rats with free access to exercise wheels: Mu-opioid tolerance and physical dependence

Psychopharmacology (Berl) 168 4 426 434

267.

Iijima

Koike

Chaki

2013

Effect of an mGlu2/3 receptor antagonist on depressive behavior induced by withdrawal from chronic treatment with methamphetamine

Behav Brain Res 246 24 28

268.

McDaid

Graham

Napier

2006

Methamphetamine-induced sensitization differentially alters pCREB and DeltaFosB throughout the limbic circuit of the mammalian brain

Mol Pharmacol 70 6 2064 2074

269.

Wang

McGinty

1995

Dose-dependent alteration in zif/268 and preprodynorphin mRNA expression induced by amphetamine or methamphetamine in rat forebrain

J Pharmacol Exp Ther 273 2 909 917