Our previous studies have shown that the selective dopamine D3 receptor antagonists SB-277011A or NGB 2904 significantly attenuate cocaine self-administration under a progressive-ratio reinforcement schedule and cocaine-, methamphetamine- or nicotine-enhanced brain stimulation reward. However, the poor bioavailability of SB-277011A has limited its potential use in humans. In the present study, we investigated the effects of the novel D3 receptor antagonist PG01037 on methamphetamine self-administration, methamphetamine-associated cue-induced reinstatement of drug seeking and methamphetamine-enhanced brain stimulation reward. Rats were allowed to intravenously self-administer methamphetamine under fixed-ratio 2 and progressive-ratio reinforcement conditions, and then the effects of PG01037 on methamphetamine self-administration and cue-induced reinstatement were assessed. Additional groups of rats were trained for intracranial electrical brain stimulation reward and the effects of PG01037 and methamphetamine on brain stimulation reward were assessed. Acute intraperitoneal administration of PG01037 (3, 10, 30 mg/kg) failed to alter methamphetamine or sucrose self-administration under fixed-ratio 2 reinforcement, but significantly lowered the break-point levels for methamphetamine or sucrose self-administration under progressive-ratio reinforcement. In addition, PG01037 significantly inhibited methamphetamine-associated cue-triggered reinstatement of drug-seeking behavior and methamphetamine-enhanced brain stimulation reward. These data suggest that the novel D3 antagonist PG01037 significantly attenuates the rewarding effects as assessed by progressive-ratio self-administration and brain stimulation reward, and inhibits methamphetamine-associated cue-induced reinstatement of drug-seeking behavior These findings support the potential use of PG01037 or other selective D3 antagonists in the treatment of methamphetamine addiction.
ArnoldJMRobertsDC. (1997) A critique of fixed and progressive ratio schedules used to examine the neural substrates of drug reinforcement. Pharmacol Biochem Behav57: 441–457.
2.
AshbyCRPaulMGardnerELHeidbrederCAHaganJJ. (2003) Acute administration of the selective D3 receptors antagonist SB-277011-A blocks the acquisition and expression of the conditioned place preference response to heroin in male rats. Synapse48: 154–156.
3.
AustinNEBaldwinSJCutlerL. (2001) Pharmacokinetics of the novel, high-affinity and selective dopamine D3 receptor antagonist SB-277011A in rat, dog and monkey: in vitro/in vivo correlation and the role of aldehyde oxidase. Xenobiotica6: 677–686.
4.
BaucoPWiseRA. (1997) Synergistic effects of cocaine with lateral hypothalamic brain stimulation reward: lack of tolerance or sensitization. J Pharmacol Exp Ther283: 1160–1167.
5.
BossertJMGhitzaUELuLEpsteinDHShahamY. (2005) Neurobiology of relapse to heroin and cocaine seeking: an update and clinical implications. Eur J Pharmacol526: 36–50.
6.
CervoLCarnovaliFStarkJAMenniniT. (2003) Cocaine-seeking behavior in response to drug-associated stimuli in rats: Involvement of D3 and D2 dopamine receptors. Neuropsychopharmacology28: 1150–1159.
7.
CollinsGTNewmanAHGrundtP. (2007) Yawning and hypothermia in rats: effects of dopamine D3 and D2 agonists and antagonists. Psychopharmacology (Berl)193: 159–70.
8.
CollinsGTWitkinJMNewmanAH. (2005) Dopamine agonist-induced yawning in rats: a dopamine D3 receptor-mediated behavior. J Pharmacol Exp Ther314: 310–319.
9.
CoulombeDMiliaressisE. (1987) Fitting intracranial self-stimulation data with growth models. Behav Neurosci101: 209–214.
10.
DiazJPilonCLe FollBGrosCTrillerASchwartzJCSokoloffP. (2002) Dopamine D3 receptors expressed by all mesencephalic dopamine neurons. Journal of Neuroscience20: 8677–8684.
11.
Di CianoPEverittBJ. (2003) Differential control over drug-seeking behavior by drug-associated conditioned reinforcers and discriminative stimuli predictive of drug availability. Behav Neurosci117: 952–960.
12.
Di CianoPUnderwoodRJHaganJJEverittBJ. (2003) Attenuation of cue-controlled cocaine-seeking by a selective D3 dopamine receptor antagonist SB-277011-A. Neuropsychopharmacology28: 329–338.
13.
FrenchEDLopezMPeperSKamenkaJMRobertsDC. (1995) A comparison of the reinforcing efficacy of PCP, the PCP derivatives TCP and BTCP, and cocaine using a progressive ratio schedule in the rat. Behav Pharmacol6: 223–228.
14.
GalKGyertyánI. (2003) Dopamine D3 receptor ligands show place conditioning effect but do not influence cocaine-induced place preference. Neuroreport14: 93–98.
15.
GardnerEL. (2000) What we have learned about addiction from animal models of drug self administration. Am J Addict9: 285–313.
16.
GilbertJGNewmanAHGardnerEL. (2005) Acute administration of SB-277011A, NGB 2904, or BP 897 inhibits cocaine cue-induced reinstatement of drug-seeking behavior in rats: role of dopamine D3 receptors. Synapse57: 17–28.
17.
GurevichEVJoyceAN. (1999) Distribution of dopamine D3 receptor expressing neurons in the human forebrain: Comparison with D2 receptor expressing neurons. Neuropsychopharmacology20: 60–80.
18.
GrundtPCarlsonEECaoJ. (2005) Novel heterocyclic trans olefin analogues of N-{4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butyl}arylcarboxamides as selective probes with high affinity for the dopamine D3 receptor. J Med Chem48: 839–848.
19.
GrundtPPrevattKMCaoJ. (2007) Heterocyclic analogues of N-(4-(4-(2,3-dichlorophenyl)piperazin-1-yl)butyl)arylcarboxamides with functionalized linking chains as novel dopamine D3 receptor ligands: Potential substance abuse therapeutic agents. J Med Chem50: 4135–4146.
20.
HeidbrederCAGardnerELXiZX. (2005) The role of central dopamine D3 receptors in drug addiction: a review of pharmacological evidence. Brain Res Brain Res Rev49: 77–105.
21.
HeidbrederAndreoliMMarconCHutchesonDMGardnerELAshbyCRJr. (2007) Evidence for the role of dopamine D3 receptors in oral operant alcohol self-administration and reinstatement of alcohol-seeking behavior in mice. Addict Biol12: 35–50.
22.
HigleyAHDillonCXiZXGardnerEL. (2007) The dopamine D3 receptor antagonist SB-277011A inhibits progressive-ratio methamphetamine self-administration and methamphetamine-induced reinstatement of drug-seeking behavior in rats. Abstracts for the 37th Annual Meeting for Society of Neuroscience; 2007 November 3–7 San Diego, CA.
23.
HymanSEMalenkaRCNestlerEJ. (2006) Neural mechanisms of addiction: the role of reward-related learning and memory. Annu Rev Neurosci29: 565–598.
KalivasPW. (2007) Neurobiology of cocaine addiction: implications for new pharmacotherapy. Am J Addict16: 71–8.
26.
KalivasPWVolkowND. (2005) The neural basis of addiction: a pathology of motivation and choice. Am J Psychiatr162: 1403–1413.
27.
KhroyanTVBarrett-LarimoreRLRowlettJKSpealmanD. (2000) Dopamine D1- and D2-like receptor mechanisms in relapse to cocaine-seeking behavior: effects of selective antagonists and agonists. J Pharmacol Exp Ther294: 680–687.
28.
KitaKShirataniTTakenouchiKFukuzakoHTakigawaM. (1999) Effects of D1 and D2 dopamine receptor antagonists on cocaine-induced self-stimulation and locomotor activity in rats. Eur Neuropsychopharmacol9: 1–7.
29.
KornetskyC. (2004) Brain-stimulation reward, morphine-induced oral stereotypy, and sensitization: implications for abuse. Neurosci Biobehav Rev27: 777–786.
30.
KumarRRiddleLGriffinSAGrundtPNewmanAHLuedtkeRR. (2009) Evaluation of the D3 dopamine receptor selective antagonist PG01037 on L-dopa-dependent abnormal involuntary movements in rats. Neuropharmacology56: 944–955.
31.
Le FollBSokoloffPStarkHGoldbergSR. (2005) Dopamine D3 receptor ligands block nicotine-induced conditioned place preferences through a mechanism that does not involve discriminative-stimulus or antidepressant-like effects. Neuropsychopharmacology30: 720–730.
32.
LevantB. (1998) Differential distribution of D3 dopamine receptors in the brains of several mammalian species. Brain Res2: 269–274.
33.
MendelsonJHMelloNK. (1996) Management of cocaine abuse and dependence. N Eng J Med334: 965–972.
34.
MeredithCWJaffeCAng-LeeKSaxonAJ. (2005) Implications of chronic methamphetamine use: a literature review. Harv Rev Psychiatry13: 141–154.
35.
National Academy of Sciences (National Research Council, Commission on Life Sciences, Institute of Laboratory Animal Resources) (1996) Guide for the Care and Use o Laboratory Animals. Washington, DC: National Academy Press.
36.
NewmanAHGrundtPNaderMA. (2005) Dopamine D3 receptor partial agonists and antagonists as potential drug abuse therapeutic agents. J Med Chem48: 3663–3679.
37.
O’BrienCP. (1997) A range of research-based pharmacotherapies for addiction. Science278: 66–70.
38.
O’BrienCPChildressARMcLellanATEhrmanR. (1992) Classical conditioning in drug-dependent humans. Ann N Y Acad Sci654: 400–415.
39.
O’BrienCPGardnerEL. (2005) Critical assessment of how to study addiction and its treatment: human and non-human animal models. Pharmacol Ther108: 18–58.
40.
PakACAshbyCRJrHeidbrederCA. (2006) The selective dopamine D3 receptor antagonist SB-277011A reduces nicotine-enhanced brain reward and nicotine-paired environmental cue functions. Int J Neuropsychopharmacol9: 585–602.
41.
PaxinosGWatsonC. (1998) The Rat Brain in Stereotaxic Coordinates. San Diego: Academic Press.
42.
PengXQAshbyCRJrSpillerKLiXLiJThomassonNMillanMJMocaërEMuńozCGardnerELXiZX. (2009) The preferential dopamine D3 antagonist S33138 inhibits cocaine reward and cocaine triggered relapse to drug- seeking behavior in rats. Neuropharmacology56, 752–760.
43.
PierceRCKumaresanV. (2006) The mesolimbic dopamine system: the final common pathway for the reinforcing effect of drugs of abuse?Neurosci Biobehav Rev30: 15–38.
44.
PillaMPerachonSSautelF. (1999) Selective inhibition of cocaine-seeking behaviour by a partial dopamine D3 receptor agonist. Nature400: 371–375.
45.
RanaldiRBeningerRJ. (1994) The effects of systemic and intracerebral injections of D1 and D2 agonists on brain stimulation reward. Brain Res651: 283–292.
46.
ReavillCTaylorSGWoodMD. (2000) Pharmacological actions of a novel, high-affinity, and selective human dopamine D3 receptor antagonist, SB-277011-A. J Pharmacol Exp Ther294: 1154–1165.
RichardsonNRRobertsDC. (1996) Progressive ratio schedules in drug self-administration studies in rats: a method to evaluate reinforcing efficacy. J Neurosci Methods66: 1–11.
49.
RobertsDCLohEAVickersG. (1989) Self-administration of cocaine on a progressive ratio schedule in rats: dose–response relationship and effect of haloperidol pretreatment. Psychopharmacology97: 535–538.
50.
RoseMEGrantCE. (2008) Pharmacotherapy for methamphetamine dependence: A review of the pathophysiology of methamphetamine addiction and the theoretical basis and efficacy of pharmacotherapeutic interventions. Ann Clin Psychiatry20: 145–155.
51.
RowlettJK. (2000) A labor-supply analysis of cocaine self-administration under progressive ratio schedules: antecedents, methodologies, and perspectives. Psychopharmacology153: 1–16.
52.
SchwartzAGozziAReeseT. (2004) Selective dopamine D3- receptor antagonist SB-277011-A potentiates phMRI response to acute amphetamine challenge in the rat brain. Synapse54: 1–10.
53.
SelfDWBarnhartWJLehmanDANestlerEJ. (1996) Opposite modulation of cocaine-seeking behavior by D1- and D2-like dopamine receptor agonists. Science271: 1586–1589.
54.
ShahamYRodarosDStewartJ. (1994) Reinstatement of heroin-reinforced behavior following long-term extinction: implications for the treatment of relapse to drug taking. Behav Pharmacol5: 360–364.
55.
ShalevUGrimmJWShahamY. (2002) Neurobiology of relapse to heroin and cocaine seeking: a review. Pharmacol Rev54: 1–42.
56.
ShalevUHighfieldDYapJShahamY. (2000) Stress and relapse to drug seeking in rats: studies on the generality of the effect. Psychopharmacology (Berl)150: 337–346.
57.
ShalevUMarinelliMBaumannMHPiazzaPVShahamY. (2003) The role of corticosterone in food deprivation-induced reinstatement of cocaine seeking in the rat. Psychopharmacology (Berl)168: 170–176.
58.
SinhaR. (2001) How does stress increase risk of drug abuse and relapse?Psychopharmacology158: 343–359.
59.
SpillerKXiZXPengXQNewmanAHAshbyCRHeidbrederCGardnerEL. (2008). The putative dopamine D3 receptor antagonists SB-277011A, NGB 2904, S33,138 or BP 897 inhibit methamphetamine-enhanced brain stimulation reward in rats. Psychopharmacology196: 533–542.
60.
SokoloffPDiazJLe FollB. (2006) The dopamine D3 receptor: A therapeutic target for the treatment of neuropsychiatric disorders. CNS Neurol Disord Drug Targets5: 25–43.
61.
SokoloffPGirosBMartresMPBouthenetMLSchwartzJC. (1990) Molecular cloning and characterization of novel dopamine receptor (D3) as a target for neuroleptics. Nature347: 146–151.
62.
SokoloffPLe FollBPerachonSBordetRRidraySSchwartzJC. (2001) The dopamine D3 receptor and drug addiction. Neurotox Res3: 433–441.
63.
SokoloffPMartresMPGirosBBouthenetMLSchwartzJC. (1992) The third dopamine receptor (D3) as a novel target for antipsychotics. Biochem Pharmacol43: 659–666.
64.
StaffordDLeSageMGGlowaJR. (1998) Progressive-ratio schedules of drug delivery in the analysis of drug self-administration: a review. Psychopharmacology139: 169–184.
65.
StanwoodGDArtymyshynRPKungMPKungHFLuckiIMcGonigleP. (2000) Quantitative autoradiographic mapping of rat brain dopamine D3 binding with [(125)I]7-OH-PIPAT: evidence for the presence of D3 receptors on dopaminergic and nondopaminergic cell bodies and terminals. J Pharmacol Exp Ther295: 1223–1231.
66.
SteinLRayOS. (1960) Brain stimulation reward ‘thresholds’ self-determined in rat. Psychopharmacologia1: 251–256.
67.
StewartJ. (2000) Pathways to relapse: the neurobiology of drug- and stress-induced relapse to drug-taking. J Psychiat Neurosci25: 125–136.
68.
ThanosPKKatanaJMAshbyCR. (2005) The selective dopamine D3 antagonist SB-277011A attenuates ethanol consumption in ethanol preferring (P) and non-preferring (NP) rats. Pharmacol Biochem Behav81: 190–197.
69.
VorelSRAshbyCRJrPaulM. (2002) Dopamine D3 receptor antagonism inhibits cocaine-seeking and cocaine-enhanced brain reward in rats. J Neurosci22: 9595–9603.
70.
WiseRA. (1996a) Addictive drugs and brain stimulation reward. Ann Rev Neurosci19: 319–340.
71.
WiseRA. (2005) Forebrain substrates of reward and motivation. J Comp Neurol493: 115–21.
72.
WiseRAGardnerEL. (2004) Animal models of addiction. In: CharneyDSNestlerEJ (eds) Neurobiology of Mental Illness, 2nd edn. London: Oxford University Press, 683–697.
73.
XiZXGardnerEL. (2007) Pharmacological actions of NGB-2904, a selective dopamine D3 receptor antagonist, in animal models of drug addiction. CNS Drug Rev13: 1–21.
74.
XiZXGilbertJGCamposAC. (2004) Blockade of mesolimbic dopamine D3 receptors inhibits stress-induced reinstatement of cocaine-seeking in rats. Psychopharmacology176: 57–65.
75.
XiZXGilbertJGPakACAshbyCRHeidbrederCAGardnerEL. (2005) Selective dopamine D3 receptor antagonism by SB-277011A attenuates cocaine reinforcement as assessed by progressive ratio and variable cost variable payoff fixed ratio cocaine self administration in rats. Eur J Neurosci21: 3427–3438.
76.
XiZXNewmanAHGilbertJG. (2006) The novel dopamine D3 receptor antagonist NGB 2904 inhibits cocaine's rewarding effects and cocaine-induced reinstatement of drug-seeking behavior in rats. Neuropsychopharmacology31: 1393–1405.
