Adenosine A2a receptors form a mutually inhibitory heteromeric complex with dopamine D2 receptors such that each receptor exhibits lower sensitivity to its agonist after the opposing receptor agonist is bound. This study analyzed the effects of CGS 21680, an adenosine A2A agonist, on nicotine conditioned place preference (CPP) in adolescence using a rodent model of schizophrenia (SZ).
Methods:
Rats were treated from postnatal day (P) 1 to P21 with saline or the dopamine D2/D3 agonist quinpirole (NQ treatment) and raised to P41. After an initial preference test, rats were conditioned with saline or nicotine (0.6 mg/kg base) from P43 to P51. CGS 21680 (0.03 or 0.09 mg/kg) was given 15 minutes before nicotine was administered. The post-conditioning test was administered on P52. On P53, the nucleus accumbens (NAcc) was analyzed for brain-derived neurotrophic factor (BDNF) and glial cell-lined neurotrophic factor (GDNF).
Results:
Results revealed that NQ treatment enhanced nicotine CPP, and both doses of CGS 21680 alleviated this enhancement. Nicotine also resulted in a CPP in controls, which was alleviated by both doses of CGS 21680. BDNF closely followed the behavioral results: CGS 21680 alleviated the enhancement in NAcc BDNF in NQ-treated animals, and eliminated the increase in NAcc BDNF produced by nicotine in controls. NQ-treated animals conditioned to nicotine resulted in an increase of NAcc GDNF, but this was eliminated by CGS 21680. Both BDNF and GDNF correlated with CPP performance.
Conclusions:
Results revealed that an adenosine A2A agonist decreased the rewarding aspects of nicotine and its accompanying neural plasticity changes in a model of SZ.
Abi-DarghamARodenhiserJPrintzD, et al. (2000) Increased baseline occupancy of D2 receptors by dopamine in schizophrenia. Proc Natl Acad Sci U S A97: 8104–8109.
2.
AttiARFerrari GozziBZulianiG, et al. (2014) A systematic review of metabolic side effects related to the use of antipsychotic drugs in dementia. Int Psychogeriatr26: 19–37.
3.
BoisonDAronicaE. (2015) Comorbidities in neurology: is adenosine the common link?Neuropharmacology97: 18–34.
4.
BoisonDSingerPShenHY, et al. (2012) Adenosine hypothesis of schizophrenia–opportunities for pharmacotherapy. Neuropharmacology62: 1527–1543.
5.
BrownRWKirbySLDentonAR, et al. (2018) An analysis of the rewarding and aversive associative properties of nicotine in the neonatal quinpirole model: effects on glial cell line-derived neurotrophic factor (GDNF). Schizophr Res194: 107–114.
6.
BrownRWSchlittMAOwensAS, et al. (2018) Effects of environmental enrichment on nicotine sensitization in rats neonatally treated with quinpirole: Analyses of glial cell line-derived neurotrophic factor and implications towards schizophrenia. Dev Neurosci40: 64–72.
7.
CaroffSN (2012) Review: extrapyramidal side effects vary between different second generation antipsychotic drugs. Evid Based Ment Health15: 47.
8.
CarrilloJAHerraizAGRamosSI, et al. (2003) Role of the smoking-induced cytochrome P450 (CYP)1A2 and polymorphic CYP2D6 in steady-state concentration of olanzapine. J Clin Psychopharmacol23: 119–127.
9.
CelverJSharmaMKovoorA (2010) RGS9-2 mediates specific inhibition of agonist-induced internalization of D2-dopamine receptors. J Neurochem114: 739–749.
10.
Committee on the Public Health Implications of Raising the Minimum Age for Purchasing Tobacco Products; Board on Population Health and Public Health Practice; Institute of Medicine; BonnieRJStrattonKKwanLY (eds) (2015) Public Health Implications of Raising the Minimum Age of Legal Access to Tobacco Products. Washington, DC: National Academies Press.
11.
FeatherstoneRESiegelSJ (2015) The role of nicotine in schizophrenia. Int Rev Neurobiol124: 23–78.
12.
FilipMZaniewskaMFrankowskaM, et al. (2012) The importance of the adenosine A2A receptor-dopamine D(2) receptor interaction in drug addiction. Curr Med Chem19: 317–355.
13.
FontinhaBMDiógenesMJRibeiroJA, et al. (2008) Enhancement of long-term potentiation by brain-derived neurotrophic factor requires adenosine A2A receptor activation by endogenous adenosine. Neuropharmacology54: 924–933.
14.
GarçãoPSzabóECWopereisS, et al. (2013) Functional interaction between pre-synaptic α6β2-containing nicotinic and adenosine A2A receptors in the control of dopamine release in the rat striatum. Br J Pharmacol169: 1600–1611.
15.
GomesCASimõesPFCanasPM, et al. (2009) GDNF control of the glutamatergic cortico-striatal pathway requires tonic activation of adenosine A receptors. J Neurochem108: 1208–1219.
16.
GomesCAVazSHRibeiroJA, et al. (2006) Glial cell line-derived neurotrophic factor (GDNF) enhances dopamine release from striatal nerve endings in an adenosine A2A receptor-dependent manner. Brain Res1113: 129–136.
17.
GrahamDLEdwardsSBachtellRK, et al. (2007) Dynamic BDNF activity in nucleus accumbens with cocaine use increases self-administration and relapse. Nat Neurosci10: 1029–1037.
18.
HwangYKimJShinJY, et al. (2013) Gene expression profiling by mRNA sequencing reveals increased expression of immune/inflammation-related genes in the hippocampus of individuals with schizophrenia. Transl Psychiatry3: e321.
19.
JannMWSakladSREreshefskyL, et al. (1986) Effects of smoking on haloperidol and reduced haloperidol plasma concentrations and haloperidol clearance. Psychopharmacology90: 468–470.
20.
JastrzębskaJNowakESmagaI, et al. (2014) Adenosine (A)(2A)receptor modulation of nicotine-induced locomotor sensitization. A pharmacological and transgenic approach. Neuropharmacology81: 318–326.
21.
JeonSJRheeSYRyuJH, et al. (2011) Activation of adenosine A2A receptor up-regulates BDNF expression in rat primary cortical neurons. Neurochem Res36: 2259–2269.
22.
KahnRSSommerIEMurrayRM, et al. (2015) Schizophrenia. Nat Rev Dis Primers1: 15067.
23.
KavanaghKASchreinerDCLevisSC, et al. (2015) Role of adenosine receptor subtypes in methamphetamine reward and reinforcement. Neuropharmacology89: 265–273.
24.
KomakiSIshikawaKArakawaY (2012) Trk and cAMP-dependent survival activity of adenosine A2A agonist CGS21680 on rat motoneurons in culture. Neurosci Lett522: 21–24.
25.
KostrzewaRM (1995) Dopamine receptor supersensitivity. Neurosci and Biobehav Rev19: 1–21.
26.
KowiańskiPLietzauGCzubaE, et al. (2018) BDNF: a key factor with multipotent impact on brain signaling and synaptic plasticity. Cell Mol Neurobiol38: 579–593.
27.
LeDucPAMittlemanG (1995) Schizophrenia and psychostimulant abuse: a review and re-analysis of clinical evidence. Psychopharmacology121: 407–427.
28.
LopesLVSebastiãoAMRibeiroJA (2011) Adenosine and related drugs in brain diseases: present and future in clinical trials. Curr Top Med Chem11: 1087–1101.
29.
LuLWangXWuP, et al. (2009) Role of ventral tegmental area glial cell line-derived neurotrophic factor in incubation of cocaine craving. Biol Psychiatry66: 137–145.
30.
MapleAMPernaMKParlamanJP, et al. (2007) Ontogenetic quinpirole treatment produces long-lasting decreases in the expression of Rgs9, but increases Rgs17 in the striatum, nucleus accumbens and frontal cortex. Eur J Neurosci26: 2532–2538.
31.
PernaMKBrownRW (2013) Adolescent nicotine sensitization and effects of nicotine on accumbal dopamine release in a rodent model of increased dopamine D2 receptor sensitivity. Behav Brain Res A242: 102–109.
32.
PerryPJMillerDDArndtSV, et al. (1993) Haloperidol dosing requirements: the contribution of smoking and nonlinear pharmacokinetics. J Clin Psychopharmacol13: 46–51.
33.
PetersonDJGillWDDoseJM, et al. (2017) The effects of nicotine in the neonatal quinpirole rodent model of psychosis: neural plasticity mechanisms and nicotinic receptor changes. Behav Brain Res325(Pt A): 17–24.
34.
PickensCLAiravaaraMThebergeF, et al. (2011) Neurobiology of the incubation of drug craving. Trends Neurosci34: 411–420.
35.
RialDLaraDRCunhaRA (2014) The adenosine neuromodulation system in schizophrenia. Int Rev Neurobiol119: 395–449.
36.
RodriguesTMJerónimo-SantosASebastiãoAM, et al. (2014) Adenosine A2AReceptors as novel upstream regulators of BDNF-mediated attenuation of hippocampal long-term depression (LTD). Neuropharmacology79: 389–398.
37.
SalokangasRKHonkonenTStengårdE, et al. (2006) Cigarette smoking in long-term schizophrenia. Eur Psychiatry21: 219–223.
38.
SeemanPSchwarzJChenJF, et al. (2006) Psychosis pathways converge via D2high dopamine receptors. Synapse60: 319–346.
39.
ShenHYSingerPLytleN, et al. (2012) Adenosine augmentation ameliorates psychotic and cognitive endophenotypes of schizophrenia. J Clin Invest122: 2567–2577.
40.
ShimazoeTYoshimatsuAKawashimoA, et al. (2000) Roles of adenosine A(1) and A(2A) receptors in the expression and development of methamphetamine-induced sensitization. Eur J Pharmacol388: 249–254.
41.
TakaradaTNakamichiNKawagoeH, et al. (2012) Possible neuroprotective property of nicotinic acetylcholine receptors in association with predominant upregulation of glial cell line-derived neurotrophic factor in astrocytes. J Neurosci Res90: 2074–2085.
42.
TaraziFIBaldessariniRJ (2000) Comparative postnatal development of dopamine D(1), D(2) and D(4) receptors in rat forebrain. Int J Dev Neurosci18: 29–37.
43.
ThackerSKPernaMKWardJJ, et al. (2006) The effects of adulthood olanzapine treatment on cognitive performance and neurotrophic factor content in male and female rats neonatally treated with quinpirole. Eur J Neurosci24: 2075–2083.
44.
UrigüenLGarcía-FusterMJCalladoLF, et al. (2009) Immunodensity and mRNA expression of A2A adenosine, D2 dopamine, and CB1 cannabinoid receptors in postmortem frontal cortex of subjects with schizophrenia: effect of antipsychotic treatment. Psychopharmacology206: 313–324.
45.
VinarovaEVinarOKalvachZ (1984) Smokers need higher doses of neuroleptic drugs. Biol Psychiatry19: 1265–1268.
46.
WydraKGołembiowskaKSuderA, et al. (2015) On the role of adenosine (A)2A receptors in cocaine-induced reward: a pharmacological and neurochemical analysis in rats. Psychopharmacology232: 421–435.
47.
ZhangJAbdallahCGWangJ, et al. (2012) Upregulation of adenosine A2A receptors induced by atypical antipsychotics and its correlation with sensory gating in schizophrenia patients. Psychiatry Res200: 126–132.
