title: Differential role of ventral tegmental area acetylcholine and N-methyl-D-aspartate receptors in cocaine-seeking.
abstract: Exposure to drug-associated cues evokes drug-seeking behavior and is regarded as a major cause of relapse. Cues evoke burst firing of ventral tegmental area (VTA) dopamine (DA) neurons and phasic DA release in the nucleus accumbens (NAc). Cholinergic and glutamatergic input to the VTA is suggested to gate phasic DA activity. However, the role of VTA cholinergic and glutamatergic receptors in regulating phasic dopamine release and cue-induced drug-seeking in cocaine experienced subjects is not known. In male Sprague-Dawley rats, we found that VTA inactivation strongly inhibited, while VTA stimulation promoted, cocaine-seeking behavior during early withdrawal. Blockade of phasic activated D1 receptors in the NAc core also strongly inhibited cue-induced cocaine-seeking--suggesting an important role of phasic DA activity in the VTA to NAc core circuit. Next, we examined the role of VTA acetylcholine receptors (AChRs) and N-methyl-D-aspartate receptors (NMDARs) in regulating both NAc core phasic DA release and cue-induced cocaine-seeking. In cocaine naïve subjects, VTA infusion of the nicotinic acetylcholine receptor (AChR) antagonist mecamylamine, the muscarinic AChR antagonist scopolamine, or the NMDAR antagonist AP-5, led to robust attenuation of phasic DA release in the NAc core. During early cocaine withdrawal, VTA infusion of AP-5 had limited effects on NAc phasic DA release and cue-induced cocaine-seeking while VTA infusion of mecamylamine or scopolamine robustly inhibited both phasic DA release and cocaine-seeking. The results demonstrate that VTA AChRs, but not NMDARs, strongly regulate cue-induced cocaine-seeking and phasic DA release during early cocaine withdrawal.
authors.affiliation: Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Solecki
authors.affiliation: Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA; Interdepartmental Neuroscience Program, Yale University, New Haven, CT, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wickham
authors.affiliation: Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Shay
authors.initials: S
authors.lastname: Behrens
authors.affiliation: Department of Diagnostic Radiology, Yale School of Medicine, New Haven, CT, USA; Wuhan Institute of Physics and Mathematics, CAS, Hubei, PR China.
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Blake
authors.initials: B
authors.lastname: Zwerling
authors.affiliation: Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA; Department of Diagnostic Radiology, Yale School of Medicine, New Haven, CT, USA.
authors.forename: Graeme F
authors.initials: GF
authors.lastname: Mason
authors.affiliation: Department of Psychiatry, Yale School of Medicine, New Haven, CT, USA; Interdepartmental Neuroscience Program, Yale University, New Haven, CT, USA; Department of Cellular and Molecular Physiology, Yale School of Medicine, New Haven, CT, USA. Electronic address: nii.addy@yale.edu.
authors.forename: Nii A
authors.initials: NA
authors.lastname: Addy
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000779:Anesthetics, Local / Q000009:adverse effects* / Q000494:pharmacology; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D018680:Cholinergic Antagonists / Q000494:pharmacology; D003042:Cocaine / Q000009:adverse effects*; D003463:Cues; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D008012:Lidocaine / Q000494:pharmacology; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012601:Scopolamine / Q000494:pharmacology; D013997:Time Factors; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D017557:Ventral Tegmental Area / Q000187:drug effects / Q000378:metabolism*
chemical_list: D000779:Anesthetics, Local; D001552:Benzazepines; D018680:Cholinergic Antagonists; D018491:Dopamine Agonists; D016194:Receptors, N-Methyl-D-Aspartate; C534628:SCH 23390; D008464:Mecamylamine; C056639:2-amino-5-phosphopentanoic acid; D008012:Lidocaine; D012601:Scopolamine; D014633:Valine; D003042:Cocaine; D000109:Acetylcholine; D004298:Dopamine
keywords: Acetylcholine; Drug-seeking; NMDA; Nucleus accumbens; Phasic dopamine; Ventral tegmental area