The stereotypy-inducing and OCD-like effects of chronic 'binge' cocaine are modulated by distinct subtypes of nicotinic acetylcholine receptors

BACKGROUND AND PURPOSE High rates of cigarette smoking occur in cocaine-dependent individuals, reflecting an involvement of nicotinic acetylcholine receptors (nAChRs) in cocaine-elicited behaviour. This study was designed to assess the contribution of different nAChR subtypes to the behavioural and neurochemical effects of chronic cocaine treatment. EXPERIMENTAL APPROACH Cocaine (15 mg.kg-1, i.p.) was administered to male C57BL/6J mice in a chronic binge paradigm, with and without the coadministration of the a7 preferring nAChR antagonist methyllycaconitine (MLA; 5 mg.kg-1, i.p.) or the beta 2* nAChR antagonist dihydro-beta-erythroidine (DH beta E; 2 mg.kg-1, i.p.). Quantitative autoradiography was used to examine the effect of cocaine exposure on a7 and a4 beta 2* nAChRs, and on the high-affinity choline transporter. KEY RESULTS MLA+cocaine administration induced an intense self-grooming behaviour, indicating a likely role for a7 nAChRs in modulating this anxiogenic, compulsive-like effect of cocaine. In the major island of Calleja, a key area of action for neuroleptics, MLA+cocaine reduced choline transporter binding compared with cocaine (with or without DH beta E) administration. DH beta E treatment prevented the induction of stereotypy sensitisation to cocaine but prolonged locomotor sensitisation, implicating heteromeric beta 2* nAChRs in the neuroadaptations mediating cocaine-induced behavioural sensitisation. Binge cocaine treatment region-specifically increased a4 beta 2* nAChR binding in the midbrain dopaminergic regions: ventral tegmental area and substantia nigra pars compacta. CONCLUSIONS AND IMPLICATIONS We have shown a differential, subtype-selective, contribution of nAChRs to the behavioural and neurochemical sequelae of chronic cocaine administration. These data support the clinical utility of targeting specific nAChR subtypes for the alleviation of cocaine-abuse symptomatology.