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 α7 preferring nAChR antagonist methyllycaconitine (MLA; 5 mg·kg(-1) , i.p.) or the ß2* nAChR antagonist dihydro-ß-erythroidine (DHßE; 2 mg·kg(-1) , i.p.). Quantitative autoradiography was used to examine the effect of cocaine exposure on α7 and α4ß2* nAChRs, and on the high-affinity choline transporter. KEY RESULTS: MLA+cocaine administration induced an intense self-grooming behaviour, indicating a likely role for α7 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 DHßE) administration. DHßE treatment prevented the induction of stereotypy sensitisation to cocaine but prolonged locomotor sensitisation, implicating heteromeric ß2* nAChRs in the neuroadaptations mediating cocaine-induced behavioural sensitisation. 'Binge' cocaine treatment region-specifically increased α4ß2* 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.