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The stereotypy‐inducing and OCD‐like effects of chronic ‘binge’ cocaine are modulated by distinct subtypes of nicotinic acetylcholine receptors
Author(s) -
Metaxas A,
Keyworth HL,
Yoo JH,
Chen Y,
Kitchen I,
Bailey A
Publication year - 2012
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2012.02023.x
Subject(s) - methyllycaconitine , nicotinic agonist , ventral tegmental area , neurochemical , stereotypy , pharmacology , disinhibition , nicotine , psychology , mecamylamine , dopamine transporter , dopaminergic , neuroscience , dopamine , nicotinic acetylcholine receptor , medicine , amphetamine , receptor
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 β2* nAChR antagonist dihydro‐β‐erythroidine (DHβE; 2 mg·kg −1 , i.p.). Quantitative autoradiography was used to examine the effect of cocaine exposure on α7 and α4β2* 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 DHβE) administration. DHβE treatment prevented the induction of stereotypy sensitisation to cocaine but prolonged locomotor sensitisation, implicating heteromeric β2* nAChRs in the neuroadaptations mediating cocaine‐induced behavioural sensitisation. ‘Binge’ cocaine treatment region‐specifically increased α4β2* 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.