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Br J Pharmacol. 2012 Sep;167(2):450-64. doi: 10.1111/j.1476-5381.2012.02023.x.

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

Author information

1
Department of Biochemistry and Physiology, Faculty of Health and Medical Sciences, Institute of Health and Medical Sciences, University of Surrey, Guildford, UK. a.metaxas@vumc.nl

Abstract

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.

PMID:
22568685
PMCID:
PMC3481050
DOI:
10.1111/j.1476-5381.2012.02023.x
[Indexed for MEDLINE]
Free PMC Article

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