title: The stereotypy-inducing and OCD-like effects of chronic 'binge' cocaine are modulated by distinct subtypes of nicotinic acetylcholine receptors.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
  
  
  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
  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.
authors.affiliation: 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
authors.forename: A
authors.initials: A
authors.lastname: Metaxas
authors.forename: Hl
authors.initials: H
authors.lastname: Keyworth
authors.forename: Jh
authors.initials: J
authors.lastname: Yoo
authors.forename: Y
authors.initials: Y
authors.lastname: Chen
authors.forename: I
authors.initials: I
authors.lastname: Kitchen
authors.forename: A
authors.initials: A
authors.lastname: Bailey
mesh_terms: D000818:Animals; D003042:Cocaine / Q000633:toxicity*; D018765:Dopamine Uptake Inhibitors / Q000633:toxicity; D004334:Drug Administration Schedule; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009771:Obsessive-Compulsive Disorder / Q000139:chemically induced*; D011978:Receptors, Nicotinic / Q000145:classification* / Q000235:genetics / Q000378:metabolism*; D013239:Stereotyped Behavior / Q000187:drug effects*
chemical_list: D018765:Dopamine Uptake Inhibitors; D011978:Receptors, Nicotinic; D003042:Cocaine