Effects of subunit selective nACh receptors on operant ethanol self-administration and relapse-like ethanol-drinking behavior.
OBJECTIVE
The sensitivity to ethanol central effects is partially determined by the subunit composition of brain nicotinic acetylcholine receptors (nAChRs). Thus, the effects of intraventral tegmental area (VTA) administration of the nicotinic subunit-specific antagonist, alpha-conotoxin MII (alphaCtxMII, alpha(3)beta(2)*, beta(3)*, alpha(6)*), were compared to those of systemic mecamylamine (MEC, an allosteric negative modulator of the nAChR), dihydro-beta-erythroidine (DHbetaE, alpha(4)beta(2)*), and methyllycaconitine (MLA, alpha(7)*) to elucidate involvement of different subunits of nAChRs in operant ethanol self-administration and relapse-like activation of ethanol consumption after ethanol deprivation in rats.


METHODS
The effects of drugs were studied in rats trained for operant oral self-administration of ethanol (FR = 1). For ethanol deprivation, trained animals were subjected to a period of alcohol deprivation for 10 days. alphaCtxMII was given directly into the VTA through implanted permanent intracranial cannulae, whereas MEC, DHbetaE, and MLA were administered systemically.


RESULTS
alphaCtxMII reduced operant ethanol self-administration and blocked the deprivation-induced relapse-like ethanol consumption. MEC reduced operant ethanol self-administration and inhibited the deprivation-induced increase in alcohol consumption. DHbetaE did not alter ethanol self-administration in the lower-dose range but inhibited ethanol intake at a higher dose (4 mg/kg), although this effect might have been nonspecific. MLA failed to block self-administration of ethanol and relapse-like drinking after deprivation.


CONCLUSIONS
Our results indicate that nAChRs are involved in the modulation of operant alcohol self-administration and relapse-like alcohol drinking behavior in rats. Our observations support the working hypothesis that systemically active selective ligands for nAChR alpha(3)beta(2)*, beta(3), and/or alpha(6)* receptor subunits might be of therapeutic value for the treatment of alcoholism.
Kuzmin
Alexander
A
Department of Clinical Neuroscience, Division of Drug Dependence, Karolinska University Hospital, Bldg M1:01, 17176, Stockholm, Sweden.
Jerlhag
Elisabet
E
Liljequist
Sture
S
Engel
Jörgen
J
D000157:Aconitine / Q000031:analogs & derivatives / Q000494:pharmacology; D000284:Administration, Oral; D000428:Alcohol Drinking / Q000378:metabolism* / Q000517:prevention & control / Q000523:psychology; D000437:Alcoholism / Q000188:drug therapy / Q000378:metabolism* / Q000523:psychology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D002491:Central Nervous System Agents / Q000008:administration & dosage*; D003216:Conditioning, Operant / Q000187:drug effects*; D020916:Conotoxins / Q000494:pharmacology; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000008:administration & dosage*; D008297:Male; D008464:Mecamylamine / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D021122:Protein Subunits; D051381:Rats; D017208:Rats, Wistar; D011978:Receptors, Nicotinic / Q000187:drug effects* / Q000378:metabolism; D012008:Recurrence; D012646:Self Administration; D017557:Ventral Tegmental Area / Q000187:drug effects* / Q000378:metabolism
D002491:Central Nervous System Agents; D020916:Conotoxins; D018733:Nicotinic Antagonists; D021122:Protein Subunits; D011978:Receptors, Nicotinic; C098872:alpha-conotoxin MII; C054634:methyllycaconitine; D004079:Dihydro-beta-Erythroidine; D000431:Ethanol; D008464:Mecamylamine; D000157:Aconitine