Contribution of dihydro-beta-erythroidine sensitive nicotinic acetylcholine receptors in the ventral tegmental area to cocaine-induced behavioral sensitization in rats

Nicotinic acetylcholine receptors (nAChRs) are known to play a role in several aspects of cocaine addiction. Recently, systemic administration of the nicotinic receptor antagonist mecamylamine was shown to block the induction of long-term locomotor sensitization to cocaine. Behavioral sensitization being a model of long-term neuroadaptations to chronic cocaine exposure, the goal of the current study was to identify the anatomical localization, as well as the nature, of the nicotinic receptors involved. Male Sprague-Dawley rats were stereotaxically implanted with bilateral cannula into either the ventral tegmental area (VTA) or the nucleus accumbens (Nacc). On each of the six consecutive days, rats were microinjected bilaterally with the selective nicotinic antagonists dihydro-beta-erythroidine (DH beta E), methyllycaconitine (MLA) or saline, followed by an intraperitoneal injection of cocaine (15 mg/kg, i.p.) or saline. Following a 2-week withdrawal period, rats received a final injection of cocaine in the absence of nicotinic antagonist to test for sensitization. When microinjected into the VTA, DH beta E, but not MLA, prevented the induction of behavioral sensitization to cocaine. In contrast, behavioral sensitization was present in rats receiving DH beta E microinjections into the Nacc. Neither antagonist, whether injected into the VTA or the Nacc had any significant effect on the acute locomotor response to cocaine. Given the subtype selectivity of the nicotinic antagonists employed, heteromeric beta 2-containing (beta 2*) nAChRs, but not homomeric alpha 7* nAChRs, in the VTA may be involved in the neuroadaptive changes underlying cocaine sensitization. (c) 2005 Elsevier B.V. All rights reserved.