To understand the mechanism of methamphetamine (MAP) craving from the viewpoint of nicotinic acetylcholinergic transmission, we examined the responsible site of the brain for anticraving effects produced by nicotinic agonists by using a MAP self-administration paradigm in rats. Systemic nicotine and an acetylcholinesterase inhibitor, donepezil, attenuated the reinstatement of MAP-seeking behavior by means of the activation of nicotinic acetylcholinergic receptors, but not muscarinic acetylcholinergic receptors, in the nucleus accumbens core, prelimbic cortex, amygdala, and hippocampus. Among these regions, with the exception of the hippocampus, we also found functional differences in this reinstatement. The nicotinic antagonist mecamylamine alone did not reinstate MAP-seeking behavior. These results suggest that the inactivation of nicotinic acetylcholinergic transmission may be an essential factor in the appearance of MAP-seeking behavior, and, thus, the normalization of the inactivated state may result in the suppression of the reinstatement. Our findings also indicate that there are functional differences in the responsible brain subregions. Extending this view to the treatment of MAP dependence, our results suggest that activators of nicotinic acetylcholinergic transmission are possible anticraving agents.craving ͉ reinstatement ͉ self-administration T he abuse of the powerfully addictive psychostimulant methamphetamine (MAP) is a growing problem worldwide (1). Many reports on MAP have focused on rewarding effects, drug-taking behavior, or hyperlocomotor activity, whereas few studies have examined the reinstatement of MAP-seeking behavior, a model of human craving.Nicotine is generally known to cause dependence, suggesting the involvement of nicotinic acetylcholine receptors (nAChRs) in the reward system. Recently, the down-regulation of choline acetyltransferase and elevation of the expression of the vesicular acetylcholine transporter have been demonstrated in a MAP user's brain (2), suggesting an inactivated state of acetylcholinergic transmission in the user's brain. In addition, Hikida et al. (3) reported that donepezil, an acetylcholinesterase inhibitor, blocked cocaine-induced behavioral sensitization by means of acetylcholinergic activation in the nucleus accumbens. From this finding, it is hypothesized that the mechanism to induce MAP craving may involve an inactivated state of acetylcholinergic transmission; however, the roles of nAChRs in craving are unknown. In this study, we clarified the roles of nAChRs in MAP-seeking behavior by using an i.v. MAP self-administration paradigm in rats. Furthermore, assuming that systemic nicotine attenuates the reinstatement of MAP-seeking behavior, we examined the responsible brain regions for the nicotine-induced attenuating effect on reinstatement.
ResultsRats were trained to self-administer MAP, followed by withdrawal sessions (on the final day of each phase, active lever responses were 35.8 Ϯ 5.2 and 3.6 Ϯ 0.7, respectively). Reexposure to the MAP-associa...
