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...

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( + /À)-3,4-Methylenedioxymethamphetamine (MDMA, 'Ecstasy') abusers have persistent neuropsychiatric deficits including memory impairments after the cessation of abuse. On the other hand, cannabinoid CB 1 receptors have been implicated in learning/memory, and are highly expressed in the hippocampus, a region of the brain believed to have an important function in certain forms of learning and memory. In this study, we clarified the mechanism underlying the cognitive impairment that develops during MDMA withdrawal from the standpoint of the cannabinoid CB 1 receptors. Mice were administered MDMA (10 mg/kg, i.p.) once a day for 7 days. On the 7th day of withdrawal, a novel object recognition task was performed and the amount of cannabinoid CB 1 receptor protein was measured with western blotting. Recognition performance was impaired on the 7th day of withdrawal. This impairment was blocked by AM251, a cannabinoid CB 1 receptor antagonist, administered 30 min before the training trial or co-administered with MDMA. At this time, the level of cannabinoid CB 1 receptor protein increased significantly in the hippocampus but not the prefrontal cortex or striatum. This increase of CB 1 receptor protein in the hippocampus was also blocked by the co-administration of AM251. Furthermore, CB 1 receptor knockout mice showed no impairment of recognition performance on the withdrawal from MDMA. The impairment of recognition memory during withdrawal from MDMA may result from the activation of cannabinoid CB 1 receptors in the hippocampus.

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BackgroundMethamphetamine is a highly addictive psychostimulant with reinforcing properties. Our laboratory previously found that Δ8-tetrahydrocannabinol, an exogenous cannabinoid, suppressed the reinstatement of methamphetamine-seeking behavior. The purpose of this study was to determine whether the elevation of endocannabinoids modulates the reinstatement of methamphetamine-seeking behavior and emotional changes in methamphetamine self-administered rats.MethodsRats were tested for the reinstatement of methamphetamine-seeking behavior following methamphetamine self-administration and extinction. The elevated plus-maze test was performed in methamphetamine self-administered rats during withdrawal. We investigated the effects of JZL184 and URB597, 2 inhibitors of endocannabinoid hydrolysis, on the reinstatement of methamphetamine-seeking and anxiety-like behaviors.ResultsJZL184 (32 and 40 mg/kg, i.p.), an inhibitor of monoacylglycerol lipase, significantly attenuated both the cue- and stress-induced reinstatement of methamphetamine-seeking behavior. Furthermore, URB597 (3.2 and 10 mg/kg, i.p.), an inhibitor of fatty acid amide hydrolase, attenuated only cue-induced reinstatement. AM251, a cannabinoid CB1 receptor antagonist, antagonized the attenuation of cue-induced reinstatement by JZL184 but not URB597. Neither JZL184 nor URB597 reinstated methamphetamine-seeking behavior when administered alone. In the elevated plus-maze test, rats that were in withdrawal from methamphetamine self-administration spent less time in the open arms. JZL184 ameliorated the decrease in time spent in the open arms.ConclusionWe showed that JZL184 reduced both the cue- and stress-induced reinstatement of methamphetamine-seeking and anxiety-like behaviors in rats that had self-administered methamphetamine. It was suggested that a decrease in 2-arachidonoylglycerol in the brain could drive the reinstatement of methamphetamine-seeking and anxiety-like behaviors.

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