[Show abstract][Hide abstract] ABSTRACT: Recent evidence suggests the involvement of corticotropin-releasing factor (CRF) in drug abuse. Here, we evaluated whether CRF modulates the reinstatement of methamphetamine (METH)-seeking behavior induced by stress using a drug-self administration paradigm in rats. Rats were trained to lever-press for intravenous METH (0.02 mg/infusion) accompanied by light and tone (drug-associated cues) and then underwent extinction training (saline substituted for METH without cues). Under the extinction condition, the inhibitory effects of a CRF receptor antagonist on the stress-induced reinstatement of METH-seeking behavior were assessed. Anxiety-like behaviors during METH withdrawal in METH self-administered rats were also evaluated. The non-selective CRF receptor antagonist α-helical CRF(9-41) attenuated METH-seeking behavior induced by footshock stress. CRF levels both in the amygdala and in plasma were significantly increased on day 10 of withdrawal after METH self-administration. However, plasma corticosterone concentrations were unchanged during the withdrawal. In addition, METH-seeking behavior was not affected by an inhibitor of corticosterone synthesis, metyrapone. In the elevated plus maze test, METH self-administered rats showed a decrease in the duration of time spent in the open arms on day 10 of withdrawal. The increased CRF levels in the amygdala may, at least in part, contribute to the footshock-induced reinstatement of METH-seeking behavior and the increase in anxiety-like behavior. The present findings indicate that CRF receptor antagonists would be useful as a therapeutic agent for METH-dependence.
[Show abstract][Hide abstract] ABSTRACT: Relapse to drug craving is problematic in treatment for drug abuse. Evidence suggests inactivation of dopaminergic neurotransmission during drug withdrawal. Meanwhile, a tryptamine analogue, (-)-1-(benzofuran-2-yl)-2-propylaminopentane [(-)-BPAP], has been reported to enhance electrical stimulation of monoamine release. This study examined the effect of (-)-BPAP on reinstatement of methamphetamine-seeking behavior in an animal model of relapse to drug abuse. Rats were trained to i.v. self-administer methamphetamine paired with a light and tone (methamphetamine-associated cues) under a fixed-ratio 1 schedule of reinforcement for 10 days. After extinction session under saline infusions without cues, a reinstatement test under saline infusions was begun. Reinstatement induced by methamphetamine-associated cues or methamphetamine-priming injections was attenuated by repeated administration of (-)-BPAP during the extinction phase. Acute administration of (-)-BPAP on test day dose-dependently attenuated both reinstatements. Acute administration of (-)-BPAP neither reinstated methamphetamine-seeking behavior alone nor affected methamphetamine self-administration. Pretreatment with either R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SCH-23390), a dopamine D(1)-like receptor antagonist, or amisulpride, a dopamine D(2)-like receptor antagonist, did not appreciably affected the acute effect of (-)-BPAP on both reinstatements. Co-pretreatment with the dopamine receptor antagonists failed to alter the effects of (-)-BPAP. Meanwhile, pretreatment with a dopamine D(1)-like receptor agonist, (+/-)-6-chloro-7,8-dihydroxy-l-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF-81297), dose-dependently attenuated reinstatement induced by the cues or methamphetamine-priming injections. In contrast to (-)-BPAP, pretreatment with SCH-23390 reversed the effects of SKF-81297. Our findings suggest activation of dopamine D(1)-like receptors results in attenuation of the reinstatement of methamphetamine-seeking behavior. Additionally, our findings provide evidence to develop (-)-BPAP and dopamine D(1)-like receptor agonists as an anti-relapse medication for methamphetamine abusers.
[Show abstract][Hide abstract] ABSTRACT: (+/-)-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.
Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 10/2009; 35(2):515-20. DOI:10.1038/npp.2009.158 · 7.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We previously reported the involvement of cannabinoid CB1 receptors (CB1Rs) and nicotinic acetylcholine receptors (nAChRs) in the reinstatement of methamphetamine (MAP)-seeking behavior (lever-pressing response for MAP reinforcement under saline infusion). The present study examined whether the reinstatement involves interactions between these receptors. Rats were trained to self-administer MAP with a light and tone (MAP-associated cues). Then, extinction sessions under saline infusion without cues were conducted. After that, a reinstatement tests were conducted by either presenting the cues or a MAP-priming injection. Systemic and intracranial administration of HU210, a cannabinoid CB1R agonist, into the nucleus accumbens core (NAC) and prelimbic cortex (PrC) reinstated MAP-seeking behavior. The reinstatement caused by the systemic HU210 treatment was attenuated by intracranial administration of AM251, a cannabinoid CB1R antagonist, into each region mentioned above. Meanwhile, reinstatement induced by the MAP-associated cues and MAP-priming injection was also attenuated by intracranial administration of AM251 in each region. In these regions, the attenuating effects of AM251 on the reinstatement induced by each stimulus were blocked by the intracranial administration of mecamylamine, a non-selective nAChR antagonist, but not by scopolamine, a muscarinic ACh receptor (mAChR) antagonist. Furthermore, the intracranial administration of DHbetaE, an alpha4beta2 nAChR antagonist, but not MLA, an alpha7 nAChR antagonist, into each region blocked the AM251-induced attenuation of the reinstatement. These findings suggest that relapses to MAP-seeking behavior may be due to two steps, first inhibition of ACh transmission by the activation of cannabinoid CB1Rs and then the inactivation of alpha4beta2 nAChRs.
[Show abstract][Hide abstract] ABSTRACT: The drug self-administration procedure is necessary for the study of addiction in terms of two similarities with human. One similarity is drug taking pattern, and the other is reinstatement of drug-seeking responses after the withdrawal. This procedure consists of two phase, called as the acquisition of drug taking behavior and the extinction. The drug taking behavior is formed on the base of reinforcing effects of drug under a fixed ratio schedule. On the other hands, a progressive ratio schedule is a useful procedure to estimate the potency of reinforcing/rewarding effect. Clinically, drug craving can be triggered by taking the other drug which has the effects similar to abused drug, by stimuli previously associated with drug-taking, or by exposure to stressors. In preclinical study, these three initiating factors also reinstate drug-seeking. From the studies that clarify the responsible brain regions, the importance of the nucleus accumbens, prefrontal cortex and hippocampus is clarified. The brain regions associated with drug craving are identified using a PET and fMRI technologies. In the future study, it is expected to integrate/reconstruct between the identified brain regions that provoke drug craving in humans and responsible brain regions that induce reinstatement of drug-seeking in animal model of drug dependence.
Nihon Arukōru Yakubutsu Igakkai zasshi = Japanese journal of alcohol studies & drug dependence 06/2008; 43(3):158-65.
[Show abstract][Hide abstract] ABSTRACT: 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.
Proceedings of the National Academy of Sciences 06/2006; 103(22):8523-7. DOI:10.1073/pnas.0600347103 · 9.67 Impact Factor