Abstract
We clarified the modulating action of the endocannabinoid system, and its possible mediation by the arachidonic acid cascade, on the reinstatement of methamphetamine (METH)-seeking behavior, using the intravenous self-administration paradigm in rats. Following 12 days of self-administration of METH, the replacement of METH with saline resulted in a gradual decrease in lever press responses (extinction). Under extinction conditions, METH-priming or re-exposure to cues previously paired with METH infusion markedly increased the responses (reinstatement of drug-seeking). The cannabinoid CB1 receptor antagonist, SR141716A, blocked this behavior. Although the cannabinoid agonist, Δ8-tetrahydrocannabinol (THC), had no effects by itself, coadministration of the agonist and METH at small doses reinstated the drug-seeking behavior. THC attenuated the effects of the reinstatement-inducing dose of METH, but enhanced the effect of cues. Either given repeatedly during the extinction or singly, 24 h before the first METH-priming or cues challenge, THC suppressed the reinstatement. In another set of experiments, we found that diclofenac, a cyclooxygenase inhibitor, also attenuated the reinstatement induced by exposure to cues or drug-priming. These results suggest that the endocannabinoid system, through possible mediation by the arachidonic acid cascade, serves as a modulator of the reinstating effects of METH-priming and cues. Extending the current view on the treatment of drug dependence, these results indicate that endocannabinoid-activating substances as well as cyclooxygenase inhibitors may be promising as antirelapse agents.
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Acknowledgements
We thank Dr Hiroyuki Tanaka and Prof Yukihiro Shoyama for the isolation and purification of Δ8-tetrahydrocannabinol.
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Anggadiredja, K., Nakamichi, M., Hiranita, T. et al. Endocannabinoid System Modulates Relapse to Methamphetamine Seeking: Possible Mediation by the Arachidonic Acid Cascade. Neuropsychopharmacol 29, 1470–1478 (2004). https://doi.org/10.1038/sj.npp.1300454
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DOI: https://doi.org/10.1038/sj.npp.1300454
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