title: Prevention of drug priming- and cue-induced reinstatement of MDMA-seeking behaviors by the CB1 cannabinoid receptor antagonist AM251.
abstract: BACKGROUND
  3,4-Methylenedioxymethamphetamine (MDMA), a methamphetamine (METH) derivative, exhibits METH-like actions at monoamine transporters and positive reinforcing effects in rodents and primates. The purposes of the present study were to determine whether cross-reinstatement would be observed between MDMA and METH and if the cannabinoid receptor, a receptor known to play critical roles in the brain reward system, could modulate MDMA craving.
  
  
  METHODS
  Rats were trained to press a lever for intravenous MDMA (0.3mg/infusion) or METH (0.02mg/infusion) infusions under a fixed ratio 1 schedule paired with drug-associated cues (light and tone). Following drug self-administration acquisition training, rats underwent extinction training (an infusion of saline). Reinstatement tests were performed once the extinction criteria were achieved.
  
  
  RESULTS
  In MDMA-trained rats, the MDMA-priming injection (3.2mg/kg, i.p.) or re-exposure to MDMA-associated cues reinstated MDMA-seeking behavior. Additionally, a priming injection of METH (1.0mg/kg, i.p.) also reinstated MDMA-seeking behavior. In contrast, none of the MDMA doses reinstated METH-seeking behavior in the METH-trained rats. The CB1 cannabinoid receptor antagonist AM251 markedly attenuated the MDMA-seeking behaviors induced by MDMA-priming injection or re-exposure to MDMA-associated cues in a dose-dependent manner.
  
  
  CONCLUSIONS
  These findings show that MDMA has obvious addictive potential for reinstating drug-seeking behavior and that METH can be an effective stimulus for reinstating MDMA-seeking behaviors. Furthermore, based on the attenuating effect of AM251 in the reinstatement of MDMA-seeking behaviors, drugs that suppress CB1 receptors may be used in treatment of MDMA dependence.
authors.affiliation: Department of Pharmacology, Faculty of Pharmaceutical Science, Nagasaki International University, 2825-7 Huis Ten Bosch Sasebo, Nagasaki 859-3298, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Nawata
authors.affiliation: Laboratory of Drug Metabolism and Pharmacokinetics, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan.
authors.forename: Kiyoyuki
authors.initials: K
authors.lastname: Kitaichi
authors.affiliation: Department of Pharmacology, Faculty of Pharmaceutical Science, Nagasaki International University, 2825-7 Huis Ten Bosch Sasebo, Nagasaki 859-3298, Japan. Electronic address: tyamamot@niu.co.jp.
authors.forename: Tsuneyuki
authors.initials: T
authors.lastname: Yamamoto
mesh_terms: D019969:Amphetamine-Related Disorders / Q000188:drug therapy / Q000523:psychology; D000818:Animals; D063387:Cannabinoid Receptor Antagonists / Q000494:pharmacology* / Q000627:therapeutic use; D003463:Cues; D004305:Dose-Response Relationship, Drug; D058999:Drug-Seeking Behavior / Q000187:drug effects*; D005108:Extinction, Psychological / Q000187:drug effects; D008297:Male; D008694:Methamphetamine / Q000031:analogs & derivatives / Q000494:pharmacology*; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000494:pharmacology*; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D012646:Self Administration
chemical_list: D063387:Cannabinoid Receptor Antagonists; D010880:Piperidines; D011720:Pyrazoles; C103505:AM 251; D008694:Methamphetamine; D018817:N-Methyl-3,4-methylenedioxyamphetamine
keywords: CB(1) cannabinoid receptor; Drug-seeking behavior; MDMA; Methamphetamine; Self-administration