title: Heteromeric nicotinic receptors are involved in the sensitization and addictive properties of MDMA in mice.
abstract: We have investigated the effect of nicotinic receptor ligands in the behavioral sensitization (hyperlocomotion) and rewarding properties (conditioned place preference paradigm, CPP) of 3,4-methylenedioxy-methamphetamine (MDMA) in mice. Each animal received intraperitoneal pretreatment with either saline, dihydro-β-erythroidine (DHβE, 1 mg/kg) or varenicline (VAR, 0.3 mg/kg), 15 min prior to subcutaneous saline or MDMA (5 mg/kg), for 10 consecutive days. On day 1, both DHβE and VAR inhibited the MDMA-induced hyperlocomotion. After 10 days of treatment, MDMA induced a hyperlocomotion that was not reduced (rather enhanced) in antagonist-pretreated animals. This early hyperlocomotion was accompanied by a significant increase in heteromeric nicotinic receptors in cortex that was not blocked by DHβE or VAR. Behavioral sensitization to MDMA was highest 2 weeks after the discontinuation of MDMA treatment. This additional increase in sensitivity was prevented in animals pretreated with DHβE or VAR. At this time, MDMA-treated mice showed a significant increase in heteromeric receptors in cortex that was prevented by DHβE and VAR. An involvement of α7 nicotinic receptors in this effect is ruled out. MDMA (10 mg/kg) induced positive CPP that was abolished by DHβE (2 mg/kg) and VAR (2 mg/kg). Moreover, chronic nicotine pretreatment (2 mg/kg, ip, b.i.d., for 14 days) caused MDMA, administered at a low dose (3 mg/kg), to induce CPP, which would otherwise not occur. Finally, present results point out that heteromeric nicotinic receptors are involved in locomotor sensitization and addictive potential induced by MDMA. Thus, varenicline might be a useful drug to treat both tobacco and MDMA abuse at once.
authors: Department of Pharmacology and Therapeutic Chemistry (Pharmacology Section), Institute of Biomedicine (IBUB), University of Barcelona, Barcelona, Spain.
authors: Andrés
authors: A
authors: Ciudad-Roberts
authors: Jorge
authors: J
authors: Camarasa
authors: David
authors: D
authors: Pubill
authors: Elena
authors: E
authors: Escubedo
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects; D018678:Cholinergic Agents / Q000493:pharmacokinetics; D003216:Conditioning, Operant / Q000187:drug effects*; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D006213:Hallucinogens / Q000633:toxicity*; D006948:Hyperkinesis / Q000139:chemically induced* / Q000378:metabolism; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000633:toxicity*; D011485:Protein Binding / Q000187:drug effects; D011810:Quinoxalines / Q000494:pharmacology; D011877:Radionuclide Imaging; D011978:Receptors, Nicotinic / Q000378:metabolism*; D019966:Substance-Related Disorders / Q000209:etiology / Q000378:metabolism* / Q000503:physiopathology; D014316:Tritium / Q000493:pharmacokinetics; D000068580:Varenicline
chemical_list: D001552:Benzazepines; D018678:Cholinergic Agents; D006213:Hallucinogens; D011810:Quinoxalines; D011978:Receptors, Nicotinic; D014316:Tritium; D004079:Dihydro-beta-Erythroidine; D018817:N-Methyl-3,4-methylenedioxyamphetamine; D000068580:Varenicline