Differential regulation of alcohol taking and seeking by antagonism at α4β2 and α3β4 nAChRs
| Autor: | Gregory S. Welmaker, Christopher J. Armishaw, Nurulain T. Zaveri, Marc A. Giulianotti, Andrea Cippitelli, Lawrence Toll, Jinhua Wu, Jennifer Schoch, Gloria Brunori |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Nicotine Alcohol Drinking Drug-Seeking Behavior Self Administration Nicotinic Antagonists Pharmacology Receptors Nicotinic Article Rats Sprague-Dawley 03 medical and health sciences 0302 clinical medicine Mecamylamine medicine Animals Acetylcholine receptor Dose-Response Relationship Drug Ethanol business.industry Antagonist Yohimbine Blockade Rats 030104 developmental biology Nicotinic agonist Self-administration business 030217 neurology & neurosurgery medicine.drug |
| Popis: | RATIONALE: Alcoholism is a serious public health problem throughout the world. Current pharmacotherapies for the treatment of this disorder are poorly effective. Preclinical and clinical findings point to nicotinic acetylcholine receptors (nAChRs) as a promising target for the development of novel and effective medications. Assuage Pharmaceuticals, in collaboration with Torrey Pines Institute for Molecular Studies, has discovered a new class of potent and selective α4β2 nAChRs antagonists. OBJECTIVE: Here it was hypothesized that α4β2 nAChR antagonism is a viable approach for treatment of alcohol use disorders RESULTS: When tested in rats, one lead compound, AP-202, attenuated both operant alcohol and nicotine self-administration in a paradigm in which the two reinforcers were concurrently available. The conotoxin TP2212-59, a selective α3β4 nAChR antagonist, was only effective in reducing nicotine self-administration. AP-202 also reduced alcohol but not food responding when alcohol was presented as the only reinforcer, whereas the commercially available α4β2 nAChR antagonist dihydro-β-erythroidine failed to alter alcohol self-administration. AP-202 did not block relapse-like behavior induced by previously alcohol-associated stimuli or yohimbine stress. In a reinstatement paradigm, in which alcohol seeking was triggered by a nicotine challenge, a behavior successfully inhibited by the nonselective nAChR antagonist mecamylamine, AP-202 was not effective, while pretreatment with TP2212-59 abolished nicotine-induced reinstatement of alcohol seeking. CONCLUSIONS: These findings suggest differential roles for α4β2 and α3β4 nAChR on alcohol taking and seeking with selective blockade of α4β2 nAChR being more implicated in modulating alcohol taking while selective blockade of α3β4 nAChR is involved in nicotine-induced alcohol seeking. |
| Databáze: | OpenAIRE |
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