title: The Nicotinic α6-Subunit Selective Antagonist bPiDI Reduces Alcohol Self-Administration in Alcohol-Preferring Rats.
abstract: Cigarettes and alcohol are the most abused substances in the world and are commonly co-abused. Nicotine primarily acts in the brain on nicotinic acetylcholine receptors (nAChR), which are also a target for alcohol. The alpha6 subunit of nAChR is expressed almost exclusively in the brain reward system and may modulate the rewarding properties of alcohol and nicotine. Recently, N,N-decane-1,10-diyl-bis-3-picolinium diiodide (bPiDI) was synthesized as a selective, brain penetrant α6 subunit antagonist that reduces nicotine self-administration. The current study aimed to examine the effects of bPiDI on alcohol self-administration in inbred alcohol-preferring (iP) rats. Adult, male iP rats were trained to self-administer alcohol or sucrose. Once stable responding was achieved, rats were injected with bPiDI (1, 3 mg/kg, i.p.) and tested for self-administration under fixed and progressive ratio schedules of reinforcement. They subsequently underwent extinction, in which no rewards or cues were presented in the operant chambers. Then, they were injected with bPiDI prior to testing for cue-induced reinstatement of reward seeking. bPiDI (3 mg/kg) significantly reduced alcohol self-administration in both fixed and progressive ratios without any effects on sucrose self-administration or locomotor activity. In contrast, bPiDI (3 mg/kg) did not inhibit cue-induced reinstatement of either alcohol or sucrose seeking. The results support the involvement of α6 containing nAChR in reinforcing effects of alcohol, but not relapse to alcohol-seeking, without any impact on responding for a natural reward or general activity. bPiDI may be a potential lead molecule for a therapeutic strategy to limit nicotine and alcohol consumption.
authors: Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakhon Pathom, Thailand.
authors: Jirawoot
authors: J
authors: Srisontiyakul
authors: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Royal Parade, Parkville, VIC, 3052, Australia.
authors: Hanna E
authors: HE
authors: Kastman
authors: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Royal Parade, Parkville, VIC, 3052, Australia.
authors: Elena V
authors: EV
authors: Krstew
authors: Research Center for Neuroscience, Institute of Molecular Biosciences, Mahidol University, Salaya, Nakhon Pathom, Thailand.|Center for Neuroscience and Department of Pharmacology, Faculty of Science, Mahidol University, Bangkok, Thailand.
authors: Piyarat
authors: P
authors: Govitrapong
authors: Florey Institute of Neuroscience and Mental Health, University of Melbourne, Royal Parade, Parkville, VIC, 3052, Australia. Andrew.Lawrence@florey.edu.au.|Florey Department of Neuroscience, University of Melbourne, Parkville, VIC, Australia. Andrew.Lawrence@florey.edu.au.
authors: Andrew J
authors: AJ
authors: Lawrence
mesh_terms: D000428:Alcohol Drinking / Q000188:drug therapy* / Q000235:genetics / Q000523:psychology; D000818:Animals; D003216:Conditioning, Operant; D003463:Cues; D058999:Drug-Seeking Behavior / Q000187:drug effects; D000431:Ethanol / Q000008:administration & dosage*; D008297:Male; D009042:Motivation / Q000187:drug effects; D018733:Nicotinic Antagonists / Q000494:pharmacology*; D010847:Picolines / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000494:pharmacology*; D011919:Rats, Inbred Strains; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012054:Reinforcement, Psychology; D012646:Self Administration; D013395:Sucrose / Q000008:administration & dosage
chemical_list: C562065:N,N-decane-1,10-diyl-bis-3-picolinium; D018733:Nicotinic Antagonists; D010847:Picolines; D011726:Pyridinium Compounds; D011978:Receptors, Nicotinic; C104518:nicotinic receptor alpha6; D000431:Ethanol; D013395:Sucrose
keywords: Acetylcholine receptor; Alcohol; Alpha6; Nicotinic; Self administration; bPiDI