title: Chronic nicotine activates stress/reward-related brain regions and facilitates the transition to compulsive alcohol drinking.
abstract: Alcohol and nicotine are the two most co-abused drugs in the world. Previous studies have shown that nicotine can increase alcohol drinking in nondependent rats, yet it is unknown whether nicotine facilitates the transition to alcohol dependence. We tested the hypothesis that chronic nicotine will speed up the escalation of alcohol drinking in rats and that this effect will be accompanied by activation of sparsely distributed neurons (neuronal ensembles) throughout the brain that are specifically recruited by the combination of nicotine and alcohol. Rats were trained to respond for alcohol and made dependent using chronic, intermittent exposure to alcohol vapor, while receiving daily nicotine (0.8 mg/kg) injections. Identification of neuronal ensembles was performed after the last operant session, using immunohistochemistry. Nicotine produced an early escalation of alcohol drinking associated with compulsive alcohol drinking in dependent, but not in nondependent rats (air exposed), as measured by increased progressive-ratio responding and increased responding despite adverse consequences. The combination of nicotine and alcohol produced the recruitment of discrete and phenotype-specific neuronal ensembles (∼4-13% of total neuronal population) in the nucleus accumbens core, dorsomedial prefrontal cortex, central nucleus of the amygdala, bed nucleus of stria terminalis, and posterior ventral tegmental area. Blockade of nicotinic receptors using mecamylamine (1 mg/kg) prevented both the behavioral and neuronal effects of nicotine in dependent rats. These results demonstrate that nicotine and activation of nicotinic receptors are critical factors in the development of alcohol dependence through the dysregulation of a set of interconnected neuronal ensembles throughout the brain.
authors: Laboratory of Pharmacology, Department of Natural Active Principles and Toxicology, School of Pharmaceutical Sciences, Universidade Estadual Paulista - UNESP, Araraquara, Sao Paulo 14801-902, Brazil, Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037, and Behavioral Neuroscience Branch, IRP/NIDA/NIH/DHHS, Baltimore, Maryland 21224 ogeorge@scripps.edu rodrigomolini@yahoo.com.br.
authors: Rodrigo M
authors: RM
authors: Leão
authors: Behavioral Neuroscience Branch, IRP/NIDA/NIH/DHHS, Baltimore, Maryland 21224.
authors: Fábio C
authors: FC
authors: Cruz
authors: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037, and Behavioral Neuroscience Branch, IRP/NIDA/NIH/DHHS, Baltimore, Maryland 21224.
authors: Leandro F
authors: http://orcid.org/0000-0002-8829-8627
authors: LF
authors: Vendruscolo
authors: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037, and.
authors: Giordano
authors: G
authors: de Guglielmo
authors: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037, and.
authors: Marian L
authors: ML
authors: Logrip
authors: Laboratory of Pharmacology, Department of Natural Active Principles and Toxicology, School of Pharmaceutical Sciences, Universidade Estadual Paulista - UNESP, Araraquara, Sao Paulo 14801-902, Brazil.
authors: Cleopatra S
authors: CS
authors: Planeta
authors: Behavioral Neuroscience Branch, IRP/NIDA/NIH/DHHS, Baltimore, Maryland 21224.
authors: Bruce T
authors: BT
authors: Hope
authors: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037, and.
authors: George F
authors: GF
authors: Koob
authors: Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, California 92037, and ogeorge@scripps.edu rodrigomolini@yahoo.com.br.
authors: Olivier
authors: http://orcid.org/0000-0002-3700-5003
authors: O
authors: George
mesh_terms: D000428:Alcohol Drinking / Q000503:physiopathology*; D000818:Animals; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002492:Central Nervous System Depressants / Q000008:administration & dosage; D003192:Compulsive Behavior / Q000150:complications*; D003216:Conditioning, Operant / Q000187:drug effects; D004195:Disease Models, Animal; D000431:Ethanol / Q000008:administration & dosage; D005968:Glutamate Decarboxylase / Q000378:metabolism; D008297:Male; D009538:Nicotine / Q000009:adverse effects*; D018722:Nicotinic Agonists / Q000009:adverse effects*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D011803:Quinine / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D012201:Reward; D012646:Self Administration; D013997:Time Factors
chemical_list: D002492:Central Nervous System Depressants; D018722:Nicotinic Agonists; D016760:Proto-Oncogene Proteins c-fos; D000431:Ethanol; D009538:Nicotine; D011803:Quinine; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D010751:Phosphopyruvate Hydratase
keywords: Fos; addiction; alcohol; compulsivity; neuronal ensembles; tobacco