Chronic nicotine activates stress/reward-related brain regions and facilitates the transition to compulsive alcohol drinking.
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.
['Leão|Rodrigo M|RM|', 'Cruz|Fábio C|FC|', 'Vendruscolo|Leandro F|LF|http://orcid.org/0000-0002-8829-8627', 'de Guglielmo|Giordano|G|', 'Logrip|Marian L|ML|', 'Planeta|Cleopatra S|CS|', 'Hope|Bruce T|BT|', 'Koob|George F|GF|', 'George|Olivier|O|http://orcid.org/0000-0002-3700-5003']
D000428:Alcohol Drinking D000818:Animals D001921:Brain D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 D002492:Central Nervous System Depressants D003192:Compulsive Behavior D003216:Conditioning, Operant D004195:Disease Models, Animal D000431:Ethanol D005968:Glutamate Decarboxylase D008297:Male D009538:Nicotine D018722:Nicotinic Agonists D010751:Phosphopyruvate Hydratase D016760:Proto-Oncogene Proteins c-fos D011803:Quinine D051381:Rats D017208:Rats, Wistar D012201:Reward D012646:Self Administration D013997:Time Factors
compulsivity alcohol neuronal ensembles Fos addiction tobacco