Nicotine enhances alcohol intake and dopaminergic responses through β2* and β4* nicotinic acetylcholine receptors

Abstract

Alcohol and nicotine are the most widely co-abused drugs. Both modify the activity of dopaminergic (DA) neurons of the Ventral Tegmental Area (VTA) and lead to an increase in DA release in the Nucleus Accumbens, thereby affecting the reward system. Evidences support the hypothesis that distinct nicotinic acetylcholine receptors (nAChRs), the molecular target of acetylcholine (ACh) and exogenous nicotine, are also in addition implicated in the response to alcohol. The precise molecular and neuronal substrates of this interaction are however not well understood. Here we used in vivo electrophysiology in the VTA to characterise acute and chronic interactions between nicotine and alcohol. Simultaneous injections of the two drugs enhanced their responses on VTA DA neuron firing and chronic exposure to nicotine increased alcohol-induced DA responses and alcohol intake. Then, we assessed the role of β4 * nAChRs, but not β2 * nAChRs, in mediating acute responses to alcohol using nAChR subtypes knockout mice (β2−/− and β4−/− mice). Finally, we showed that nicotine-induced modifications of alcohol responses were absent in β2−/− and β4−/− mice, suggesting that nicotine triggers β2* and β4 * nAChR-dependent neuroadaptations that subsequently modify the responses to alcohol and thus indicating these receptors as key mediators in the complex interactions between these two drugs.

Chronic Nicotine Exposure Initiated in Adolescence and Unpaired to Behavioral Context Fails to Enhance Sweetened Ethanol Seeking

“…Synergistic or additive effects on reinforcement circuitry due to co-administration or co-consumption of nicotine and ethanol (Leão et al, 2015 ; Tolu et al, 2017 ) are unlikely to contribute to the present results. The half-life of available nicotine in the brain is approximately 52 min (Ghosheh et al, 1999 ).…”

“…Studies show that co-administration of nicotine increases alcohol seeking (Smith et al, 1999 ; Lê et al, 2014 ; Lárraga et al, 2017 ) and VTA dopamine neuron activity in rodents (Tolu et al, 2017 ). However, this may be due to nicotine’s well-known ability to enhance the reinforcing properties of conditioned cues (Donny et al, 2003 ; Olausson et al, 2004a , b ; Chaudhri et al, 2006 ; Palmatier et al, 2007 , 2013 ; Caggiula et al, 2009 ; Guy and Fletcher, 2014a , b ; Yager and Robinson, 2015 ).…”

Nicotine and alcohol: the role of midbrain dopaminergic neurons in drug reinforcement

“…Consequently, nicotine's priming effect on ethanol consumption is occluded by prior exposure to nAChRs antagonists, involving the nAChRs as a substrate of nicotine‐ethanol interactive effects. In line with these studies, nAChRs inhibition or genetic manipulation of nAChRs also alters ethanol consumption (Blomqvist et al., ; Ericson et al., ) and VTA DA neuron's activity in response to alcohol (Liu et al., ; Tolu et al., ).…”

“…Concomitant acute injection of nicotine and ethanol increases VTA DA neurons firing both in vitro (Clark & Little, ) and in vivo (Tolu et al., ), followed by a subsequent release of DA in the NAc (Tizabi et al., , ). Nicotine and ethanol exhibit an additive effect for ‘low’ doses, which is blunted at higher doses.…”

“…Several studies have shown that pre‐exposure to nicotine increases alcohol consumption (Smith et al., ; Tolu et al., ) and the acquisition of self‐administration (Clark et al., ; Doyon et al., ). As previously mentioned, nicotine exposure directly alters innate VTA DA neuron functionality due to its similarity to ACh mechanism of action, but later promotes the reinforcing properties of other natural reinforces.…”