Nicotine enhances alcohol intake and dopaminergic responses through β2* and β4* nicotinic acetylcholine receptors.
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.
Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Neurosciences Paris Seine - Institut de Biologie Paris Seine (NPS - IBPS), 75005, Paris, France.
Stefania
S
Tolu
Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Neurosciences Paris Seine - Institut de Biologie Paris Seine (NPS - IBPS), 75005, Paris, France.
Fabio
F
Marti
Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Neurosciences Paris Seine - Institut de Biologie Paris Seine (NPS - IBPS), 75005, Paris, France.
Carole
C
Morel
Groupe Hospitalier Paul Guiraud, BP 20065, F-94806, Villejuif, France.
Carole
C
Perrier
Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Neurosciences Paris Seine - Institut de Biologie Paris Seine (NPS - IBPS), 75005, Paris, France.
Nicolas
N
Torquet
Institut Pasteur, Unité Neurobiologie Intégrative des Systèmes Cholinergiques, Département de Neuroscience, F-75724, Paris, France.|CNRS, UMR 3571, F-75724, Paris, France.
Stephanie
S
Pons
Groupe Hospitalier Paul Guiraud, BP 20065, F-94806, Villejuif, France.
Renaud
R
de Beaurepaire
Sorbonne Universités, UPMC Univ Paris 06, INSERM, CNRS, Neurosciences Paris Seine - Institut de Biologie Paris Seine (NPS - IBPS), 75005, Paris, France.
Philippe
P
Faure
D000200:Action Potentials / Q000187:drug effects; D000438:Alcohols / Q000494:pharmacology*; D000818:Animals; D059290:Dopaminergic Neurons / Q000187:drug effects* / Q000378:metabolism*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D009538:Nicotine / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D012201:Reward
D000438:Alcohols; D009419:Nerve Tissue Proteins; D009538:Nicotine; D011978:Receptors, Nicotinic; C486720:Chrnb4 protein, mouse