Nicotinic Acetylcholine Receptors Containing the α4 Subunit Modulate Alcohol Reward

doi:10.1016/j.biopsych.2012.09.019

Biological Psychiatry

Volume 73, Issue 8, 15 April 2013, Pages 738-746

https://doi.org/10.1016/j.biopsych.2012.09.019 Get rights and content

Background

Nicotine and alcohol are the two most co-abused drugs in the world, suggesting a common mechanism of action might underlie their rewarding properties. Although nicotine elicits reward by activating ventral tegmental area dopaminergic (DAergic) neurons via high-affinity neuronal nicotinic acetylcholine receptors (nAChRs), the mechanism by which alcohol activates these neurons is unclear.

Methods

Because most high-affinity nAChRs expressed in ventral tegmental area DAergic neurons contain the α4 subunit, we measured ethanol-induced activation of DAergic neurons in midbrain slices from two complementary mouse models, an α4 knock-out (KO) mouse line and a knock-in line (Leu9′Ala) expressing α4 subunit-containing nAChRs hypersensitive to agonist compared with wild-type (WT). Activation of DAergic neurons by ethanol was analyzed with both biophysical and immunohistochemical approaches in midbrain slices. The ability of alcohol to condition a place preference in each mouse model was also measured.

Results

At intoxicating concentrations, ethanol activation of DAergic neurons was significantly reduced in α4 KO mice compared with WT. Conversely, in Leu9′Ala mice, DAergic neurons were activated by low ethanol concentrations that did not increase activity of WT neurons. In addition, alcohol potentiated the response to ACh in DAergic neurons, an effect reduced in α4 KO mice. Rewarding alcohol doses failed to condition a place preference in α4 KO mice, paralleling alcohol effects on DAergic neuron activity, whereas a sub-rewarding alcohol dose was sufficient to condition a place preference in Leu9′Ala mice.

Conclusions

Together, these data indicate that nAChRs containing the α4 subunit modulate alcohol reward.

Section snippets

Animals

C57BL/6J mice (Jackson Laboratory, West Grove, Pennsylvania) were used in all experiments in addition to α4 knock-out (KO) homozygous mice, Leu9′Ala heterozygous, and their respective wild-type (WT) littermates as indicated. All experiments were conducted in accordance with the guidelines for care and use of laboratory animals provided by the National Research Council (26) as well as with an approved animal protocol from the Institutional Animal Care and Use Committee of the University of

Results

Cell-attached patch clamp recordings were made from VTA DAergic neurons in C57BL/6J mouse slices. Slices were cut in the sagittal plane, allowing for preservation of cholinergic input from lateral dorsal tegmentum into the VTA (Supplement 1). To test the effects of ethanol on DAergic neuron activity, AP frequency was monitored in cell-attached mode at baseline, during application of an intoxicating concentration of alcohol (100 mmol/L), and after wash-out. Because the focus of our experiments

Discussion

Alcohol and nicotine are often co-abused, suggesting that they might share a common mechanism of action in the central nervous system. Here we show that, in VTA midbrain slices, alcohol significantly increased DAergic neuron activity, an effect that was blocked by mecamylamine—indicating a critical role for nAChRs in alcohol-induced activation of these neurons. This observation is also in agreement with our previous data illustrating that mecamylamine prevents alcohol-induced c-Fos expression

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: Authors LL, LMH, and MJG contributed equally to this work.

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Archival ReportNicotinic Acetylcholine Receptors Containing the α4 Subunit Modulate Alcohol Reward

Background

Methods

Results

Conclusions

Section snippets

Animals

Results

Discussion

Eur J Pharmacol

Eur J Pharmacol

Eur J Pharmacol

Biol Psychiatry

Alcohol

Alcohol

Eur J Pharmacol

Biochem Pharmacol

Alcohol

Relationship between alcohol and tobacco dependencies among alcoholics who smoke

Addiction

Mortality following inpatient addictions treatment. Role of tobacco use in a community-based cohort

JAMA

Intracranial self-administration of ethanol within the ventral tegmental area of male Wistar rats: Evidence for involvement of dopamine neurons

J Neurosci

Hyperpolarization-activated cation current (Ih) is an ethanol target in midbrain dopamine neurons of mice

J Neurophysiol

Phasic firing in dopaminergic neurons is sufficient for behavioral conditioning

Science

Nicotine activates and desensitizes midbrain dopamine neurons

Nature

Nicotine reinforcement and cognition restored by targeted expression of nicotinic receptors

Nature

Serotonin-3 receptors in the actions of alcohol, alcohol reinforcement, and alcoholism

Alcohol Clin Exp Res

Acute alcohol action and desensitization of ligand-gated ion channels

Pharmacol Rev

Mammalian nicotinic acetylcholine receptors: From structure to function

Physiol Rev

Neuronal nicotinic acetylcholine receptors and nicotine dependence

The neurobiology of nicotine addiction: Bridging the gap from molecules to behaviour

Nat Rev Neurosci

Voluntary ethanol intake increases extracellular acetylcholine levels in the ventral tegmental area in the rat

Alcohol Alcohol

Effects of ethanol on recombinant human neuronal nicotinic acetylcholine receptors expressed in Xenopus oocytes

J Pharmacol Exp Ther

Alcohol modulation of neuronal nicotinic acetylcholine receptors is alpha subunit dependent

Alcohol Clin Exp Res

Archival Report
Nicotinic Acetylcholine Receptors Containing the α4 Subunit Modulate Alcohol Reward