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Annu Rev Pharmacol Toxicol. 2018 Jan 6;58:547-566. doi: 10.1146/annurev-pharmtox-010617-052735. Epub 2017 Oct 4.

Convergent Neuronal Plasticity and Metaplasticity Mechanisms of Stress, Nicotine, and Alcohol.

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Department of Neuroscience, Mahoney Institute for Neurosciences, Perelman School for Medicine, Philadelphia, Pennsylvania 19104, USA; email: ,


Stress and tobacco smoking are risk factors for alcoholism, but the underlying neural mechanisms are not well understood. Although stress, nicotine, and alcohol have broad, individual effects in the brain, some of their actions converge onto the same mechanisms and circuits. Stress and nicotine augment alcohol-related behaviors, in part via modulation of alcohol-evoked neuronal plasticity and metaplasticity mechanisms. Stress modulates alcohol-evoked plasticity via the release of signaling molecules that influence synaptic transmission. Nicotine also activates some of the same signaling molecules, cells, and circuits, producing a convergence of both stress and nicotine onto common plasticity mechanisms that influence alcohol self-administration. We describe several forms of alcohol-induced plasticity, including classic Hebbian plasticity at glutamatergic synapses, and we highlight less appreciated forms, such as non-Hebbian and GABAergic synaptic plasticity. Risk factors such as stress and nicotine initiate lasting neural changes that modify subsequent alcohol-induced synaptic plasticity and increase the vulnerability to alcohol addiction.


GABA; HPA axis; KCC2; alcohol use disorder; mesolimbic; nucleus accumbens

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