GABA is an inhibitory neurotransmitter that decreases nerve signaling in the brain. When a person experiences stress, their GABA levels can decrease, causing some neurons to become hyperactive. Using an animal model, Burt Sharp and colleagues wanted to find out if giving rats compounds that stimulate GABA_A, a specific type of GABA receptor, on certain neurons, called basolateral amygdala principal output neurons, could lessen the rats' relapse to nicotine during stressful conditions.

In the animal model, rats were taught to press a lever to self-administer nicotine. After a week, the animals were withdrawn from nicotine for 8 days. To cause stress, the researchers confined the rats in a small space. After releasing the rodents, the team injected one of three compounds, called positive allosteric modulators of GABA_A, or PAMs, into a specific region of the stressed rats' brains, and then gave them access to the nicotine-administering levers. Untreated stressed rats pressed the levers about 1.5 times more frequently than they had before the abstinence period, while rats treated with any of the PAMs reduced nicotine intake to levels seen in unstressed rats before the abstinence period. If similar effects are confirmed in humans, novel, selective PAMs could be helpful in alleviating the stress-induced relapse to smoked tobacco, with potentially fewer side effects than GABA administration, the researchers say.

The authors acknowledge the gift of NS16085 from Karin S. Nielsen at Saniona AB, Denmark and partial funding from Lohocla Research, Inc.

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Materials provided by American Chemical Society. Note: Content may be edited for style and length.

Journal Reference:

1. Burt M. Sharp, Qin Jiang, Xenia Simeone, Petra Scholze. Allosteric Modulation of GABA_A Receptors in Rat Basolateral Amygdala Blocks Stress-Enhanced Reacquisition of Nicotine Self-Administration. ACS Pharmacology & Translational Science, 2020; DOI: 10.1021/acsptsci.0c00111