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"Elevation of TRPV1 function in the lateral habenula mediates aversive behaviors during alcohol withdrawal"

Danielle Gregor
Cell Biology, Neuroscience and Physiology
B.A., 2011, Drew University, Madison, NJ

Thesis Advisor: Jiang-Hong Ye, M.D., M.Sc.
Department of Anesthesiology
Pharmacology & Physiology

Tuesday, November 28, 2017
1:00 P.M., MSB Room B610


Background: TRPV1, a vanilloid receptor, is expressed in the lateral habenula (LHb), a brain structure important for the pathophysiology of abused drugs, including alcohol. Alcoholics often suffer from pain, anxiety, and depression. However, whether LHb TRPV1 contributes to these ailments remains unknown.
Methods: We examined the effects of TRPV1 agonist (capsaicin) and antagonist (capsazepine) on the following outcomes in rats: (1) spontaneous EPSCs (sEPSCs) and spiking of LHb neurons; (2) pain, anxiety- and depressive-like behaviors; and (3) ethanol intake.
Results: Comparing the frequency of sEPSCs and spiking of LHb neurons in brain slices of ethanol-withdrawn rats with those of ethanol-na´ve rats, the basal rate was higher, capsazepine-induced inhibition was stronger, but the potentiation induced by capsaicin and acute ethanol was weaker. Conversely, capsazepine-induced inhibition on the potentiation induced by acute ethanol was stronger.
Hyperalgesia, anxiety- and depressive-like behaviors were observed in ethanol-withdrawn rats and in ethanol-na´ve rats that received an intra-LHb infusion of capsaicin. In withdrawn rats, intra-LHb infusion of capsazepine attenuated these aberrant behaviors, decreased alcohol consumption upon resuming drinking, and elicited a conditioned place preference. Intriguingly, capsaicin mimicked the effects of capsazepine during withdrawal.
Conclusions: Enhanced TRPV1 function may contribute to increased glutamate transmission and activity of LHb neurons, and consequently the aberrant behaviors during ethanol withdrawal. These results have identified TRPV1 in LHb as a key molecular determinant regulating negative emotions, which may help to understand the molecular and cellular basis of alcoholism.

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