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NEUROPHARMACOLOGY

Short-Term Cocaine Treatment Causes Neuroadaptive Changes in G_q and G₁₁ Proteins in Rats Undergoing Withdrawal

Center for Serotonin Disorders Research and Department of Pharmacology Loyola University of Chicago, Stritch School of Medicine, Maywood, Illinois

One of the characteristics of drug dependence is that a drug has to be administered repeatedly before withdrawal effects can be observed. We have previously shown that withdrawal after 14 days of cocaine treatment produces a supersensitivity of hypothalamic 5-hydroxytryptamine (serotonin) 2A (5-HT_2A) receptors, which is accompanied by increases in the levels of G_q and G₁₁ proteins. Unfortunately, the exact duration of cocaine treatment necessary to induce alterations in G protein levels during cocaine withdrawal is unknown. The present study investigated the minimum cocaine treatment period required to produce changes in protein levels of membrane- and cytosol-associated G_q and G₁₁ proteins in the hypothalamic paraventricular nucleus, amygdala, and frontal cortex. Rats were injected with cocaine (15 mg/kg i.p., b.i.d.) for 0, 1, 3, 5, and 7 days and tested after 2 days of withdrawal. The levels of G_q and G₁₁ proteins were increased in the paraventricular nucleus and the amygdala but not in the frontal cortex. Although 1 and 3 days of cocaine treatment were sufficient to maximally elevate the protein levels of G₁₁ and G_q proteins in the amygdala, 5 days of treatment were required to maximally increase the levels of G₁₁ and G_q proteins in the paraventricular nucleus. The data suggest that the amygdala shows a faster neuroadaptation to the effects of cocaine than the hypothalamic paraventricular nucleus. These findings provide insight into the relative importance of individual components of 5-HT_2A receptor signal transduction system in regulating the overall sensitivity of this signaling in cocaine-treated rats.

Address correspondence to: Dr. Louis D. Van de Kar, Department of Pharmacology, Loyola University of Chicago, Stritch School of Medicine, 2160 South First Ave., Maywood, IL 60153. E-mail: lvandek{at}lumc.edu

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