Short-Term Cocaine Treatment Causes Neuroadaptive Changes in Gα_q and Gα₁₁ Proteins in Rats Undergoing Withdrawal

Abstract

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 G␣ 11 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 G␣ 11 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 G␣ 11 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 G␣ 11 and G␣ q proteins in the amygdala, 5 days of treatment were required to maximally increase the levels of G␣ 11 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.

Cocaine-mediated supersensitivity of 5-HT2A receptors in hypothalamic paraventricular nucleus is a withdrawal-induced phenomenon

“…In contrast, withdrawal from cocaine produces supersensitivity of 5-HT 2A receptors (Carrasco et al, 2003;Carrasco et al, 2004b). In the present study, the (â)DOI-evoked release of corticosterone and prolactin was greater in rats undergoing cocaine withdrawal, a result that is consistent with reports in the literature (Baumann et al, 1993;Baumann and Rothman, 1998;Levy et al, 1992).…”

“…Our present results support this interpretation, as we detected an increase in 125 I-DOI-labeled 5-HT 2A receptors in rats withdrawn from cocaine for 24 h in the absence of increases in the levels of membrane-associated GÎ q and GÎ 11 proteins in the PVN. Importantly, we have reported increases in the levels of membrane-associated GÎ q and GÎ 11 proteins in the PVN that require at least 48 h of withdrawal (Carrasco et al, 2003;Carrasco et al, 2004b), suggesting longer withdrawal times may evoke additional mechanism(s) of supersensitivity of 5-HT 2A receptormediated responses.…”

“…Expression of membrane-and cytosol-associated GÎ q , GÎ 11 and GÎ z proteins was measured by Western blot as previously described (Carrasco et al, 2004b). Negative controls included either omission of primary antibody or addition of pre-immune rabbit immunoglobulins.…”

“…These include: (1) increases in 5-HT 2A receptor-mediated neuroendocrine responses, suggesting supersensitivity of postsynaptic 5-HT 2A receptors in PVN (Levy et al, 1992;Baumann et al, 1993;Baumann and Rothman, 1998); and (2) increases in GÎ q and GÎ 11 G-proteins in the membrane fraction of PVN (Carrasco et al, 2003;Carrasco et al, 2004b). Since agonists and antagonists of 5-HT 2A receptors produces desensitization of 5-HT 2A receptors (Gray and Roth, 2001;Hanley and Hensler, 2002;Damjanoska et al, 2004), the increases in 5-HT 2A receptor signaling during withdrawal from cocaine represents a unique adaptive response of this system.…”

The G-Protein-Coupled Serotonin Receptor SER-1 Regulates Egg Laying and Male Mating Behaviors inCaenorhabditis elegans

“…For example, withdrawal effects are seen with many drugs of abuse, including cocaine, which causes increases in levels of monoamines such as serotonin at synapses. Withdrawal from cocaine has been shown to result in changes of levels of G-proteins and activators of G-protein signaling (Carrasco et al, 2003;Bowers et al, 2004;Carrasco et al, 2004). These initial results suggest that C. elegans may be a useful model system to study mechanisms of withdrawal responses.…”