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-HT2A) receptors, which is accompanied by increases in the levels of Gαq and Gα11 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 Gαq and Gα11 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 Gαq and Gα11 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 Gα11 and Gαq proteins in the amygdala, 5 days of treatment were required to maximally increase the levels of Gα11 and Gαq 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-HT2A receptor signal transduction system in regulating the overall sensitivity of this signaling in cocaine-treated rats.
Footnotes
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This study was supported by United States Health Service Grant DA13669 (to L.D.V.d.K.), MH068612 (to N.A.M.), and DA07741 (to G.B).
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.104.069807.
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ABBREVIATIONS: 5-HT, 5-hydroxytryptamine (serotonin); ACTH, adrenocorticotropic hormone; DOI, (±)-1-(2,5 dimethoxy-4-iodophenyl)-2-amino-propane HCl; RGS, regulators of G protein signaling; IOD, integrated optical density; ANOVA, analysis of variance; AGS, activator of G protein signaling; MDL 100,907 (+)-〈-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidinemethanol.
- Received April 8, 2004.
- Accepted June 1, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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