Abstract
We have previously documented that chronic alcohol consumption or alcohol withdrawal affects μ-opioid receptor density and receptor-mediated G protein coupling in Fawn-Hooded (FH) rat brain, especially in mesolimbic regions. FH rats demonstrate comorbid depression and high voluntary alcohol consumption; treatment with standard antidepressants improves both facets of this phenotype. Accordingly, we sought to examine whether μ-opioid receptor binding and the receptor-mediated functional coupling to G protein is affected by this drug treatment. Using quantitative autoradiography, binding of μ-opioid receptors labeled by [125I]FK33,824 (d-Ala2,N-Me-Phe4,Met(O)5-ol enkephalin) and the coupling between receptors and G proteins determined by agonist-stimulated guanosine 5′-O -(3-[35S]thio)triphosphate ([35S]GTPγS) binding was mapped throughout brain sections of FH rats after 10-day treatment with vehicle, desipramine, or sertraline. Both desipramine and sertraline produced significant decreases of [125I]FK33,824 binding in many brain regions; 13 of 20 measured regions for desipramine and 16 of 20 measured regions for sertraline. The coupling efficiency of μ-opioid receptors to G proteins was determined by an increase of [35S]GTPγS binding induced by stimulation with the μ-opioid receptor agonist [d-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (10 μM). In contrast to the receptor binding profile, functional coupling of receptors to G proteins was only significantly reduced in the amygdala, whereas it remained unchanged in other regions compared with control. The present findings suggest that antidepressants regulate opioid systems; however, this occurs differentially, and region-specific alteration of functional coupling of μ-opioid receptors to G proteins in the amygdala suggests that opioid function within the amygdala may be modulated by antidepressants.
Footnotes
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This study was supported by grants from the National Health and Medical Research Council of Australia, of which A.J.L. is a Senior Research Fellow.
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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.104.068692.
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ABBREVIATIONS: ATD, antidepressant; TCA, tricyclic antidepressant; SSRI, selective serotonin reuptake inhibitor; FH rat, Fawn-Hooded rat; FK33,824, d-Ala2,N-Me-Phe4,Met(O)5-ol enkephalin; [35S]GTPγS, guanosine 5′-O-(3-[35S]thio)triphosphate; DAMGO, [d-Ala2,N-Me-Phe4-Gly5-ol]-enkephalin; DMI, desipramine; DMSO, dimethyl sulfoxide; NAcc, nucleus accumbens; VP, ventral pallidum; VTA, ventral tegmental area; ANOVA, analysis of variance; CPu, caudate-putamen; FStr, fundus striatum; olivary pretectal nucleus.
- Received March 21, 2004.
- Accepted April 28, 2004.
- The American Society for Pharmacology and Experimental Therapeutics
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