Chronic antidepressant treatment causes a selective reduction of mu-opioid receptor binding and functional coupling to G Proteins in the amygdala of fawn-hooded rats.
We have previously documented that chronic alcohol consumption or alcohol withdrawal affects mu-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 mu-opioid receptor binding and the receptor-mediated functional coupling to G protein is affected by this drug treatment. Using quantitative autoradiography, binding of mu-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]GTPgammaS) 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 mu-opioid receptors to G proteins was determined by an increase of [35S]GTPgammaS binding induced by stimulation with the mu-opioid receptor agonist [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (10 microM). 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 mu-opioid receptors to G proteins in the amygdala suggests that opioid function within the amygdala may be modulated by antidepressants.
Chen
Feng
F
Howard Florey Institute, The University of Melbourne, Parkville, Victoria 3010, Australia. f.chen@hfi.unimelb.edu.au
Lawrence
Andrew J
AJ
D000679:Amygdala / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D005405:D-Ala(2),MePhe(4),Met(0)-ol-enkephalin / Q000494:pharmacology; D003891:Desipramine / Q000494:pharmacology; D004347:Drug Interactions; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D008297:Male; D051381:Rats; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D020280:Sertraline / Q000494:pharmacology; D013462:Sulfur Radioisotopes
D000928:Antidepressive Agents; D017450:Receptors, Opioid, mu; D013462:Sulfur Radioisotopes; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D005405:D-Ala(2),MePhe(4),Met(0)-ol-enkephalin; D019204:GTP-Binding Proteins; D020280:Sertraline; D003891:Desipramine