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NEUROPHARMACOLOGY

Chronic Antidepressant Treatment Causes a Selective Reduction of µ-Opioid Receptor Binding and Functional Coupling to G Proteins in the Amygdala of Fawn-Hooded Rats

Howard Florey Institute, University of Melbourne, Parkville, Australia (F.C., A.J.L.); and Department of Pharmacology, Monash University, Clayton, Australia (F.C.)

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]GTPS) 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]GTPS 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.

Address correspondence to: Dr. Feng Chen, Howard Florey Institute, The University of Melbourne, Parkville, Victoria 3010, Australia. E-mail: f.chen{at}hfi.unimelb.edu.au