Delayed desensitization of alpha 2-adrenoceptor-mediated platelet aggregation in depressed patients.
After prolonged exposure to epinephrine, platelets are observed to desensitize alpha 2-adrenoceptor-mediated aggregation responses in vitro. Herein, this phenomenon was studied as a possible in vitro model for alpha 2-adrenoceptor dysregulation in depression. Platelet-rich plasmas obtained from 22 unipolar depressed patients and 25 healthy subjects were preincubated with 20 mumol/L of epinephrine for various lengths of time prior to stirring. By comparing the subsequent extents of aggregation, we observed significantly less desensitization at 4, 20, 30, or 60 minutes postepinephrine exposure (p < or = .05) in depressed patients as compared to healthy controls. This blunted desensitization appeared to be due to a delayed onset of desensitization during the first 0.5 to 2 minutes after epinephrine exposure, since thereafter, the monoexponential desensitization rate did not differ in depressed patients, but the extent of desensitization remained less as compared to healthy subjects. The extent of desensitization was correlated (r = -0.48, p = .02) with the density (Bmax) of the alpha 2-adrenoceptor high-affinity state, as detected in undesensitized platelet membranes by p125I-clonidine binding. An elevation was also observed in the density of nonadrenergic p125I-clonidine-binding sites (putative imidazoline I1 sites) in platelet membranes from depressed patients compared to healthy control subjects. Following treatment with desipramines, the patients (n = 15) displayed more normal (nonblunted) extents of desensitization of aggregation, and the Bmax values for the putative I1 sites were at the levels of healthy controls. If similar aberrations exist in neurons of depressed patients, this may explain a dysregulation of the noradrenergic system believed to underlie depression.
Department of Psychiatry, Case Western Reserve University, Cleveland, Ohio.
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Piletz
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Chikkala
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Khaitan
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Jackson
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Qu
D000328:Adult; D002395:Catecholamines / Q000097:blood; D003000:Clonidine; D003866:Depressive Disorder / Q000097:blood*; D004837:Epinephrine / Q000494:pharmacology; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D006801:Humans; D007457:Iodine Radioisotopes; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D010974:Platelet Aggregation / Q000187:drug effects*; D011869:Radioligand Assay; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects*
D002395:Catecholamines; D007457:Iodine Radioisotopes; D018341:Receptors, Adrenergic, alpha-2; D019204:GTP-Binding Proteins; D003000:Clonidine; D004837:Epinephrine