The Effect Of Gonadectomy On Biochemical Indices Of Striatal Dopamine D(1) And D(2) Receptors, Their Activity And Adaptive Response To Antipsychotic Drug Treatment In Rat.

We studied the effects of gonadectomy of male and female rats on biochemical indices of striatal dopamine D(,1) and D(,2) receptors, their activity, and adaptive response to sub-chronic D(,2) receptor blockade. Endogenous gonadal steroids in male and female rats were removed by gonadectomy (Gnx). Striatal D(,1) receptors and their activity were characterized by ('3)H SCH23390 binding parameters and D(,1) receptor-stimulated adenylate cyclase activity in striatal membranes. Striatal D(,2) receptors and their activity were characterized by ('3)H sulpiride binding parameters in striatal slices and D(,2) receptor-mediated inhibition of forskolin-activated adenylate cyclase activity in striatal membranes. Sub-chronic D(,2) receptor blockade consisted of the administration of the D(,2) specific antagonist sulpiride (20 mg/kg) or vehicle i.p., 2x daily for 21 days followed by a 3 day drug withdrawal period. Gnx of female rats had no affect on striatal D(,1)-stimulated adenylate cyclase activity nor on the striatal D(,2) receptor-mediated inhibition of forskolin-activated adenylate cyclase activity. Sub-chronic sulpiride treatment produced no adaptive changes in D(,1)-stimulated adenylate cyclase activity in sham-operated or Gnx female rats. Gnx of male rats produced a statistically significant 10% decrease in striatal ('3)H SCH23390 binding sites with no change in D(,1)-stimulated adenylate cyclase activity and no change in striatal ('3)H sulpiride binding parameters. Sub-chronic sulpiride treatment of sham-operated male rats produced a desensitization of the striatal D(,1)-stimulated adenylate cyclase activity with no change in the number of ('3)H SCH23390 binding sites and no change in ('3)H sulpiride binding parameters. Gnx of male rats blocked the development of the striatal D(,1) receptor desensitization response elicited by sub-chronic sulpiride treatment, without affecting striatal ('3)H SCH23390 or ('3)H sulpiride binding parameters. We have demonstrated that sub-chronic D(,2) receptor blockade in sham-operated male rats results in the desensitization of striatal D(,1) receptor activity. This suggests a functional interaction between D(,1) and D(,2) receptors at a biochemical level in the regulation of striatal dopaminergic activity and adaptive response to fluctuations in the neurochemical environment. The D(,1) receptor desensitization occurred with no concomitant change in the number of D(,1) receptors suggesting that the desensitization response takes place at a point beyond the receptor. Testicular hormones permitted the development of the sub-chronic sulpiride-induced D(,1) receptor desensitization. Testicular hormones played no role in striatal D(,1) and D(,2) receptor activity until an adaptive response was elicited by pharmacological manipulation.PhDBiological SciencesNeurosciencesUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/128014/2/8712139.pd