Activation and desensitization by cyclic antidepressant drugs of alpha(2)-autoreceptors, alpha(2)-heteroreceptors and 5-HT1A-autoreceptors regulatingmonoamine synthesis in the rat brain in vivo

The effects of antidepressant drugs on the synthesis of noradrenaline and s erotonin (5-HT) were assessed using the accumulation of 3,4-dihydroxyphenyl alanine (dopa) and 5-hydroxytryptophan (5-HTP) after decarboxylase inhibiti on as a measure of the rate of tyrosine and tryptophan hydroxylation in the rat brain in vivo. Three inhibitory synthesis-modulating receptors were in vestigated simultaneously: the alpha(2C)-autoreceptor modulating dopa/norad renaline synthesis, and the alpha(2A)-heteroreceptor and 5-HT1A-autorecepto r modulating 5-HTP/5-HT synthesis. Acute treatment (2 h, i.p.) with desipra mine (1-10 mg/kg), protriptyline (0.3-10 mg/kg) and nisoxetine (3-10 mg/kg) , selective NA reuptake blockers, dose-dependently decreased dopa synthesis in cortex (15%-40%) and hippocampus (20%-53%). Fluoxetine (1-10 mg/kg) and zimelidine (1-10 mg/kg), selective 5-HT reuptake blockers, did not alter d opa synthesis. Fluoxetine and zimelidine dose-dependently decreased 5-HTP s ynthesis in cortex (14%-3%) and hippocampus (27%-54%). Desipramine and prot ryptyline did not alter 5-HTP synthesis in cortex but in hippocampus it was decreased (36%). Repeated desipramine (10 mg/kg for 1-21 days) or fluoxeti ne (3 mg/kg for 3-21 days) treatment resulted in a time-dependent loss in t heir ability to decrease dopa or 5-HTP synthesis. Desipramine (1-21 days) d id not alter 5-HTP synthesis in cortex, but in hippocampus it was decreased (21%-37%, days 1-14) followed by recovery to control values (day 21). Fluo xetine (3-21 days) did not alter brain dopa synthesis. To further assess th e desensitization of alpha(2C)-autoreceptors, alpha(2A)-heteroreceptors and 5-HT1A autoreceptors regulating the synthesis of dopa/NA or 5-HTPI 5-HT af ter chronic desipramine and fluoxetine, the effects of clonidine (agonist a t alpha(2)-auto/heteroreceptors) and 8-OHDPAT (agonist at 5-HT1A-autorecept ors) were tested. In saline-treated rats, clonidine (1 mg/kg, 1 h) decrease d dopa and 5-HTP synthesis in cortex (58% and 54%) and hippocampus (54% and 42%). In desipramine-treated rats (10 mg/kg, 21 days), but not in fluoxeti ne-treated ones (3 mg/kg, 14 days), the effect of clonidine was attenuated in cortex (12% and 18%) and only for dopa synthesis in hippocampus (31%). I n saline-treated rats, 8-OH-DPAT (1 mg/kg, 1 h) decreased 5-HTP synthesis i n cortex (63%) and hippocampus (75%). In fluoxetine-treated rats, but not i n desipramine-treated ones, this inhibitory effect was markedly attenuated in cortex (26%) and hippocampus (9%). These findings indicate that acute tr eatment with cyclic antidepressant drugs results in activation of inhibitor y alpha(2C)-autoreceptors, alpha(2A)-heteroreceptors and/or 5-HT1A-autorece ptors regulating the synthesis of dopa/NA and/or 5-HTP/5-HT in brain, where as chronic treatment with these drugs is followed by desensitization of the se presynaptic receptors.