Activation and desensitization by cyclic antidepressant drugs of α2-autoreceptors, α2-heteroreceptors and 5-HT1A-autoreceptors regulating monoamine synthesis in the rat brain in vivo
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The effects of antidepressant drugs on the synthesis of noradrenaline and serotonin (5-HT) were assessed using the accumulation of 3,4-dihydroxyphenylalanine (dopa) and 5-hydroxytryptophan (5-HTP) after decarboxylase inhibition as a measure of the rate of tyrosine and tryptophan hydroxylation in the rat brain in vivo. Three inhibitory synthesis-modulating receptors were investigated simultaneously: the α2C-autoreceptor modulating dopa/noradrenaline synthesis, and the α2A-heteroreceptor and 5-HT1A-autoreceptor modulating 5-HTP/5-HT synthesis.
Acute treatment (2 h, i.p.) with desipramine (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 dopa synthesis. Fluoxetine and zimelidine dose-dependently decreased 5-HTP synthesis in cortex (14%–43%) and hippocampus (27%–54%). Desipramine and protryptyline 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 fluoxetine (3 mg/kg for 3–21 days) treatment resulted in a time-dependent loss in their ability to decrease dopa or 5-HTP synthesis. Desipramine (1–21 days) did 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). Fluoxetine (3–21 days) did not alter brain dopa synthesis. To further assess the desensitization of α2C-autoreceptors, α2A-heteroreceptors and 5-HT1A autoreceptors regulating the synthesis of dopa/NA or 5-HTP/5-HT after chronic desipramine and fluoxetine, the effects of clonidine (agonist at α2-auto/heteroreceptors) and 8-OH-DPAT (agonist at 5-HT1A-autoreceptors) were tested. In saline-treated rats, clonidine (1 mg/kg, 1 h) decreased 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 fluoxetine-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%). In saline-treated rats, 8-OH-DPAT (1 mg/kg, 1 h) decreased 5-HTP synthesis in cortex (63%) and hippocampus (75%). In fluoxetine-treated rats, but not in desipramine-treated ones, this inhibitory effect was markedly attenuated in cortex (26%) and hippocampus (9%).
These findings indicate that acute treatment with cyclic antidepressant drugs results in activation of inhibitory α2C-autoreceptors, α2A-heteroreceptors and/or 5-HT1A-autoreceptors regulating the synthesis of dopa/NA and/or 5-HTP/5-HT in brain, whereas chronic treatment with these drugs is followed by desensitization of these presynaptic receptors.
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