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

Abstract

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 alpha2C-autoreceptor modulating dopa/noradrenaline synthesis, and the alpha2A-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 alpha2C-autoreceptors, alpha2A-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 alpha2-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 alpha2C-autoreceptors, alpha2A-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.

Regulation of Platelet α2A-Adrenoceptors, Gi Proteins and Receptor Kinases in Major Depression: Effects of Mirtazapine Treatment

“…Therefore, the observed clinical efficacy and downregulation of a 2A -adrenoceptors induced by mirtazepine also support a relevant role of supersensitive a 2A -adrenoceptors in the pathogenesis of major depression (Fu et al, 2001;González-Maeso et al, 2002). Chronic antidepressant treatments have been repeatedly shown to induce downregulation and desensitization of a 2 -adrenoceptors and/or Gai proteins in the platelets of depressed patients (García-Sevilla et al, 1986, 1987, 1990Piletz et al, 1991;Gurguis et al, 1999), and in the rat Barturen and García-Sevilla, 1992;Kovachich et al, 1993;Mongeau et al, 1994;Esteban et al, 1999;Mateo et al, 2001) and human (De Paermentier et al, 1997;García-Sevilla et al, 1999) brains. Similar to other antidepressant drugs, mirtazapine could also induce the downregulation of platelet a 2 -adrenoceptors, indirectly, through the rise in plasma norepinephrine induced by the drug.…”

“…The regulation of a 2A -adrenoceptors is also an important issue in major depression because most antidepressant drugs have indirect regulatory effects on these receptors (Charney, 1998;Esteban et al, 1999). The homologous regulation of receptors is induced by a family of G-proteincoupled receptor kinases (named GRK 1-7), some of which translocate from the cytosol to the plasma membrane (eg GRK 2 but not GRK 6) to phosphorylate the agonist (endogenous ligand)-activated receptors (Pitcher et al, 1998).…”

Neurotransmitter receptor-mediated activation of G-proteins in brains of suicide victims with mood disorders: selective supersensitivity of α2A-adrenoceptors

“…14 Many antidepressant treatments are able to modulate ␣ 2 -adrenoceptor density and/or function. Thus, chronic administration of antidepressant drugs reduces the density and activity of ␣ 2 -adrenoceptors in rat brain [15][16][17][18][19] and in platelets of depressed patients. 20,21 Based on these observations, it has been suggested that patients with mood disorders might have an underlying disturbance of noradrenergic and/or serotonergic function, perhaps due to hyperactive ␣ 2 -adrenoceptor function.…”

Increased mRNA Expression of α2A-Adrenoceptors, Serotonin Receptors and μ-Opioid Receptors in the Brains of Suicide Victims

“…Thus, stimulation of presynaptic a 2 -and 5-HT-autoreceptors induce a decrease in the synthesis and release of norepinephrine and 5-HT (Esteban et al, 1999). Further evidence of the involvement of a 2 -adrenoceptors and 5-HT receptors in the pathophysiology of suicide and depression is that chronic antidepressant administration reduces the density and activity of these receptors in rat brain (Esteban et al, 1999;Invernizzi et al, 2001;Smith et al, 1981;Sibug et al, 1998;Subhash and Jagadeesh, 1997), and in the platelets of depressed subjects (García-Sevilla et al, 1986;Stahl, 1994;Sargent et al, 1997). Based on these observations, it has been suggested that patients with mood disorders might suffer an underlying disturbance of noradrenergic and/or serotonergic function.…”