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.
The sensitivity of 5-HT1A serotonin receptors and alpha2-adrenoceptors (autoreceptors and heteroreceptors) modulating brain monoamine synthesis was investigated in rats during morphine treatment and after naloxone-precipitated withdrawal. The accumulation of 5-hydroxytryptophan (5-HTP) and 3,4-dihydroxyphenylalanine (DOPA) after decarboxylase inhibition was used as a measure of the rate of tryptophan and tyrosine hydroxylation in vivo. Acute morphine (3-100 mg/kg, 1 h) increased the synthesis of 5-HTP/5-HT in various brain regions (15%-35%) and that of DOPA/dopamine (DA) in striatum (28%-63%), but decreased the synthesis of DOPA/noradrenaline (NA) in hippocampus and cortex (20%-33%). Naloxone (2-60 mg/kg, 1 h) did not alter the synthesis of 5-HTP or DOPA in brain. Tolerance to the inhibitory effect of morphine on DOPA/NA synthesis and a sensitization to its stimulatory effects on DOPA/DA and 5-HTP/5-HT synthesis were observed after chronic morphine and/or in morphine-withdrawn rats. In morphine-dependent rats (tolerant and withdrawn states) the inhibitory effects of the 5-HT1A agonists 8-OH-DPAT and buspirone (0.1 mg/kg, 1 h), and that of the alpha2-adrenoceptor agonist clonidine (0.1 mg/kg, 1 h), on the synthesis of 5-HTP/5-HT were potentiated (25%-50%). Moreover, the effect of 8-OH-DPAT was antagonized by WAY 100135, a selective 5-HT1A antagonist. In morphine-dependent rats (tolerant state), the inhibitory effects of clonidine on the synthesis of DOPA/NA (hippocampus, hypothalamus) and DOPA/DA (striatum) also were potentiated (35%-55%). In summary, we conclude that morphine addiction is associated with supersensitivity of 5-HT1A serotonin receptors and alpha2-adrenoceptors (autoreceptors and heteroreceptors) that modulate the synthesis of monoamines in brain.
This study was designed to assess the effects of imidazoline drugs on putative presynaptic imidazoline receptors modulating brain monoamine synthesis in vivo. The accumulation of 3,4-dihydroxyphenylalanine (dopa) and 5-hydroxytryptophan (5-HTP) after decarboxylase inhibition was used as a measure of the rate of tyrosine and tryptophan hydroxylation in various brain regions of naive rats and after irreversible alpha2-adrenoceptor inactivation with EEDQ (1.6 mg/kg, i.p., 6 h). Clonidine (1-3 mg/kg), moxonidine (1-10 mg/kg) and rilmenidine (10 mg/kg) (mixed I1/alpha2 agonists) decreased dopa and 5-HTP synthesis in the cerebral cortex (14%-81%), hippocampus (27%-84%) and/or striatum (29%-56%), but these inhibitory effects were abolished in N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ)-treated rats. Similarly, the stimulatory effect of efaroxan (mixed I1/alpha2 antagonist; 10 mg/kg) on dopa synthesis in the cortex (77%) and hippocampus (57%) was abolished by EEDQ. The selective I1-ligand 2-endo-amino-3-exoisopropylbicyclo-heptane (AGN-192403; 5-10 mg/kg) did not modify dopa or 5-HTP synthesis in any brain region in naive or EEDQ-treated rats. Idazoxan (mixed I2/alpha2 antagonist; 20 mg/kg) increased dopa synthesis in the cortex (111%) and hippocampus (87%), but the stimulatory effects were abolished by EEDQ. Moreover, idazoxan and efaroxan decreased 5-HTP synthesis in the cortex (12%-34%) and hippocampus (30%-34%) in a manner sensitive to blockade by the 5-HT1A receptor antagonist WAY 100135. The selective I2-igands 2-(2-benzofuranyl)-2-imidazoline (2-BFI; 20 mg/kg) and 2-styryl-2-imidazoline (LSL 61122; 10 mg/kg) did not alter the synthesis of dopa or 5-HTP in the cortex or hippocampus. In striatum, 2-BFI (1-20 mg/kg) dose-dependently decreased dopa synthesis (ED50: 5.9 mg/kg), reduced dopamine levels (6%-36%) and increased those of its metabolites DOPAC (15%-95%) and HVA (24%-74%). The inhibitory effect of 2-BFI on dopa/dopamine synthesis in striatum remained unchanged after alkylation of imidazoline receptors with isothiocyanatobenzyl imidazoline (IBI; 60 mg/kg, 6 h) or blockade of these receptors with 2-(2-ethyl 2,3-dihydro-2-benzofuranyl)-2-imidazole (KU-14R; 7-20 mg/kg). Therefore, most imidazoline drugs modulated the synthesis of brain monoamines through interaction with alpha2-adrenoceptors or 5-HT1A receptors. The results do not provide functional evidence for the existence of presynaptic imidazoline receptors regulating the synthesis of monoamines in the rat brain.
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