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Antidepressant treatments, including those that increase serotonin (5-HT) neurotransmission, require several weeks or months until the onset of the therapeutic effect in depressed patients. The negative feedback on 5-HT transmission exhibited by the 5-HT(1A) and 5-HT(1B) autoreceptors has been postulated as a possible delaying factor. The aim of the present study was to assess the effect of the acute and subchronic treatment with pindolol, a 5-HT(1A/1B,) β₁ and β₂ adrenoceptor antagonist, on 5-HT synthesis, one of the key parameters of 5-HT neurotransmission. Male Sprague-Dawley (SPD) rats (180-220 g) were treated with pindolol or an adequate volume of saline, administered either acutely (15 mg/kg i.p.; SPD-AC-SAL, SPD-AC-TR) or subchronically (15 mg/kg day i.p. for 7 days; SPD-SUBCHR-SAL, SPD-SUBCHR-TR). Thirty minutes following the single i.p. injection (acute experiment) or at the 8th day following the commencement of the subchronic treatment (subchronic experiment), 5-HT synthesis was measured using α-[¹⁴C]methyl-L-tryptophan autoradiography. The analysis of variance (ANOVA), followed by the Benjamini-Hochberg correction for multiple comparisons, revealed: (1) a significant increase of 5-HT synthesis in the SPD-AC-TR rats, relative to the SPD-AC-SAL rats in all brain regions examined except the substantia nigra--pars reticularis, dorsal subiculum, inferior olive, raphe magnus and raphe obscurus and (2) a significant increase of 5-HT synthesis in the SPD-SUBCHR-TR rats, relative to the SPD-SUBCHR-SAL rats in all brain regions except the median raphe, hypothalamus and raphe pontine. On the basis of these results, we hypothesized that the antagonism of the 5-HT(1A/1B) receptors prevents the negative feedback mediated by these receptors on 5-HT synthesis, resulting in a persistent increase of 5-HT synthesis. The results accord with clinical reports on the utility of pindolol in the augmentation of antidepressant treatment., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

The effects of the administration of the serotonin (5-HT)(2A) antagonist, M100907, on 5-HT synthesis rates, were evaluated using the α-[(14)C]methyl-l-tryptophan (α-MTrp) autoradiographic method. In the treatment study, M100907 (10mg/kg) was injected intraperitoneally 30 min before the α-MTrp injection (30 μCi over 2 min). A single dose of M100907 caused a significant decrease in the synthesis in the anterior olfactory nucleus, accumbens nucleus, frontal cortex, sensory-motor cortex, cingulate cortex, medial caudate-putamen, dorsal thalamus, substantia nigra, inferior collicus, raphe magnus nucleus, superior olive, and raphe pallidus nucleus. These data suggest that the terminal 5-HT(2A) receptors are involved in the regulation of 5-HT synthesis in the entire brain. Further, 5-HT synthesis is likely regulated by the 5-HT(2A) antagonistic property of M100907 in the cortices, anterior olfactory nucleus, caudate putamen, and nucleus accumbens., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The effects of acute and repeat administration of the serotonin (5-HT)(1) agonists TFMPP [N -(3-trifluoromethyl)phenylpiperazine hydrochloride] and CGS12066B [7-trifluoromethyl-4- (4-methyl-1-piperazinyl)pyrrolo[1,2-a ]-quinoxaline dimaleate] were evaluated on 5-HT synthesis rates using the alpha-[(14) C]methyl-l-tryptophan (alpha-MTrp) autoradiographic method. In the acute treatment study, TFMPP (10 mg/kg) and CGS12066B (5 mg/kg) were injected intraperitoneally 30 min before an alpha-MTrp injection. In an acute study TFMPP reduced overall brain 5-HT synthesis, in the dorsal and median raphe, and in almost all of their projection areas, with the exception of the parietal, sensory-motor, and frontal cortices, the accumbens nucleus, and the caudate. Acute CGS12066B treatment did not have overall significant effect, but the rates did decrease in the cell body areas of 5-HT neurons. In a 7-day treatment with TFMPP (10 mg/kg/day) or CGS12066B (5 mg/kg/day), the 5-HT synthesis rates (24 h after last dose) decrease, with both compounds, in almost all of the nerve terminal structures. TFMPP reduced the synthesis in the dorsal and median raphe, while CGS12066B reduced it only in the dorsal raphe. This data suggests that after a 7-day treatment with TFMPP and CGS12066B, the rate of 5-HT synthesis in the dorsal raphe is restored and is reduced in many projection areas. The observed effects in the 7-day treatment could also be related to actions through the postsynaptic 5-HT(1B) sites and/or other 5-HT receptors since this compounds have limited selectivity.

The effects of acute and chronic administration of WAY100635 and WAY100135, serotonin (5-HT)1A antagonists, on 5-HT synthesis rates, calculated from the trapping of alpha-[14C]methyl-L-tryptophan (alpha-MTrp), were evaluated in the rat brain using autoradiography. In the acute treatment studies, WAY100635 (1 mg/kg) induced a significant increase in 5-HT synthesis in the median raphe nucleus and some nerve terminal structures (range between 18 and 53%), while WAY100135 (10 mg/kg) produced a significant decrease of synthesis, in the range between 16 and 33%, in the raphe magnus nucleus and several projection areas. The action of WAY100635 given acutely was likely a result of antagonist actions at the 5-HT1A somato-dendritic autoreceptors. WAY100135 probably acted acutely as a partial agonist. In the chronic treatment studies, WAY100635 (1 mg/kg/day) and WAY100135 (10 mg/kg/day) were administered for 7 days as s.c. injections once a day. Chronic treatment with both compounds significantly reduced the rate of 5-HT synthesis in the nerve terminal structures and produced a significant increase in the raphe nuclei. These treatments did not have any effect on the plasma free or total tryptophan.