Alterations in 5-HT1A receptors and adenylyl cyclase response by trazodone in regions of rat brain

Subhash, M. N.; Srinivas, B. N.; Vinod, K. Yaragudri

doi:10.1016/s0024-3205(02)01926-4

Cited by 14 publications

(9 citation statements)

References 27 publications

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“…5-HT 1A receptor down-regulation (Subhash et al, 2002). As outlined above, the increase in 5-HT release is accompanied by the rise in GABA release which may explain the sedative and anxiolytic actions that accompany the antidepressant activity of trazodone.…”

mentioning

confidence: 93%

5-HT Receptor Regulation of Neurotransmitter Release

Fink¹,

Göthert²

2007

Pharmacol Rev

325

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mentioning

confidence: 93%

5-HT Receptor Regulation of Neurotransmitter Release

Fink¹,

Göthert²

2007

Pharmacol Rev

325

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“…At high concentrations, TRZ increases 5-HT release by inhibiting its transporter. The increase in 5-HT release, resulting from this double mechanism, may be responsible for the antidepressant properties of TRZ, possibly through a 5HT 1A receptor downregulation (Subhash et al, 2002). The 5-HT increase is accompanied by a rise in GABA release.…”

Section: Resultsmentioning

confidence: 99%

A cortical GABA–5HT interaction in the mechanism of action of the antidepressant trazodone

Luparini

Garrone

Pazzagli

et al. 2004

Progress in Neuro-Psychopharmacology and Biological Psychiatry

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The aim of the study was to investigate whether the antidepressant trazodone (TRZ), a serotonin-2 receptor antagonist/reuptake inhibitor, modifies gamma-amino-butyric acid (GABA) extracellular levels in the cerebral cortex, by acting on 5-HT(2A) receptors, and through this mechanism increases 5-HT levels. For this purpose the effect of TRZ on the release of GABA was studied in adult male rats in synaptosomes, cortical slices, and "in vivo" by microdialysis. In cortical slices, the release of both GABA and 5-HT was determined. GABA and 5-HT were identified and their levels quantified by HPLC. The inhibition of 5-HT uptake by TRZ was also measured. In synaptosomes, TRZ antagonized dose-dependently, at concentrations from 10(-10) to 10(-6) M, the increase in GABA release induced by (+/-)DOI, a 5-HT(2A/2C) agonist, and the alpha receptor agonist phenylephrine, both 10(-6) M. The pIC50 values were 8.31+/-0.24, and 5.99+/-0.52, respectively. In the same preparation, [3H]5-HT accumulation was inhibited by citalopram and TRZ with pIC(50) of 7.8+/-0.44 and 5.9+/-0.09, respectively, a finding confirming the weak activity of TRZ in comparison with a SSRI. In cortical slices, TRZ exerted a biphasic effect on GABA release. At concentrations from 10(-10) to 10(-7) M it inhibited and from 10(-6) to 10(-4) M increased GABA release. 5-HT release was enhanced by TRZ throughout the entire range of concentrations tested. However, the increase was delayed after low and rapid after high concentrations. AMI-193, a 5-HT(2A) antagonist (10(-10) to 10(-5) M), reduced GABA release in a dose-response manner, while it induced an increase of 5-HT outflow. On the contrary, (+/-)DOI (10(-10) to 10(-5) M) increased GABA release and inhibited 5-HT levels. Perfusion with the GABA(A) receptor antagonist bicuculline was also followed by an increase in 5-HT release. In microdialysis experiments, TRZ 1.25 mg kg(-1) s.c. brought about a decrease in GABA extracellular levels, while an increase was found after the dose of 2.5 mg kg(-1). These findings demonstrate that TRZ, at concentrations which do not inhibit 5-HT uptake, reduces the cortical GABAergic tone by decreasing GABA extracellular levels, through the blockade of 5-HT(2A) receptors. The attenuation of GABAergic tone is responsible for an increase in 5-HT levels. A further increase also results from 5-HT uptake inhibition caused by higher doses of TRZ. The ensuing high 5-HT levels enhance GABA release, which in turn inhibits 5-HT release.

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“…repeated milnacipran treatment might induce desensitization of postsynaptic 5-HT 1A receptors. Indeed, several reports showed that the 5-HT 1A receptor-mediated inhibition of adenylate cyclase response was down-regulated following long-term treatment with antidepressants (Newman et al, 1992;Subhash et al, 2002). Mochizuki and co-workers (2002) reported, using rat hippocampal slices, that repeated treatment with milnacipran (30 mg/kg, p.o.…”

Section: Discussionmentioning

confidence: 99%

Electrophysiological and neurochemical characterization of the effect of repeated treatment with milnacipran on the rat serotonergic and noradrenergic systems

et al. 2006

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The present study was undertaken to elucidate the effects of repeated treatment with milnacipran, a serotonin (5-HT) and noradrenaline (NA) reuptake inhibitor (SNRI), on the synaptic plasticity in the hippocampal CA1 field, focusing on the interaction between the serotonergic and noradrenergic system. Repeated treatment with milnacipran (30 mg/kg, i.p. after 30 mg/kg, p.o. x 14 days) completely restored the suppression of the long-term potentiation (LTP) induced by single milnacipran treatment (30 mg/kg, i.p.). Single and repeated milnacipran increased to a similar extent extracellular NA in the hippocampus. Single milnacipran increased extracellular 5-HT and this effect tended to be enhanced by repeated treatment. The restoration of LTP and facilitation of the 5-HT level were not shown after repeated treatment with a selective 5-HT reuptake inhibitor (SSRI) fluvoxamine (30 mg/kg, p.o. x 14 days). These results suggest that milnacipran-induced restoration of LTP suppression is responsible for the enhancement of 5-HT neurotransmission, which appears to be associated with noradrenergic neuronal activity. In addition, the 5-HT1A receptor agonist tandospirone-induced suppression of LTP was completely blocked by repeated treatment with milnacipran, indicating the possibility that this reversal effect is due to the functional changes in postsynaptic 5-HT1A receptors. Taken together, the present data suggest that the interaction between the serotonergic and noradrenergic mechanism play an important role in the modulation of synaptic plasticity caused by repeated treatment with milnacipran, which may be implicated in the therapeutic effects of SNRI on psychiatric disorders.

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Alterations in 5-HT1A receptors and adenylyl cyclase response by trazodone in regions of rat brain

Cited by 14 publications

References 27 publications

5-HT Receptor Regulation of Neurotransmitter Release

5-HT Receptor Regulation of Neurotransmitter Release

A cortical GABA–5HT interaction in the mechanism of action of the antidepressant trazodone

Electrophysiological and neurochemical characterization of the effect of repeated treatment with milnacipran on the rat serotonergic and noradrenergic systems

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