Effects of 5-HT1A receptor antagonists on fluoxetine-induced changes in extracellular serotonin concentrations in rat frontal cortex

Subanesthetic doses of ketamine, an N-methyl-D-aspartic acid (NMDA) antagonist, have a rapid antidepressant effect which lasts for up to 2 weeks. However, the neurobiological mechanism regarding this effect remains unclear. In the present study, the effects of subanesthetic doses of ketamine on serotonergic systems in conscious monkey brain were investigated. Five young monkeys underwent four positron emission tomography measurements with [ 11 C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)benzonitrile ([ 11 C]DASB) for the serotonin transporter (SERT), during and after intravenous infusion of vehicle or ketamine hydrochloride in a dose of 0.5 or 1.5 mg/kg for 40 min, and 24 h post infusion. Global reduction of [ 11 C]DASB binding to SERT was observed during ketamine infusion in a dose-dependent manner, but not 24 h later. The effect of ketamine on the serotonin 1A receptor (5-HT 1A -R) and dopamine transporter (DAT) was also investigated in the same subjects studied with [ 11 C]DASB. No significant changes were observed in either 5-HT 1A -R or DAT binding after ketamine infusion. Microdialysis analysis indicated that ketamine infusion transiently increased serotonin levels in the extracellular fluid of the prefrontal cortex. The present study demonstrates that subanesthetic ketamine selectively enhanced serotonergic transmission by inhibition of SERT activity. This action coexists with the rapid antidepressant effect of subanesthetic doses of ketamine. Further studies are needed to investigate whether the transient combination of SERT and NMDA reception inhibition enhances each other's antidepressant actions.

Section: Resultsmentioning

confidence: 85%

Subanesthetic Doses of Ketamine Transiently Decrease Serotonin Transporter Activity: A PET Study in Conscious Monkeys

Yamamoto

Ohba

Nishiyama

et al. 2013

“…In support of this hypothesis, clinical data have indicated that the coadministration of an SSRI with the mixed b-adrenergic and 5-HT 1A receptor antagonist (7) pindolol can hasten the commencement of antidepressant efficacy from several weeks to between 3 and 7 days (Artigas et al, 1994;Blier and Bergeron, 1995), although there has been evidence to the contrary in depression (Berman et al, 1997(Berman et al, , 1999 and anxiety (Stein et al, 2001). There are also a substantial number of preclinical rodent neurochemistry studies that support the proposal that the increase in forebrain 5-HT seen with SSRIs after chronic administration can been seen acutely with concurrent blockade of the 5-HT 1A autoreceptors (Dawson and Nguyen, 1998;Gartside et al, 1995). In addition, 5-HT1 B/D antagonists augment an SSRI-induced increase in 5-HT (Dawson and Nguyen, 2000) and further potentiate the increase in 5-HT following WAY100635 and fluoxetine (Gobert et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

“…The adaptive changes required for SB-649915-B to show anxiolytic behavior potentially occur between days 4 and 7 in this assay, whereas the paroxetine effects have been postulated to occur between days 14 and 21 of administration (Lightowler et al, 1994). There are also a substantial number of preclinical rodent neurochemistry studies that support the proposal that the increase in forebrain 5-HT seen with SSRIs alone after chronic administration can be seen acutely with concurrent blockade of the 5-HT 1A autoreceptors using (7) pindolol (Dreshfield et al, 1996;Romero et al, 1996a;Hjorth, 1996;Hjorth and Auerbach, 1996;Dawson and Nguyen, 2000) or more selective 5-HT 1A receptor antagonist compounds such as WAY100635 (Romero et al, 1996a, b;Hjorth et al, 1997;Dawson and Nguyen, 1998). A combination of 5-HT 1A and 5-HT 1B (or 5-HT 1B/D ) receptor antagonists and SSRIs (Sharp et al, 1997;Gobert et al, 2000;Dawson and Nguyen, 2000) augments extracellular 5-HT even further.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, preclinical neurochemical studies have shown that blockade of the inhibitory 5-HT 1A autoreceptors with (7) pindolol induces an acute, rapid elevation of extracellular forebrain 5-HT that is not seen with SSRIs alone (Artigas, 1993;Hjorth, 1996;Dawson and Nguyen, 2000). Data with the highly selective 5-HT 1A receptor antagonist WAY100635 (Forster et al, 1995;Fletcher et al, 1996) combined with SSRIs provide further evidence to support the role of 5-HT 1A receptors in this response (Gartside et al, 1995;Dawson and Nguyen, 1998).…”

Section: Introductionmentioning

confidence: 92%

See 1 more Smart Citation

SB-649915-B, a Novel 5-HT1A/B Autoreceptor Antagonist and Serotonin Reuptake Inhibitor, is Anxiolytic and Displays Fast Onset Activity in the Rat High Light Social Interaction Test

Starr

Price

Watson

et al. 2007

Preclinically, the combination of an SSRI and 5-HT autoreceptor antagonist has been shown to reduce the time to onset of anxiolytic activity compared to an SSRI alone. In accordance with this, clinical data suggest the coadministration of an SSRI and (7) pindolol can decrease the time to onset of anxiolytic/antidepressant activity. Thus, the dual-acting novel SSRI and 5-HT 1A/B receptor antagonist, SB-649915-B, has been assessed in acute and chronic preclinical models of anxiolysis. SB-649915-B (0.1-1.0 mg/kg, i.p.) significantly reduced ultrasonic vocalization in male rat pups separated from their mothers (ED 50 of 0.17 mg/kg). In the marmoset human threat test SB-649915-B (3.0 and 10 mg/kg, s.c.) significantly reduced the number of postures with no effect on locomotion. In the rat high light social interaction (SI), SB-649915-B (1.0-7.5 mg/kg, t.i.d.) and paroxetine (3.0 mg/kg, once daily) were orally administered for 4, 7, and 21 days. Ex vivo inhibition of [ 3 H]5-HT uptake was also measured following SI. SB-649915-B and paroxetine had no effect on SI after 4 days. In contrast to paroxetine, SB-649915-B (1.0 and 3.0 mg/kg, p.o., t.i.d.) significantly (po0.05) increased SI time with no effect on locomotion, indicative of an anxiolytic-like profile on day 7. Anxiolysis was maintained after chronic (21 days) administration by which time paroxetine also increased SI significantly. 5-HT uptake was inhibited by SB-649915-B at all time points to a similar magnitude as that seen with paroxetine. In conclusion, SB-649915-B is acutely anxiolytic and reduces the latency to onset of anxiolytic behavior compared to paroxetine in the SI model.

“…The effective antagonism of the 5-HT 1A autoreceptors by WAY 100,635 would have the tendency to drive up 5-HT neuronal firing, but the attenuated activation of excitatory a 1 -adrenoceptors resulting from the concomitant inhibition of LC NE neuron firing has the opposite effect on DRN firing, the net result being an unaltered firing rate for most 5-HT neurons. Microdialysis studies using WAY 100,635 presumably also failed to demonstrate that somatodendritic 5-HT 1A autoreceptors are tonically activated by endogenous 5-HT likely due to its indirect NE action mentioned above Gurling et al, 1994;Invernizzi et al, 1997;Dawson and Nguyen, 1998).…”

Section: Discussionmentioning

confidence: 99%

Electrophysiological Evidence for the Tonic Activation of 5-HT1A Autoreceptors in the Rat Dorsal Raphe Nucleus

Haddjeri

Lavoie

Blier

2004

Serotonin (5-hydroxytryptamine, 5-HT) and norepinephine (NE) neurons have reciprocal connections. These may thus interfere with anticipated effects of selective pharmacological agents targeting these neurons. The main goal of the present study was to assess whether the somatodendritic 5-HT 1A autoreceptor is tonically activated by endogenous 5-HT in anesthetised rats, using in vivo extracellular unitary recordings. In rats with their NE neurons lesioned using 6-hydroxydopamine (6-OHDA) and in controls administered the NE reuptake inhibitor desipramine to suppress NE neuronal firing, the a 2 -adrenoceptor agonist clonidine no longer inhibited 5-HT neuron firing, therefore indicating the important modulation of the firing activity of 5-HT neurons by NE neurons. In control rats, the administration of the potent and selective 5-HT 1A receptor antagonist WAY 100,635 ((N-{2-[4(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridinyl)cyclohexanecarboxamide trihydroxychloride) (100 mg/kg, i.v.) did not modify the spontaneous firing activity of 5-HT neurons, but in NE-lesioned rats using either 6-OHDA or DSP-4, WAY 100,635 produced a mean firing increase of 80 and 69%, respectively. When desipramine and D-amphetamine were used in control rats to prevent alterations in the availability of NE in the dorsal raphe, again WAY 100,635 produced a significant disinhibition of the firing of 5-HT neurons (83 and 53%, respectively). These data support the notion that the NE system tonically activates the firing activity of 5-HT neurons. When the fluctuations of the function of NE neurons normally produced by WAY 100,635 were prevented, a tonic activation of 5-HT 1A autoreceptors by endogenous 5-HT was unmasked.