5-HT3-like receptors in the rat medial prefrontal cortex: an electrophysiological study

doi:10.1016/0006-8993(91)91316-S

Brain Research

Volume 550, Issue 2, 7 June 1991, Pages 181-191

https://doi.org/10.1016/0006-8993(91)91316-S Get rights and content

Abstract

In this study, we have identified and characterized 5-HT₃-like receptors in the rat medial prefrontal cortex (mPFc), an area with a moderate density of 5-HT₃ binding sites, using the techniques of single unit recording and microiontophoresis. The microiontophoresis of the 5-HT₃ receptor agonist 3-methylserotonin (2-Me-5HT), similar to the action of 5-HT), produced a current-dependent (10–80 nA) suppression of the firing rate of both spontaneously active and glutamate (GLU)-activated (quiescent) mPFc cells. Phenylbiguanide (PBG), another 5-HT₃ receptor agonist, suppressed the firing rate of mPFc cells but was less effective compared to 2-Me-5HT. The continuous iontophoresis (10–20 min) of 1 M magnesium chloride markedly attenuated the suppressant effect produced by electrical stimulation of the ascending 5-HT pathway, but did not alter 2-Me-5HT's action, suggesting that the action of 2-Me-5HT is a direct one. The suppressant action of 2-Me-5HT on mPFc cells was blocked by a number of structurally diverse and selective 5-HT₃ antagonists, with a rank order of effectiveness as follows: JCS 205930=(±)-zacopride>granisetron=ondansetron= LY 278584 >MDL72222. Furthermore, the intravenous administration of(±)-zacopride antagonized the action of 2-Me-5HT and PBG on mPFc cells. In contrast to the effects of the 5-HT₃ receptors antagonists, other receptor antagonists such as metergoline (5-HT_1A,1B,1C,2), (±)-pindolol (5-HT_1A,1B,β), SCH 23390 (5-HT_1C,2, D1), 1-sulpiride (D2) or SR 95103 (GABA_A) failed to block 2-Me-5HT's action. These results combined suggest that 2-Me-5HT's suppressive action on mPFc cells is mediated directly by 5-HT₃-like receptors.

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The present results suggest that vortioxetine increases glutamatergic and serotonergic neurotransmission in rat forebrain by blocking 5-HT₃ receptors in GABA interneurons.
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In similar lines, activation of 5HT3Rs by agonists suppressed spontaneous glutamate release (Ashby et al., 1991) and NMDA-evoked response of pyramidal neurons in rat medial prefrontal cortex (Liang et al., 1998). Moreover, the suppressant effect was blocked by selective 5HT3R antagonists (Ashby et al., 1991; Liang et al., 1998). As evidenced by preclinical reports, classical antidepressants modulate glutaminergic activity via 5HT3Rs; for example, fluvoxamine administration in mice exposed to chronic restraint stress increased cortical glutamatergic release via 5HT3R activation coupled with sigma-1 receptors (Fu et al., 2012).
5HT₃ receptors (5HT3Rs) have long been identified as a potential target for antidepressants. Several studies have reported that antagonism of 5HT3Rs produces antidepressant-like effects. However, the exact role of 5HT3Rs and the mode of antidepressant action of 5HT3R antagonists still remain a mystery. Here, we provide a comprehensive overview of 5HT3Rs: (a) regional and subcellular distribution of 5HT3Rs in discrete brain regions, (b) preclinical and clinical evidence supporting the antidepressant effect of 5HT3R antagonists, and (c) neurochemical, biological and neurocellular signaling pathways associated with the antidepressant action of 5HT3R antagonists. 5HT3Rs located on the serotonergic and other neurotransmitter interneuronal projections control their release and affect mood and emotional behavior; however, new evidence suggests that apart from modulating the neurotransmitter functions, 5HT3R antagonists have protective effects in the pathogenic events including hypothalamic–pituitary–adrenal-axis hyperactivity, brain oxidative stress and impaired neuronal plasticity, pointing to hereby unknown and novel mechanisms of their antidepressant action. Nonetheless, further investigations are warranted to establish the exact role of 5HT3Rs in depression and antidepressant action of 5HT3R antagonists.
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Although major depressive disorder is primarily considered a mood disorder, depressed patients commonly present with clinically significant cognitive dysfunction that may add to their functional disability. This review paper summarizes the available preclinical data on the effects of antidepressants, including monoamine reuptake inhibitors and the multimodal antidepressant vortioxetine, in behavioral tests of cognition such as cognitive flexibility, attention, and memory, or in potentially cognition-relevant mechanistic assays such as electroencephalography, in vivo microdialysis, in vivo or in vitro electrophysiology, and molecular assays related to neurogenesis or synaptic sprouting. The available data are discussed in context with clinically relevant doses and their relationship to target occupancy levels, in order to evaluate the translational relevance of preclinical doses used during testing. We conclude that there is preclinical evidence suggesting that traditional treatment with monoamine reuptake inhibitors can induce improved cognitive function, for example in cognitive flexibility and memory, and that the multimodal-acting antidepressant vortioxetine may have some advantages by comparison to these treatments. However, the translational value of the reviewed preclinical data can be questioned at times, due to the use of doses outside the therapeutically-relevant range, the lack of data on target engagement or exposure, the tendency to investigate acute rather than long term antidepressant administration, and the trend towards using normal rodents rather than models with translational relevance for depression. Finally, several suggestions are made for advancing this field, including expanded use of target occupancy assessments in preclinical and clinical experiments, and the use of translationally valuable techniques such as electroencephalography.
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In scopolamine-treated mice, ondansetron attenuated the performance deficits (Roychoudhury and Kulkarni, 1997), suggesting the role of 5-HT3 receptors in the normalization of the cholinergic system disrupted by scopolamine. Furthermore, blockade of 5-HT3 receptors may also enhance glutamate transmission since these receptors can suppress both the spontaneous firing and N-methyl-d-aspartic acid-evoked responses of the pyramidal neurons in the rat medial prefrontal cortex (Ashby et al., 1991; Liang et al., 1998). As previously mentioned, the 5-HT3 receptor seems to exert an inhibitory tone on the ACh efflux in the brain.
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Several lines of evidence from our studies and the literature indicate that the dysfunction of the mPFC and 5-HT neurotransmitter system appears to be an etiological and pathophysiological factor for depression, anxiety and cognitive decline in PD (Scholtissen et al., 2006; Ziemssen and Reichmann, 2007; Lohle et al., 2009; Wang et al., 2009a,b,c). 5-HT3 receptors are also known to be involved in the cortical actions of 5-HT because early electrophysiological studies have shown that 5-HT and 5-HT3 receptor agonists suppressed activity of pyramidal neurons in rat prefrontal cortex (PFC) through the activation of 5-HT3 receptors by a direct action (Ashby et al., 1989, 1991, 1992). Therefore, 5-HT3 receptor antagonists display anxiolytic and antipsychotic activity in animal models and PD patients (Zoldan et al., 1995; Higgins and Kilpatrick, 1999).
In the present study, effect of SR 57227A, a selective 5-hydroxytryptamine-3 (5-HT₃) receptor agonist, on the firing activity of pyramidal neurons in the medial prefrontal cortex (mPFC) was studied in normal rats and rats with 6-hydroxydopamine lesions of the substantia nigra pars compacta by using extracellular recording. Systemic administration of SR 57227A (40–640 μg/kg, i.v.) decreased the mean firing rate of pyramidal neurons in normal and the lesioned rats. This inhibition was significant only at doses higher than 320 μg/kg and 640 μg/kg in normal and the lesioned rats, respectively, and was reversed by i.v. administration of 5-HT₃ receptor antagonist tropisetron or GABA_A receptor antagonist bicuculline. Furthermore, local application of SR 57227A (0.01 μg) in the mPFC inhibited the firing rate of pyramidal neurons in normal rats while having no effect on firing rate in the lesioned rats. The i.v. administration of bicuculline excited the pyramidal neurons in normal rats, and then local application of SR 57227A did not alter the mean firing rate of these neurons. However, these two drugs did not affect the activity of the pyramidal neurons in the lesioned rats. We conclude that activation of 5-HT₃ receptors inhibited pyramidal neurons in the mPFC of normal rats via GABAergic interneurons, and degeneration of the nigrostriatal pathway decreased response of the pyramidal neurons to SR 57227A, suggesting the dysfunction of 5-HT₃ receptors and/or down-regulation of the expression on GABAergic interneurons in the lesioned rats.

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5-HT3-like receptors in the rat medial prefrontal cortex: an electrophysiological study

Abstract

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Life Sci.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Neurosci. Lett.

J. Med. Chem.

Eur. J. Pharmacol.

Neuropharmacology

Neuropharmacology

Biochem. Pharmacol.

Eur. J. Pharmacol.

Trends Neurol. Sci.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Brain Res. Rev.

Trends Pharmacol Sci.

Eur. J. Pharmacol.

Neuron

Serotonin: release in the forebrain by stimulation of midbrain raphe

Science

Characterization of 5-hydroxytryptamine3, receptors in the medial prefrontal cortex: a microiontophoretic study

Eur. J. Pharmacol.

Electrophysiological characterization of 5-hydroxytryptamine2 receptors in the rat medial prefrontal cortex

J. Pharmacol. Exp. Ther.

An autoradiographic analysis of the differential ascending projections of the dorsal and median raphe nuclei in the rat

J. Comp. Neurol.

Profile of the stereoisomers of zacopride as 5-HT3 receptor antagonists

[3H]Zacopride: ligand for the identification of 5-HT3 recognition sites

J. Pharm. Pharmacol.

5-HT3 receptors mediate the inhibition of acetylcholine release in cortical tissue

Nature

5-HT₃-like receptors in the rat medial prefrontal cortex: an electrophysiological study

Characterization of 5-hydroxytryptamine₃, receptors in the medial prefrontal cortex: a microiontophoretic study

Electrophysiological characterization of 5-hydroxytryptamine₂ receptors in the rat medial prefrontal cortex

Profile of the stereoisomers of zacopride as 5-HT₃ receptor antagonists

[³H]Zacopride: ligand for the identification of 5-HT₃ recognition sites

5-HT₃ receptors mediate the inhibition of acetylcholine release in cortical tissue