5-HT3 receptors mediate rapid responses in cultured hippocampus and a clonal cell line

doi:10.1016/0896-6273(88)90111-0

Neuron

Volume 1, Issue 7, September 1988, Pages 615-621

https://doi.org/10.1016/0896-6273(88)90111-0 Get rights and content

Abstract

Serotonin (5-HT) induces a large inward current accompanied by a conductance increase when applied focally to either neurons of mouse hippocampal cultures or cells of the NG108-15 clonal cell line. In both systems, the response is blocked by ICS 205–930, curare, and metoclopramide, while 2-methyl-5-HT is an agonist. The actions of ICS 205–930 and 2-methyl-5-HT indicate that the response is mediated by the 5-HT₃ receptor. In NG108-15 cells the response activated in as little as 35 ms. The rapidity of the response suggests a direct coupling between the 5-HT₃ receptor and a channel, which are probably both part of a single membrane protein. In both cell types, prolonged application of 5-HT resulted in desensitization; the rates of desensitization were accelerated by the adenylate cyclase activator forskolin. The 5-HT₃ receptor has much in common with the nicotinic receptor and is probably involved in rapid synaptic transmission in the mammalian brain. Since this response is modulated by manipulations that elevate intracellular CAMP levels, the central synapses in which this receptor operates may exhibit plasticity.

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The role of parental morphine exposure before gestation on mood disorder in the offspring was well described. Besides, physical activity can improve the symptoms of mood disorders. So, the current study aimed to investigate the role of physical activity on depressive and OCD-like behaviors induced by parental morphine exposure.
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Serotonin plays an important yet underappreciated role in the physiology and function of the striatum, impacting numerous behaviors including reward seeking, decision-making, and motor planning. This review discusses how the anatomical pattern of innervation of striatum by serotonergic neurons from midbrain raphe and the complex distribution of serotonin receptors within striatum impact how serotonin modulates the striatal function. We highlight data from studies employing in vivo microdialysis to discuss the neurochemistry of striatal serotonin receptors with respect to their role on serotonin and dopamine release. Finally, we discuss behaviors impacted by serotonin in the striatum and attempt to provide a framework to understand the complicated role of serotonin in modulating the striatum neurochemically, behaviorally, and functionally.
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Citation Excerpt :
The assembly of five 5-HT3 subunits constitutes a central ion-channel which is permeable to the monovalent cations, Na+ and K+ (Yang, 1990), and the divalent cation Ca++ (Hargreaves et al., 1994). The 5-HT3R activation-induced influx of cations via its intrinsic ion channel results in a rapid depolarization of the neuronal cell membrane (Yakel and Jackson, 1988). 5-HT3R mediated depolarization of the presynaptic nerve terminal modulates the release of a spectrum of neurotransmitters, including dopamine (DA), GABA, acetylcholine (ACh), glutamate and substance P (Fink and Gothert, 2007; Giovannini et al., 1998; Koyama et al., 2000; Wang et al., 1998), whereas postsynaptically, it evokes excitatory fast synaptic neurotransmission (Sugita et al., 1992).
The FDA-approved antidepressant and smoking cessation drug bupropion is known to inhibit dopamine and norepinephrine reuptake transporters, as well as nicotinic acetylcholine receptors (nAChRs) which are cation-conducting members of the Cys-loop superfamily of ion channels, and more broadly pentameric ligand-gated ion channels (pLGICs). In the present study, we examined the ability of bupropion and its primary metabolite hydroxybupropion to block the function of cation-selective serotonin type 3A receptors (5-HT_3ARs), and further characterized bupropion's pharmacological effects at these receptors. Mouse 5-HT_3ARs were heterologously expressed in HEK-293 cells or Xenopus laevis oocytes for equilibrium binding studies. In addition, the latter expression system was utilized for functional studies by employing two-electrode voltage-clamp recordings. Both bupropion and hydroxybupropion inhibited serotonin-gated currents from 5-HT_3ARs reversibly and dose-dependently with inhibitory potencies of 87 μM and 112 μM, respectively. Notably, the measured IC₅₀ value for hydroxybupropion is within its therapeutically-relevant concentrations. The blockade by bupropion was largely non-competitive and non-use-dependent. Unlike its modulation at cation-selective pLGICs, bupropion displayed no significant inhibition of the function of anion-selective pLGICs. In summary, our results demonstrate allosteric blockade by bupropion of the 5-HT_3AR. Importantly, given the possibility that bupropion's major active metabolite may achieve clinically relevant concentrations in the brain, our novel findings delineate a not yet identified pharmacological principle underlying its antidepressant effect.
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The serotonergic system has often been defined as a neuromodulator system, and is specifically involved in learning and memory via its various receptors. Serotonin is involved in many of the same processes affected by cannabinoids. The present study investigated the influence of bilateral post-training intra-prelimbic (PL) administrations of serotonergic 5-hydroxytryptamine type-3 (5-HT3) receptor agents on arachidonylcyclopropylamide (ACPA) (cannabinoid CB1 receptor agonist)-induced amnesia, using the step-through inhibitory avoidance (IA) task to assess memory in adult male Sprague–Dawley rats. The results indicated that sole intra-PL microinjection of ACPA (0.1 and 0.5 μg/rat) and 5-HT3 serotonin receptor agonist (m-Chlorophenylbiguanide hydrochloride, m-CPBG; 0.001, 0.01 and 0.1 μg/rat) impaired, whereas Y-25130 (a selective 5-HT3 serotonin receptor antagonist; 0.001 and 0.01 and 0.1 μg/rat) did not alter IA memory consolidation, by itself. Moreover, intra-PL administration of subthreshold dose of m-CPBG (0.0005 μg/rat) potentiated, while Y-25130 (0. 1 μg/rat) restored ACPA-induced memory consolidation deficit. The isobologram analysis showed that there is a synergistic effect between ACPA and m-CPBG on memory consolidation deficit. These findings suggest that 5-HT3 receptor mechanism(s), at least partly, play(s) a role in modulating the effect of ACPA on memory consolidation in the PL area.

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Neuron

Article5-HT3 receptors mediate rapid responses in cultured hippocampus and a clonal cell line

Abstract

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Eur. J. Pharmacol.

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J. Physiol.

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J. Physiol.

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Nature

Agents that activate protein kinase C reduce acetylcholine sensitivity in cultured myotubes

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Article
5-HT₃ receptors mediate rapid responses in cultured hippocampus and a clonal cell line