Novel regulation of 5-HT1C receptors: down-regulation induced both by 5-HT1C/2 receptor agonists and antagonists

doi:10.1016/0922-4106(93)90052-B

European Journal of Pharmacology: Molecular Pharmacology

Volume 244, Issue 1, 4 January 1993, Pages 1-5

https://doi.org/10.1016/0922-4106(93)90052-B Get rights and content

Abstract

The 5-hydroxytryptamine_1C (5-HT_1C) receptor shares many features with the 5-HT₂ receptor. To determine if the regulation of the sites is also similar we studied the effects of chronic treatment with drugs active at 5-HT_1C/2 receptors on [³H]mesulergine-labelled 5-HT_1C binding sites in spinal cord. The 5-HT receptor agonists 1-(3-chlorophenyl)piperazine (m-CPP) (-38%), 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) (-35%), quipazine (-27%) and m-trifluoromethylphenylpiperazine (TFMPP) (-27%) significantly down-regulated spinal 5-HT_1C sites with chronic injection compared to vehicle treatment. The 5-HT receptor antagonist methiothepin (-71%), mianserin (-24%), methysergide (-21%), and cyproheptadine (-27%) also induced down-regulation, and ritanserin and metergoline further reduced [³H]mesulergine specific binding to undetectable levels. There were no significant changes in K_d to implicate presence of residual drug except for mianserin, methiothepin, and TFMPP. Pindolol and spiperone had no significant effects. In acute dose-response studies, injection of a single dose of DOI did not result in a significant change in any receptor parameters. The capacity of a drug to lower B_max correlated significantly with its pK_d (r = 0.84, P < 0.0007). This drug regulation pattern for 5-HT_1C sites of down-regulation by both 5-HT_1C/2 receptor agonists and antagonists is similar to that for 5-HT₂ receptors and is consistent with the classification of 5-HT_1C and 5-HT₂ receptors in the same superfamily.

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In contrast to most other receptors, the 5-HT2C receptor is not classically regulated. Chronic treatment with 5-HT2 receptor agonists or antagonists resulted in a paradoxical down-regulation at the 5-HT2A and 5-HT2C receptors (Barker and Sanders-Bush, 1993; Newton and Elliott, 1997; Pranzatelli et al., 1993; Serretti et al., 2004; Van Oekelen et al., 2003). The mechanism of down-regulation for 5-HT2 receptors has been related to molecular events during the internalization process; a phosphorylation step and possible degradation in lysosomes would have for consequence to reduce the number of activated receptors at cell surface in the plasma membrane (Van Oekelen et al., 2003).
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As a large number of psychotropic drugs, including atypical antipsychotics, antidepressants and anxiolitics, can all induce down-regulation of 5-HT2C receptors, it has been suggested that this receptor adaptation plays a role in the therapeutic action of these drugs (Van Oekelen et al., 2003; Serretti et al., 2004). In this respect, it is interesting to note that chronic treatment with 5-HT2 agonists or antagonists resulted in a paradoxical down-regulation at the 5-HT2A and 5-HT2C receptors (Barker and Sanders-Bush, 1993; Pranzatelli et al., 1993; Newton and Elliott, 1997; Van Oekelen et al., 2003; Serretti et al., 2004) and it seems that the down-regulation state occurring after chronic exposure to mianserin in isolated systems as well as in cell cultures is a direct receptor-mediated mechanism of this drug at these receptors (Newton and Elliott, 1997). Therefore, the down-regulating capacity of 5-HT2C agonists and antagonists may play a particularly important role in treating the supersensitivity of 5-HT2C receptors resulting from a depressive state (Moreau et al., 1996; Jenck et al., 1998; Serretti et al., 2004).
In this review, the functional interactions between serotonin (5-HT) and dopamine (DA) neuronal systems are discussed with the focus on microdialysis studies in the rodent brain (mainly rats). 5-HT by itself is involved both directly and indirectly via actions on complex neuronal circuitry, in the regulation of DA release through multiple 5-HT receptors, playing a critical role in the development of normal and abnormal behaviours. Recent evidence suggests that dysfunction of dopaminergic and serotoninergic neurotransmitter systems contributes to various disorders including depression, schizophrenia, Parkinson's disease and drug abuse. Here we summarize recent neurochemical works that have extensively explored the role of 5-HT receptors in the control of DA central systems in both basal and drug-induced conditions, using in vivo microdialytic techniques. Several 5-HT receptor subtypes, including the 5-HT_1A, 5-HT_1B, 5-HT_2A, 5-HT₃ and 5-HT₄ receptors, act to facilitate DA release, while the 5-HT_2C receptor mediates an inhibitory effect of 5-HT on DA release. Taken together, neurochemical approaches using microdialysis can not only contribute to clarification of the physiological role of the serotonergic neuronal systems but may also be a powerful pharmacological approach for the development of therapeutic strategies to the treatment of depression, schizophrenia, Parkinson's disease and drug abuse.
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It was recently reported that depletion of serotonin increases expression of 5-HT2C mRNA isoforms encoding receptors with higher sensitivity to serotonin (Gurevich et al., 2002). In addition, repeated administration of 5HT2C agonists downregulates 5HT2C receptors (Pranzatelli et al., 1993). These results suggest that the expression and activity of the 5HT2C receptor are affected by serotonin levels.
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The effects of upper lumbar level intrathecal injection of yohimbine, an α₂-noradrenergic antagonist, on overground locomotion in intact rats was studied. This treatment caused dose-dependent impairment of hindlimb locomotor movement, which varied from transient hindlimb paralysis at a dose of 200 μg/20 μl to transient trunk instability at 50 μg/20 μl. Repetitive (every 48 h) injections of yohimbine at high (200 μg/20 μl) and medium (100 μg/20 μl) doses caused tachyphylaxis, which usually led to a lack of reaction to the third injection. This phenomenon was not observed after repetitive injections of the low (50 μg/20 μl) dose of the drug. These results show that the noradrenergic system is involved in the control of locomotion, since intrathecal administration of a specific antagonist affects this activity in intact rats.
Heterologous desensitization is evoked by both agonist and antagonist stimulation of the human 5-HT<inf>7</inf> serotonin receptor
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Previously, we demonstrated that human serotonin (5-HT) 5-HT₇ receptors display marked constitutive activity. Here, we tested if the constitutive activation of adenylyl cyclase by 5-HT₇ receptors influenced both the desensitization properties of transfected 5-HT₇ receptors and the ability of endogenous G_s-coupled receptors to activate adenylyl cyclase. Using membranes from stably transfected HEK293 cells expressing the recombinant human 5-HT₇ receptor splice variants (5-HT_7(a), 5-HT_7(b) and 5-HT_7(d)), we compared the effects of 1-h or 24-h preincubation of the agonist 5-HT, partial inverse agonists mesulergine and SB269970, and full inverse agonists clozapine and methiothepin on subsequent activation of adenylyl cyclase by both 5-HT through transfected 5-HT₇ receptors and the endogenous G_s-coupled β-adrenoceptors and prostaglandin receptors of HEK293 cells. The data show that stable expression of 5-HT₇ receptors is sufficient to attenuate adenylyl cyclase activation by endogenous G_s-coupled receptors. Interestingly, preincubation with inverse agonists not only failed to result in the predicted resensitization of all receptor mediated adenylyl cyclase activation, but some inverse agonists further attenuated (desensitized) β-adrenoceptor and prostaglandin-stimulated adenylyl cyclase activation similar to long-term agonist exposure by 5-HT. These effects were not correlated with inverse agonist efficacy, were not accompanied by receptor down-regulation and appear to be mediated by a protein kinase A (PKA) independent mechanism. It is concluded that the human 5-HT₇ receptor mediates heterologous desensitization of endogenous G_s-coupled receptors through an unknown and potentially novel mechanism.
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The effect of ligand pretreatment on human 5-hydroxytryptamine_2C (5-HT_2C) receptors was examined in CHO cells expressing high (CHO-1C7; 67±3 pmol/mg) or low (CHO-1C19; 72±10 fmol/mg) levels of the receptor. Seventy-two hours pretreatment of CHO-1C7 cells with various ligands did not affect receptor expression. Pretreatment with inverse agonists enhanced 5-HT-mediated inositol phosphate accumulation with no change in constitutive receptor activity. The enhanced agonist responsiveness was inversely correlated with the intrinsic activity of the pretreatment ligand. Seventy-two hours of pretreatment with the weak agonist, 5-methoxygramine, caused an elevation in constitutive activity but no alteration in 5-HT-mediated signaling. In CHO-1C19 cells, 24 but not 72 h of pretreatment with the inverse agonist mianserin enhanced 5-HT-mediated signaling, with no effect on basal signaling; pretreatment with 5-methoxygramine had no significant effect. These findings highlight differences in the pattern of chronic regulation of 5HT_2C receptor signaling between high and low receptor expression levels in a common cellular background.

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Regular paperNovel regulation of 5-HT1C receptors: down-regulation induced both by 5-HT1C/2 receptor agonists and antagonists

Abstract

Eur. J. Pharmacol.

Brain Res. Bull.

Neuropharmacology

Brain Res.

Trends Pharmacol. Sci.

Eur. J. Pharmacol.

Neuropharmacology

Comput. Programs Biomed.

Brain Res.

Brain Res. Bull.

Neurosci. Lett.

Regular paper
Novel regulation of 5-HT_1C receptors: down-regulation induced both by 5-HT_1C/2 receptor agonists and antagonists