Serotonin2C ligands exhibiting full negative and positive intrinsic activity elicit purposeless oral movements in rats: distinct effects of agonists and inverse agonists in a rat model of Parkinson's disease

Abstract

This study examined in naive or hemiparkinsonian rats the effect of various serotonin 2C (5-HT(2C)) receptor ligands differing in their intrinsic activity at 5-HT(2C) receptors on purposeless oral movements, a motor response integrated in the basal ganglia. Intraperitoneal administration of a non-selective [meta-chlorophenylpiperazine (m-CPP) 0.1-3 mg/kg], preferential [S-2-(6-chloro-5-fluoroindol-1-yl)-1-methylethylamine, Ro60-0175, 0.1-3 mg/kg] or selective [(7bR,10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7,1hi]indole, WAY163909, 0.3-10 mg/kg] 5-HT(2C) agonists enhanced oral bouts in naive rats. The 5-HT(2C) inverse agonists SB206553 [1-20 mg/kg; 5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole] and S32006 [1-20 mg/kg; N-pyridin-3-yl-1,2-dihydro-3H-benzo[e]indole-3-carboxamide], but not the 5-HT(2C) antagonist SB243213 [1-10 mg/kg; 5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-6-trifluoromethylindoline], likewise dose-dependently enhanced oral movements. The effects induced by preferential 5-HT(2C) agonists and inverse agonists, but not by the cholinomimetic drug pilocarpine (5 mg/kg), were abolished by SB243213 underpinning its specificity. S32006-induced oral bouts was unaffected by the 5,7-dihydroxytryptamine lesions of 5-HT neurons. Nigrostriatal dopaminergic lesions potentiated oral effects induced by the agonists Ro60-0175 (3 mg/kg) and WAY163909 (1 mg/kg), but not by the inverse agonist SB206553 (10 mg/kg). The effect of Ro60-0175 in dopamine-lesioned rats was suppressed by SB243213. These data show that 5-HT(2C) agonists and full inverse agonists (but not neutral antagonists) perturb oral activity in rodents, paralleling studies of common antidepressant, anxiolytic and antipsychotic properties. The differential sensitivity of their actions to depletion of dopamine suggests recruitment of different contrasting neural mechanisms in the basal ganglia.

Atypical antipsychotics and inverse agonism at 5-HT₂ receptors

“…Interestingly, applications of 5-HT 2 receptor inverse agonists have recently extended beyond schizophrenia. For example, in addition to psychosis associated with Parkinson’s disease [86], 5-HT 2 receptor inverse agonists are also being evaluated as treatments for psychosis related to Alzheimer’s disease [85] and for treatment of movement disorders related to Parkinson’s disease [87]. Overall, a better understanding of inverse agonism at 5-HT 2 receptor systems could have far-reaching implications for the development of novel therapeutics.…”

“…However, although pimavanserin is reported to enhance the efficacy and tolerability of the atypical antipsychotic, risperidone, but not the typical antipsychotic, haloperidol [83], clinical trials conducted with pimavanserin monotherapy have been disappointing. By contrast, recent studies suggest that pimavanserin may be effective for treating the secondary psychosis associated with Parkinson’s disease which is thought to be due to 5-HT 2A receptor activity [86, 87]. Currently, pimavanserin is in clinical trials for treatment of psychosis associated with Parkinson’s disease [88 and see www.clinicaltrials.gov].…”

Nucleus accumbens shell excitability is decreased by methamphetamine self-administration and increased by 5-HT2C receptor inverse agonism and agonism

“…5-HT 2C R inverse agonists and agonists exhibit similar behavioral effects in rats (Graves and Napier, 2012, Navailles et al, 2013). In contrast, neurochemical studies show that inverse agonists increase accumbal and striatal dopamine (De Deurwaerdere et al, 2004), whereas agonists have no effect, or decrease dopamine (Di Matteo et al, 1998, Willins and Meltzer, 1998, Di Matteo et al, 2000, Gobert et al, 2000).…”

A short history of the 5-HT2C receptor: from the choroid plexus to depression, obesity and addiction treatment

“…Niswender et al 2011;Gurevich et al 2002;Lyddon et al 2013). It is clear that is some brain regions and depending on state, native 5-HT2CR display constitutive activity which can vary largely (Di Giovanni et al 1999;Di Matteo et al 2000;Gobert et al 2000;Leggio et al 2009;Navailles et al 2004;2013a;2013b). A number of antipsychotics behave actually as inverse agonists (Berg et al 1999;Herrick-Davis et al 2000;Rauser et al 2001;Navailles et al, 2004;Aloyo et al 2009;Sullivan et al; and if the 5-HT2CR is a target, their effectiveness may depend on the level of constitute activity of the receptor (Navailles et al 2013b).…”

“…It is clear that is some brain regions and depending on state, native 5-HT2CR display constitutive activity which can vary largely (Di Giovanni et al 1999;Di Matteo et al 2000;Gobert et al 2000;Leggio et al 2009;Navailles et al 2004;2013a;2013b). A number of antipsychotics behave actually as inverse agonists (Berg et al 1999;Herrick-Davis et al 2000;Rauser et al 2001;Navailles et al, 2004;Aloyo et al 2009;Sullivan et al; and if the 5-HT2CR is a target, their effectiveness may depend on the level of constitute activity of the receptor (Navailles et al 2013b). A complicating factor is that constitutive activity may vary with transduction pathway (Berg et al 1994;1998a;1998b;2001;2008a;2008b;Moya et al 2007;Wang et al 2000;Werry et al 2005;2008;Berg and Clarke 2009), receptor desensitization and trafficking may be at play as well Marion et al, 2004) and different ligands may possess different pathway selectivity.…”