5HT-2 mediation of acute behavioral effects of hallucinogens in rats

Wing, Lauren L.; Tapson, Gregory S.; Geyer, Mark A.

doi:10.1007/bf02244617

Cited by 90 publications

(86 citation statements)

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“…Before evaluation in rat sleep, nelotanserin was tested in a DOI-screening assay. DOI is a 5-HT 2 partial agonist that induces a biphasic locomotor response (hypolocomotion followed by hyperlocomotion) in rats (Wing et al, 1990). The hypolocomotive response is readily measured by counting the number of times an animal rears within 10 min after DOI administration.…”

Section: In Vivo Studiessupporting

confidence: 42%

Nelotanserin, a Novel Selective Human 5-Hydroxytryptamine_2A Inverse Agonist for the Treatment of Insomnia

Al-Shamma¹,

Anderson²,

Chuang³

et al. 2009

J Pharmacol Exp Ther

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5-Hydroxytryptamine (5-HT) 2A receptor inverse agonists are promising therapeutic agents for the treatment of sleep maintenance insomnias. Among these agents is nelotanserin, a potent, selective 5-HT 2A inverse agonist. Both radioligand binding and functional inositol phosphate accumulation assays suggest that nelotanserin has low nanomolar potency on the 5-HT 2A receptor with at least 30-and 5000-fold selectivity compared with 5-HT 2C and 5-HT 2B receptors, respectively. Nelotanserin dosed orally prevented (Ϯ)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI; 5-HT 2A agonist)-induced hypolocomotion, increased sleep consolidation, and increased total nonrapid eye movement sleep time and deep sleep, the latter marked by increases in electroencephalogram (EEG) delta power. These effects on rat sleep were maintained after repeated subchronic dosing. In healthy human volunteers, nelotanserin was rapidly absorbed after oral administration and achieved maximum concentrations 1 h later. EEG effects occurred within 2 to 4 h after dosing, and were consistent with vigilance-lowering. A dose response of nelotanserin was assessed in a postnap insomnia model in healthy subjects. All doses (up to 40 mg) of nelotanserin significantly improved measures of sleep consolidation, including decreases in the number of stage shifts, number of awakenings after sleep onset, microarousal index, and number of sleep bouts, concomitant with increases in sleep bout duration. Nelotanserin did not affect total sleep time, or sleep onset latency. Furthermore, subjective pharmacodynamic effects observed the morning after dosing were minimal and had no functional consequences on psychomotor skills or memory. These studies point to an efficacy and safety profile for nelotanserin that might be ideally suited for the treatment of sleep maintenance insomnias.Serotonin has long been implicated in the regulation of sleep and wakefulness. Central serotonergic neurons of the dorsal raphe nucleus form part of the reticular activating system that innervates cortical and subcortical regions of the forebrain. As its name implies, this system modulates arousal in the central nervous system (CNS) and regulates sleep/wake states (Abrams et al., 2005). Within this system, 5-HT neurons are active during wakefulness, less active during nonrapid eye movement (NREM) sleep, and inactive during rapid eye movement (REM) sleep.5-HT activity in the CNS is mediated by multiple receptor subtypes that are classified into seven subfamilies (5-HT 1 to 5-HT 7 ) (Hoyer et al., 1994). The 5-HT 2 subfamily includes three subtypes: 5-HT 2A , 5-HT 2B , and 5-HT 2C . Unlike 5-HT 2B receptors, which have limited CNS expression, 5-HT 2A and 5-HT 2C receptors are widely distributed in the CNS in areas that are implicated in the regulation of sleep and waking (Leysen, 2004). There is compelling preclinical and clinical evidence that supports a role for 5-HT 2A antagonism in the treatment of sleep maintenance insomnias (Borbély et al., This work was supported by Arena Phar...

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Section: In Vivo Studiessupporting

confidence: 42%

Nelotanserin, a Novel Selective Human 5-Hydroxytryptamine_2A Inverse Agonist for the Treatment of Insomnia

Al-Shamma¹,

Anderson²,

Chuang³

et al. 2009

J Pharmacol Exp Ther

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“…As summarized above, direct agonists at 5-HT 1A or 5-HTlC/2 receptors suppress rather than increase loco motor activity in this paradigm (Mittman and Geyer 1989;Wing et al 1990). Hence, the hypothesis tested in these studies was that the 5-HTlB receptor might mediate the activating effects of the indirect 5-HT agonists.…”

Section: Minute Blockssupporting

confidence: 38%

“…Similarly, di rect agonists at 5-HflC/2 receptors, including quipazine and both indoleamine and phenethylamine hallucino gens, also decrease activity in the BPM, at least when the animals are not familiar with the test environment NEUROPSYCHOPHARMACOLOGY 1993-VOL. 8, NO.3 (Adams and Geyer 1985a, b;Wing et al 1990). These effects of the direct agonists are selectively antagonized by the appropriate 5-HTI or 5-HTlC/2 antagonists and can be differentiated behaviorally using the profIle of measures provided by the BPM system (Mittman and Geyer 1989;Wing et al 1990).…”

mentioning

confidence: 44%

“…8, NO.3 (Adams and Geyer 1985a, b;Wing et al 1990). These effects of the direct agonists are selectively antagonized by the appropriate 5-HTI or 5-HTlC/2 antagonists and can be differentiated behaviorally using the profIle of measures provided by the BPM system (Mittman and Geyer 1989;Wing et al 1990). Hence, it seems unlikely that the hyperactivity produced by the indirect agonists reflect an activation of postsynaptic 5-HflA' 5-HfIe, or 5-HT 2 receptors.…”

mentioning

confidence: 44%

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Serotonin1B Receptor Activation Mimics Behavioral Effects of Presynaptic Serotonin Release

Rempel

Callaway

Geyer

1993

Neuropsychopharmacol

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“…The administration of the 5-HT 2A/B/C agonist DOI to rats elicits a constellation of behavioral and physiological effects including head shakes or headtwitches, skin jerks, forepaw treading, rearing, chewing, changes in locomotor activity, hyperthermia and neophobia (Gudelsky et al 1986;Pranzatelli 1990;Wing et al 1990). The head shakes induced by 5-HT agonists can be blocked by non-selective 5-HT 2 antagonists (Colpaert and Janssen 1983;Lucki et al 1984;Peroutka et al 1981; Yap and Taylor 1983).…”

mentioning

confidence: 44%

Behavioral Evidence for Interactions between a Hallucinogenic Drug and Group II Metabotropic Glutamate Receptors

Gewirtz

Marek

2000

Neuropsychopharmacology

157

107

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Recent electrophysiological studies in our laboratory have demonstrated a physiological interaction between 5-HT 2A and metabotropic glutamate2/3 (mGlu2/3) Activation of 5-hydroxytryptamine 2A (5-HT 2A ) receptors is thought to mediate many effects of ergoline (e.g., lysergic acid diethylamide; LSD), simple indoleamine (e.g., psilocybin), and phenethylamine (e.g., 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane; DOI) hallucinogens in both rodents and humans (Glennon 1990;Marek and Aghajanian 1996;Titeler et al. 1988;Vollenweider et al. 1998). The administration of the 5-HT 2A/B/C agonist DOI to rats elicits a constellation of behavioral and physiological effects including head shakes or headtwitches, skin jerks, forepaw treading, rearing, chewing, changes in locomotor activity, hyperthermia and neophobia (Gudelsky et al. 1986;Pranzatelli 1990;Wing et al. 1990). The head shakes induced by 5-HT agonists can be blocked by non-selective 5-HT 2 antagonists (Colpaert and Janssen 1983;Lucki et al. 1984;Peroutka et al. 1981; Yap and Taylor 1983). Moreover, studies employing antagonists selective for 5-HT 2A or 5-HT 2C receptors have shown that head shakes induced by DOI are mediated via activation of 5-HT 2A receptors (Schreiber et al. 1995;Willins and Meltzer 1997). Recent work similarly finds that DOI and other hallucinogenic drugs fail to induce head twitches when administered to 5-HT 2A receptor knockout mice, in contrast to wild-type mice (Gingrich et al. 1999). Thus, DOI-induced head shakes have become the most widely used behavioral model for the study of 5-HT 2A receptors in rodents.It has been reported that local infusion of 1-(2,5-dimethoxyphenyl-4-bromo)-2-aminopropane (DOB) and NO . 5 DOI into the medial prefrontal cortex induces head shakes (Granhoff et al. 1992a;Willins and Meltzer 1997). 5-HT 2A receptors appear to be prominently expressed on the apical dendrites of pyramidal cells in the neocortex (Jakab and Goldman-Rakic 1998;. In addition to activation of postsynaptic 5-HT 2A receptors on these pyramidal cells, 5-HT 2A agonists have a presynaptic action to release glutamate from afferents with a restricted laminar expression (Aghajanian and Marek 1997). The majority of these afferents appear to originate in the medial thalamus (Marek and Gewirtz 1999). Recently, we have found that activation of metabotropic glutamate2/3 (mGlu2/3) receptors suppresses the 5-HT 2A receptor-mediated increase in excitatory postsynaptic potentials/currents (EPSPs/ EPSCs) in layer V medial prefrontal cortical pyramidal cells (Marek et al. 2000). Conversely, blockade of mGlu2/3 receptors by the mGlu2/3 antagonist LY341495 enhances the frequency and amplitude of 5-HT-induced EPSCs. This latter result suggests that endogenous glutamate, released by activation of 5-HT 2A receptors, tonically activates mGlu2/3 receptors that function to decrease the frequency of 5-HT-induced EPSCs. Taken together, these results imply that mGlu2/3 receptors (likely mGlu2, see Marek et al. (2000)) function as autoreceptors on thalamocortical...

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5HT-2 mediation of acute behavioral effects of hallucinogens in rats

Cited by 90 publications

References 31 publications

Nelotanserin, a Novel Selective Human 5-Hydroxytryptamine_2A Inverse Agonist for the Treatment of Insomnia

Nelotanserin, a Novel Selective Human 5-Hydroxytryptamine_2A Inverse Agonist for the Treatment of Insomnia

Serotonin1B Receptor Activation Mimics Behavioral Effects of Presynaptic Serotonin Release

Behavioral Evidence for Interactions between a Hallucinogenic Drug and Group II Metabotropic Glutamate Receptors

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5HT-2 mediation of acute behavioral effects of hallucinogens in rats

Cited by 90 publications

References 31 publications

Nelotanserin, a Novel Selective Human 5-Hydroxytryptamine2A Inverse Agonist for the Treatment of Insomnia

Nelotanserin, a Novel Selective Human 5-Hydroxytryptamine2A Inverse Agonist for the Treatment of Insomnia

Serotonin1B Receptor Activation Mimics Behavioral Effects of Presynaptic Serotonin Release

Behavioral Evidence for Interactions between a Hallucinogenic Drug and Group II Metabotropic Glutamate Receptors

Contact Info

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Nelotanserin, a Novel Selective Human 5-Hydroxytryptamine_2A Inverse Agonist for the Treatment of Insomnia

Nelotanserin, a Novel Selective Human 5-Hydroxytryptamine_2A Inverse Agonist for the Treatment of Insomnia