Behavioral Effects of a Novel Benzofuranyl-Piperazine Serotonin-2C Receptor Agonist Suggest a Potential Therapeutic Application in the Treatment of Obsessive–Compulsive Disorder

Abstract

Selective serotonin reuptake inhibitors (SSRIs) are the only effective pharmacological treatments for obsessive–compulsive disorder (OCD). Nonetheless, their generally limited efficacy, side-effects, and delayed onset of action require improved medications for this highly prevalent disorder. Preclinical and clinical findings have suggested serotonin2C (5-HT2C) receptors as a potential drug target. Data in rats and mice are presented here on the effects of a novel 5-HT2C receptor agonist ((3S)-3-Methyl-1-[4-(trifluoromethyl)-7-benzofuranyl]-piperazine) (CPD 1) with high potency and full efficacy at 5-HT2C receptors and less potency and partial agonism at 5-HT2A and 5-HT2B receptors. Effects of CPD 1 on consummatory (schedule-induced polydipsia in rats) and non-consummatory behaviors (marble-burying and nestlet-shredding in mice) that are repetitive and non-habituating were studied. We also evaluated the effects of CPD 1 in rats with isoproterenol- and deprivation-induced drinking in rats to compare with the polydipsia studies. The SSRIs, fluoxetine, and chlomipramine decreased the high rates of drinking in rats engendered by a schedule of intermittent food delivery (schedule-induced polydipsia). The effects of fluoxetine, but not of d-amphetamine, were prevented by the selective 5-HT2C receptor antagonist SB242084. The 5-HT2C receptor agonists Ro 60-0175 and CPD 1 also decreased drinking, but unlike the SSRIs and Ro 60-0175, CPD 1 dose-dependently decreased excessive drinking without affecting lever press responses that produced food. The effects of CPD 1 were prevented by SB242084. CPD 1 also suppressed drinking induced by isoproterenol and by water deprivation without affecting normative drinking behavior. CPD 1, like fluoxetine, also suppressed marble-burying and nestlet-shredding in mice at doses that did not affect rotarod performance or locomotor activity. The behavioral specificity of effects of CPD 1 against repetitive and excessive behaviors suggests a potential therapeutic application in OCD.

Increased Fear Memory and Glutamatergic Modulation in Compulsive Drinker Rats Selected by Schedule-Induced Polydipsia

“…Thus, HD and LD rats selected by SIP has shown consistent behavioral differences among different behavioral paradigms. Otherwise, SIP is considered a good model for researching the psychopharmacology of the compulsive phenotype (Platt et al, 2008; Moreno and Flores, 2012; Rodriguez et al, 2017). Indeed, studies on SIP revealed the efficacy of antipsychotic (haloperidol, clozapine, and pimozide) and antidepressant (fluoxetine) drugs in reducing SIP water intake (Snodgrass and Allen, 1989; Didriksen et al, 1993; Mittleman et al, 1994; Hogg and Dalvi, 2004; Dwyer et al, 2010).…”

The Psychopharmacology of Obsessive-Compulsive Disorder: A Preclinical Roadmap

“…One of those models (schedule-induced polydipsia in rats) relies on performance of consummatory behaviors, whereas the other two (marble burying and nestlet shredding in mice) depend on performance of nonconsummatory behaviors that are repetitive and nonhabituating. Both CPD 1 and fluoxetine suppressed marble burying and nestlet shredding, with CPD 1 dose-dependently decreasing excessive drinking engendered by a schedule of intermittent food delivery (schedule-induced polydipsia) (Rodriguez et al, 2017). The researchers concluded that the behavioral specificity of effects of CPD 1 against repetitive and excessive behaviors suggests a potential therapeutic application in OCD, thus supportive of the therapeutic utility of stimulating 5-HT2C receptors in OCD.…”

“…A recent study (Rodriguez et al, 2017) considered the effects of a novel 5-HT2C receptor agonist, (3S)-3methyl-1-[4-(trifluoromethyl)-7-benzofuranyl]-piperazine (CPD 1), with high potency and full efficacy at 5-HT2C receptors in three animal model preparation of OCD. One of those models (schedule-induced polydipsia in rats) relies on performance of consummatory behaviors, whereas the other two (marble burying and nestlet shredding in mice) depend on performance of nonconsummatory behaviors that are repetitive and nonhabituating.…”

“…Some coupling of vigor and satiety may be experimentally unavoidable because induction of "satiety" should diminish the incentive of motivational stimuli (Barrozo et al, 2010a,b) and thus motor vigor (Niv et al, 2007). However, the double effect with mCPP may result also from stimulating multiple serotonin receptors, given that mCPP is more aptly a nonselective 5-HT2A/2C agonist (Rajkumar et al, 2009;Rodriguez et al, 2017). The two receptor subtypes have a different distribution in the brain (Pompeiano et al, 1994) and sometimes opposite effects on behavior (Winstanley et al, 2004b;Boulougouris et al, 2008;Kontis et al, 2008;Halberstadt et al, 2009;Zeeb et al, 2010).…”

The Bed Nucleus of the Stria Terminalis, Homeostatic Satiety, and Compulsions: What Can We Learn From Polydipsia?

“…In SIP-prone rats, differences in the binding affinity of DA D1-like/D2-like receptors exist in limbic and cortical circuits (amygdala, VTA, NAc, and medial prefrontal cortex [mPFC]) (Pellón et al, 2011). Furthermore, pharmacological pretreatment with either DA agonists/antagonists, serotonergic or monoamine modulators, reduce SIP behaviors (i.e., drinking and licking; see Table 2) (Moreno and Flores, 2012; Navarro et al, 2015; Rodriguez et al, 2017; Sukhanov et al, 2019). High drinking rats also show elevated serotonergic activity in the amygdala (Moreno et al, 2012) and reduced 5-HT 2A receptor binding in the mPFC (Mora et al, 2018) with additional evidence for changes in DA activity in the PFC, NAc, and amygdala (Moreno et al, 2012).…”