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.
Highlights
Obsessive–compulsive disorder (OCD) was formally classified as an anxiety disorder (DSMIV) but was recently given its own category (DSMV) due to greater commonalities found between this disorder and other OCD-related disorders
In contrast to generalized anxiety disorders that can be fairly well managed by benzodiazepines or selective serotonin reuptake inhibitors (SSRIs), patients with OCD are poorly served by current psychotherapic and pharmacotherapeutic interventions [2, 6], and it is reported that >10% of patients do not respond to any of the available treatments [7]
The overall findings that CPD 1 suppressed a host of excessive and repetitive behaviors without notable effects on ancillary behaviors suggest that 5-HT2C receptor agonists may be efficacious in the clinical management of OCD
Summary
Obsessive–compulsive disorder (OCD) was formally classified as an anxiety disorder (DSMIV) but was recently given its own category (DSMV) due to greater commonalities found between this disorder and other OCD-related disorders. OCD and OCD symptoms demonstrate high comorbidity with other psychiatric disorders [4, 5]. In contrast to generalized anxiety disorders that can be fairly well managed by benzodiazepines or selective serotonin reuptake inhibitors (SSRIs), patients with OCD are poorly served by current psychotherapic and pharmacotherapeutic interventions [2, 6], and it is reported that >10% of patients do not respond to any of the available treatments [7]. SSRIs require doses that are generally well in excess of the doses required for treatment of depression or anxiety. A further failing of the SSRIs used for treatment of OCD is that even when they demonstrate symptom suppression in an individual, the overall symptom improvement is not typically impressive [2]. There is room for substantial improvement in the pharmacological management of OCD
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