trans-Pat, a novel 5HT2C receptor agonist/5HT2A receptor antagonist exhibits antipsychotic and appetite suppressant properties”

BIVENS. NM; WEISSTAUB.N.V;; BRADLEY-MOORE, M;; KUMARK; BOOTH, R.G;; GINGRICH,J.A

Boca Raton

Congreso; American College of Neuropsychopharmacology 46th Annual Meeting; 2007

American College of Neuropsychopharmacology

Background: Utilizing a new compound, (1R,3S)-(-)-trans-1-phenyl-3-dimethylamino-1,2,3,4-tetrahydronaphthalene (Trans-PAT), we have explored theeffects of simultaneous agonism at 5HT2C receptors and antagonism at 5HT2A and5HT2B receptors in the mouse, showing antipsychotic and appetite suppressingeffects. Serotonin (5HT) 2A receptor antagonist activity is a component of secondgeneration antipsychotics and 5HT2A receptor agonists such as LSD and psilocincan cause psychomimetic symptoms of hallucination and psychomotor activation.Mice deficient in 5HT2AR have decreased response to psychomimetic drugs,including LSD, PCP, and amphetamine. 5HT2C receptor expressed in the arcuatenucleus of the hypothalamus controls melanocortin signaling, and influencesappetite. 5HT2CR-/- mice are obese, have increased feeding and are resistant toanorectic effects of the serotonergic drug fenfluramine. Interestingly, clozapinetreatment of 5HT2AR-/- animals increases locomotion due to lack of selectivity for5HT2AR and antagonist activity at 5HT2C receptors. A pure 5HT2C receptoragonist could reduce abnormally elevated mesolimbic dopaminergic signaling,through inhibitory projections in the ventral tegmental area. Conversely, 5HT2Areceptor antagonism on cell bodies of dopaminergic neurons may reduce theactivity of mesolimbic and mesocortical projections, countering the imbalanceshown in schizophrenia.Methods: Adult male 129 mice were pretreated by intraperitoneal injection withTrans-PAT, saline, or the 5HT2A antagonist M100907 15 minutes prior tointraperitoneal injection of amphetamine, saline, or the NMDA antagonist MK-801,then placed in darkened open field boxes with automated activity recording for 30or 60 minutes. Total ambulatory distance was the primary outcome measure.Animals were weighed prior to activity monitoring and at 24 hours with ad libidumfood and water. Percent change in body weight was the outcome measure.Individually housed adult male 129 animals were habituated to a wet mash diet for5 days and food deprived for 24 hours. During the dark cycle animals werepretreated intraperitoneally with Trans-PAT at 3 and 10 mg/kg with or withoutamphetamine, then exposed to wet mash. The weight of mash consumed in 60minutes was the outcome measure.Results and Discussion: Acute Trans-PAT treatment reduces amphetamine andMK-801 induced locomotion by approximately 80% at doses (10mg/kg) that do notaffect spontaneous locomotion. Additionally, acute Trans-PAT treatment at 10mg/kg is synergistic with stimulant as an anorectic causing 30% reduction in foodconsumed after deprivation, and 2% weight loss over 24 hours. Trans-PAT mayhave anorectic properties independent of stimulant administration with animalsshowing 0.5-2.0% weight loss at 24 hours after a single 10 mg/kg dose, in contrastto the activity of MK-801. These results have implications for the treatment ofpsychosis while potentially avoiding the weight gain that is a common side effectof antipsychotic medications.