title: Pimavanserin, a 5-HT2A inverse agonist, reverses psychosis-like behaviors in a rodent model of Parkinson's disease.
abstract: Parkinson's disease psychosis (PDP) is a condition for which a safe, tolerated, and effective therapy is lacking. Treatment with typical or atypical antipsychotics may be contraindicated in patients with PDP because of the potential for aggravating motor symptoms. This study used a novel animal model with features of both Parkinson's disease (PD) and psychosis to examine a potential mechanism for reversing PDP. Animals with bilateral 6-hydroxydopamine lesions of the substantia nigra displayed motoric impairments characteristic of humans with PD. In addition, they displayed augmented head twitches, augmented amphetamine-induced locomotor activity, and disrupted prepulse inhibition compared with sham controls, behavioral indices frequently used to assess antipsychotic activity in animal models. Pimavanserin, a selective 5-HT2A antagonist/inverse agonist, reversed the psychotic-like behavioral deficits, suggesting that nigrostriatal (6-hydroxydopamine) lesions induced alterations in 5-HT2A-mediated signaling. The selective 5-HT2A inverse agonist M100907, but not the selective 5-HT2C inverse agonist SB 252084 paralleled the effects of pimavanserin. Of note, the reversal of psychotic-like behaviors produced by 5-HT2A inverse agonists occurred without disrupting motor behaviors in lesioned subjects, suggesting that 5HT2A antagonism/inverse agonism may be beneficial in the treatment of PDP.
authors.affiliation: ACADIA Pharmaceuticals Inc., 3911 Sorrento Valley Blvd, San Diego, CA 92121, USA. kmcfarland@acadia-pharm.com
authors.forename: Krista
authors.initials: K
authors.lastname: McFarland
authors.forename: Diana L
authors.initials: DL
authors.lastname: Price
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Bonhaus
mesh_terms: D000661:Amphetamine / Q000494:pharmacology; D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D001522:Behavior, Animal; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004195:Disease Models, Animal; D020820:Dyskinesias / Q000378:metabolism*; D005277:Fenfluramine / Q000494:pharmacology; D005464:Fluorobenzenes / Q000494:pharmacology; D006948:Hyperkinesis; D008297:Male; D009043:Motor Activity; D016627:Oxidopamine / Q000633:toxicity; D010300:Parkinson Disease / Q000150:complications / Q000188:drug therapy* / Q000209:etiology; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use / Q000633:toxicity; D011618:Psychotic Disorders / Q000188:drug therapy / Q000503:physiopathology; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000502:physiology; D055139:Sensory Gating; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000494:pharmacology* / Q000633:toxicity; D018490:Serotonin Agents / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013378:Substantia Nigra / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000032:analysis; D014508:Urea / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity
chemical_list: D000662:Amphetamines; D014150:Antipsychotic Agents; D000697:Central Nervous System Stimulants; D005464:Fluorobenzenes; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D058830:Serotonin 5-HT2 Receptor Antagonists; D018490:Serotonin Agents; D017366:Serotonin Receptor Agonists; D005277:Fenfluramine; D016627:Oxidopamine; D014508:Urea; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase; C079049:volinanserin; C510793:pimavanserin; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine