Pimavanserin, a 5-HT2A inverse agonist, reverses psychosis-like behaviors in a rodent model of Parkinson's disease

• Published in: Behavioural pharmacology Vol. 22; no. 7; p. 681
• Main Authors: McFarland, Krista, Price, Diana L, Bonhaus, Douglas W
• Format: Journal Article
• Language: English
• Published: England 01.10.2011
• Subjects: Amphetamine - pharmacology; Amphetamines - pharmacology; Animals; Antipsychotic Agents - pharmacology; Antipsychotic Agents - therapeutic use; Antipsychotic Agents - toxicity; Behavior, Animal; Central Nervous System Stimulants - pharmacology; Disease Models, Animal; Dyskinesias - metabolism; Fenfluramine - pharmacology; Fluorobenzenes - pharmacology; Hyperkinesis; Male; Motor Activity; Oxidopamine - toxicity; Parkinson Disease - complications; Parkinson Disease - drug therapy; Parkinson Disease - etiology; Piperidines - pharmacology; Piperidines - therapeutic use; Piperidines - toxicity; Psychotic Disorders - drug therapy; Psychotic Disorders - physiopathology; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT2A - physiology; Sensory Gating; Serotonin 5-HT2 Receptor Antagonists - pharmacology; Serotonin 5-HT2 Receptor Antagonists - toxicity; Serotonin Agents - pharmacology; Serotonin Receptor Agonists - pharmacology; Substantia Nigra - physiology; Tyrosine 3-Monooxygenase - analysis; Urea - analogs & derivatives; Urea - pharmacology; Urea - therapeutic use; Urea - toxicity
• ISSN: 1473-5849
• DOI: 10.1097/FBP.0b013e32834aff98

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.