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.

Parkinson's disease, visual hallucinations and apomorphine: A review of the available evidence

“…Use of the selective 5-HT2A antagonist pimavanserin has been shown to resolve psychotic behavior in an animal model (6-hydroxydopamine), while in clinical trials use of pimavanserin, previously demonstrated to be well tolerated, has more recently been reported to have a beneficial effect on VH in PD patients [56][57][58].…”

Rational drug discovery design approaches for treating Parkinson’s disease

“…Other receptor drug targets for which ligands have been developed include the serotonin 5-HT 2A receptor (highly selective 5-HT 2A receptor inverse agonists have been hypothesized to provide symptomatic control in patients suffering from PD psychosis) [122] (pimavanserin) [123] and the a-2 adrenergic receptor [124] (fipamezole: a-2 adrenergic receptor antagonists such as fipamezole have been shown to alleviate Ldopa-induced dyskinesia and enhance the duration of the antiparkinsonian action of L-dopa) [125].…”

Evidence for the use of pimavanserin in the treatment of Parkinson’s disease psychosis

“…Compensatory excessive dopaminergic signaling in response to striatal degeneration was impacted by pimavanserin. However, the normal dopaminergic response to amphetamine in nonlesioned animals was not impaired [McFarland et al 2011].…”

“…The compound was readily bioavailable at 10 mg/kg orally [Vanover et al 2006]. It has also been studied in rodent models of PDP [McFarland et al 2011;Vanover et al 2008]. Pimavanserin reduced psychotic behaviors (increased or altered head twitches) after treating rats with fenfluramine, a serotonin releasing agent [McFarland et al 2011].…”

“…It has also been studied in rodent models of PDP [McFarland et al 2011;Vanover et al 2008]. Pimavanserin reduced psychotic behaviors (increased or altered head twitches) after treating rats with fenfluramine, a serotonin releasing agent [McFarland et al 2011]. Pimavanserin was also studied in combination with olanzapine and risperidone, leading to improvements in psychotic features in rats such as novel object recognition [Snigdha et al 2010], and it allowed for dose-sparing of antipsychotic agents [Gardell et al 2007].…”