Journal
BEHAVIOURAL PHARMACOLOGY
Volume 24, Issue 7, Pages 628-632Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/FBP.0b013e3283656db6
Keywords
6-hydroxydopamine lesion; animal model; Parkinson's disease psychosis; rat; serotonin; substantia nigra; therapeutic index
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No safe, tolerated, and effective treatment for Parkinson's disease psychosis (PDP) is available; however, clozapine and quetiapine are often used off-label. An ideal PDP drug should have a therapeutic window that alleviates psychotic symptoms at doses that allow for maintained motor control and do not cause sedation. The present study determined the effective doses of quetiapine, clozapine, and the nondopaminergic, selective 5-HT2A inverse agonist/antagonist, pimavanserin, in an animal model of PDP and compared them with the doses that caused dopamine blockade and sedation. Augmented amphetamine-induced locomotion in rats with bilateral substantia nigra lesions was used to assess antipsychotic efficacy, whereas blockade of apomorphine-induced rotations in rats with unilateral 6-hydroxydopamine lesions was used to assess antidopaminergic action and reduction in spontaneous locomotion was used to assess sedation. The estimated therapeutic ratios for clozapine and quetiapine varied between 0.81 and 3.3. In contrast, the estimated therapeutic ratios for pimavanserin were at or above 170. These results suggest that a selective 5-HT2A inverse agonist/antagonist, such as pimavanserin, may provide distinct advantages compared with clozapine or quetiapine as a therapy for PDP.
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