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

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by a progressive deterioration in cognitive functioning. Overall, 25-50% of patients with AD also show symptoms of psychosis including hallucinations and delusions. As all available antipsychotic drugs have a 'black-box' warning for use in these patients because of increased mortality, no appropriate treatment for psychotic symptoms in AD currently exists. In the present study, we examined whether selective antagonism of 5-HT(2A) serotonin receptors has antipsychotic-like activity in an animal model of AD. Mice receiving an intracerebroventricular infusion of the amyloid β(25-35) peptide fragment showed AD-like histopathology and a psychosis-related behavioral phenotype with enhanced responses to the psychostimulants 2,5-dimethoxy-4-iodoamphetamine hydrochloride and amphetamine as well as disrupted prepulse inhibition. Treatment with pimavanserin, a selective serotonin 5-HT(2A) receptor inverse agonist, prevented 2,5-dimethoxy-4-iodoamphetamine hydrochloride-induced head twitches, reversed the augmented locomotor response to amphetamine, and normalized prepulse inhibition in mice with amyloid pathology. These data suggest that an infusion of amyloid β might induce alterations in serotonergic function that underlie a psychosis-like phenotype that can be normalized by treatment with a 5-HT(2A) inverse agonist. This in turn suggests that 5-HT(2A) inverse agonists, such as pimavanserin, might have therapeutic benefits in the treatment of psychosis in AD patients.

• Authors: Diana L Price, Douglas W Bonhaus, Krista McFarland
• Journal: Behavioural pharmacology (Behav Pharmacol) Vol. 23 Issue 4 Pg. 426-33 (Aug 2012) ISSN: 1473-5849 [Electronic] England
• PMID: 22750845 (Publication Type: Journal Article)

Chemical References

• Amphetamines
• Antipsychotic Agents
• Piperidines
• Serotonin 5-HT2 Receptor Antagonists
• Urea
• Amphetamine
• pimavanserin
• 4-iodo-2,5-dimethoxyphenylisopropylamine

Topics

• Alzheimer Disease (drug therapy, physiopathology)
• Amphetamine (pharmacology)
• Amphetamines (pharmacology)
• Animals
• Antipsychotic Agents (pharmacology)
• Behavior, Animal (drug effects)
• Disease Models, Animal
• Drug Inverse Agonism
• Male
• Mice
• Piperidines (pharmacology)
• Psychotic Disorders (drug therapy, etiology)
• Serotonin 5-HT2 Receptor Antagonists (pharmacology)
• Urea (analogs & derivatives, pharmacology)