Behavioral analysis of putative antipsychotic actions at serotonin and dopamine receptors

Laura Scarlota

doi:10.17918/00007903

Schizophrenia is a debilitating mental disorder affecting approximately 1% of the population. Current antipsychotics can manage positive symptoms, and, to a much lesser extent, negative, cognitive and affective symptoms. All antipsychotics on the market bind to dopamine receptors and often their efficacy is attributed to receptor antagonism; however, accumulating evidence has suggested that further benefits and fewer side effects may be derived from altering dopamine levels. One possible way to achieve this effect is through serotonin-2 (5-HT2) receptor inverse agonism, which has been shown to modulate dopamine release. Therefore, the goal of this project was to evaluate the antipsychotic potential of 5-HT2 receptor inverse agonism. First, using radioligand binding, 5-HT2 receptor agonists, antagonists, and inverse agonists were classified according to their effects following chronic treatment (i.e. agonists down-regulate and inverse agonists up-regulate receptors). Then, the 5-HT2A/2C receptor inverse agonist, SR46349B, was selected for subsequent behavioral analysis. The first study investigated the effects of SR46349B on hallucinogen-elicited behavior as a rabbit model of psychosis. After hallucinogen administration, the frequency of a motor behavior (head bob) was measured. SR46349B significantly reduced hallucinogen-elicited behavior suggesting it may diminish psychosis. Following this, we tested the effect of SR46349B on cognition. In schizophrenia, there is an enhanced response in associative learning, possibly due to an inability to ignore irrelevant stimuli. Therefore, an antipsychotic should disrupt these types of associations. Administering SR46349B during eyeblink classical conditioning reduced acquisition of conditioned responses, thus SR46349B may improve cognitive deficits in schizophrenia. Next, to test anxiety, rabbits were exposed to a novel environment and motor behaviors were measured. SR46349B attenuated the novelty-elicited effects suggesting it may be anxiolytic-like. Finally, we investigated the role of dopamine receptors in SR46349B-elicited behavior given the presumed effect of 5-HT2 receptor inverse agonism on the modulation of dopamine release. Of the two dopamine receptors (D1 and D2), only D1 were found to be involved in the 5-HT2 inverse agonist response. Collectively, these results indicate that 5-HT2 receptor inverse agonism and subsequent D1 agonism can diminish hallucinogen effects, cognitive impairments, and anxiety and thus may manage multiple symptoms of schizophrenia.

Behavioral analysis of putative antipsychotic actions at serotonin and dopamine receptors

Files and links (1)

Abstract

Metrics

Details

Behavioral analysis of putative antipsychotic actions at serotonin and dopamine receptors

Files and links (1)

Abstract

Metrics

Details

Drexel University Social media