Chronic fluoxetine treatment is associated with persistent desensitization of the 5HT2A receptor and decreased cocaine‐primed reinstatement in rhesus monkeys

Abstract

Previously, we showed that chronic selective serotonin reuptake inhibitor (SSRI) treatment resulted in a significant suppression of cocaine‐primed reinstatement that persisted after 6 weeks of washout. The therapeutic effects of selective serotonin reuptake inhibitors (SSRIs) for depression are believed to rely on neuroadaptive changes in the serotonin system that emerge during chronic treatment, but these effects have not been evaluated in the context of cocaine use. Therefore, we examined the effects of chronic fluoxetine treatment (10 mg/kg/day, p.o.) in rhesus macaques trained to self administer cocaine and evaluated pre‐and post‐synaptic receptor level and function using positron emission tomography and concurrent in vivo microdialysis and prolactin response. A significant increase in serotonin 2A receptor binding potential was observed, which persisted following a 6‐week washout period. Serotonin transporter binding potential and serotonin release in response to fenfluramine (3.0 mg/kg, i.v.) were not affected, while prolactin release was significantly blunted. Furthermore, cocaine‐induced increases in dopamine and cocaine‐primed reinstatement were also significantly blunted following fluoxetine treatment and washout. Together, these results suggest that chronic fluoxetine treatment is associated with a persistent change in 5HT2A receptor function which may contribute to suppressed cocaine‐primed reinstatement.This research was supported by NIH grants DA10344 (LLH), DA000517 (LLH), T‐32 DA015040 (support for EKS), and RR00065 (YNPRC).