The Effects of a Selective Serotonin 2C (5HT2C) Receptor Agonist WAY 163909 on Cocaine Self‐Administration in Male and Female Rhesus Macaques Exposed to Early Life Stress
Authors: Wakeford Alison GP. , Shields Hannah , Katznelson Sarah , Sanchez Mar M. , Howell Leonard L. 
Published: June 2021

Cocaine use disorder represents a prominent health concern in the United States, and there are currently no accepted pharmacotherapies for the treatment of ongoing cocaine use. Additionally, the occurrence of stressors early in life, such as physical abuse and neglect, is a major predictor in the emergence of cocaine abuse later in life. Rhesus monkeys demonstrate a similar prevalence rate of infant abuse and rejection as humans, and serve as ideal candidates to examine the relationship between early life stress (ELS) and cocaine use. Finally, previous data suggest serotonin 2C (5HT2C) agonists may be viable candidates in the treatment of ongoing drug use. Accordingly, the effectiveness of the 5HT‐2C agonist WAY 163909 (WAY) to decrease cocaine self‐administration was examined in male and female rhesus macaques.

Subjects were 8 adolescent male and female rhesus macaques who experienced infant maltreatment (MALT) or competent maternal care (MALT males n=4; MALT females, n=2; Control males, n=0; Control females, n=2). During adolescence, animals were trained to respond under a fixed‐ratio 20 response (FR 20) schedule of reinforcement to receive an infusion of cocaine (0.01–0.1 mg/kg/infusion). After meeting criteria for stable self‐administration (SA), animals progressed through a full dose‐effect curve to establish the dose that engendered the highest response rate (EDMax), and were then examined under maintenance conditions. During each testing week, WAY pretreatments (3 consecutive daily treatments administered 45 minutes prior to sessions) were preceded by normal maintenance sessions without any pretreatments, which provided a baseline of responding. Each WAY dose (0.1–1 mg/kg IM) was tested weekly interspersed by weeks of vehicle treatment.

WAY dose‐dependently decreased cocaine self‐administration in males and females, with males demonstrating significantly lower response rates in comparison to females at 0.3 mg/kg WAY. MALT animals also demonstrated an overall lower response rate across doses of WAY in comparison to control subjects.

These preliminary data suggest that females may be more resistant to serotonergic interventions of ongoing cocaine SA, given that females from MALT and Control groups were less sensitive to the effects of WAY in comparison to males. Furthermore, MALT animals overall showed a lower response rate in comparison to control animals across doses of WAY, suggesting that MALT subjects may be uniquely sensitive to serotonergic interventions aimed at decreasing ongoing drug use. The addition of male controls will be critical in determining whether robust sex differences persist, and if male controls demonstrate a similar response pattern as female controls.

Support or Funding Information

This research was supported by USPHS grants DA 038588 (MMS/LLH), DA 010344 (LLH), DA 031246 (LLH), and P51OD11132 (YNPRC).

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.