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Investigating the effects of CP94,253, a selective 5-HT1BR receptor agonist on self-administration in female rats

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In 2014 alone, 40% of all drug abuse-related emergency department visits involved cocaine, and despite the detrimental effects there is still no FDA approved treatment for cocaine use disorders (CUDs; Dawn, 2014). Studies show that serotonin 1B receptor (5HT1BR) agonists modulate cocaine abuse-related behaviors in opposite directions depending on the phase of the addiction cycle in male rats. In particular, the selective 5HT1BR agonist, CP94,253, facilitates cocaine intake during maintenance of daily cocaine self-administration. Paradoxically, after 21 days of abstinence, CP94,253 attenuates cocaine intake in male rats on a low effort fixed ratio 5 (FR5) and a high effort progressive ratio (PR) schedule of reinforcement. PR measures motivation as it requires an exponentially increasing number of lever responses to obtain the next reinforcer after a successful reinforcer. In contrast to male rats, we recently found CP94,253 attenuates cocaine intake before and after abstinence on an FR5 schedule of reinforcement in female rats, suggesting the attenuating effects of CP94,253 on cocaine intake is not dependent on a period of abstinence in females. However, the effect of CP94,253 on motivation for cocaine has not yet been examined in female rats. Therefore, we addressed this gap in the present study. Female Sprague-Dawley rats were trained to self-administer 0.375 mg/kg, IV cocaine or to obtain sucrose pellets (45 mg) on a PR schedule of reinforcement and were then pretreated with vehicle or CP94,253 (3.2, 5.6 and 10 mg/kg, SC) prior to their self-administration session. A separate cohort was pretreated with CP94,253 to examine the effects of CP94,253 on cocaine-seeking behavior (i.e., operant responses when cocaine is no longer available) and spontaneous locomotion after 21 or 60 days of abstinence. The preliminary findings show that CP94,253 has minimal impacts on decreasing cocaine intake on a PR schedule in female rats but decreases cue reactivity up to 60 days after abstinence in female rats. These findings suggest that 5-HT1BR agonists may be useful treatments for cocaine craving.

ContributorsRuscitti, Brielle Allesandra (Author) / Neisewander, Janet (Thesis director) / Powell, Gregory (Committee member) / Scott, Samantha (Committee member) / School of Life Sciences (Contributor, Contributor) / School of Human Evolution & Social Change (Contributor) / Barrett, The Honors College (Contributor)

Created2021-05

5-HT1B receptor agonist CP 94,253 reduces cocaine intake in female rats post-abstinence and after resuming self-administration

Description

Approximately five million Americans suffer from cocaine use disorder with no FDA approved pharmaceutical to help their path to recovery (Yerby, 2019). Serotonin is heavily implicated in cocaine use and in the reward system, and is therefore a suggested target for pharmaceuticals aiming to aid in psychostimulant addiction (Sarlin, 2019; Clark and Neumaier, 2001). CP 94,253, a 5-HT1BR agonist, has been shown to increase cocaine intake during maintenance of daily cocaine self-administration, though it has also been shown to decrease intake after a period of forced abstinence (Parsons et al., 1998; Pentowski et al., 2009). While a decrease in cocaine intake post-abstinence is promising post-abstinence, it remains to be seen whether this is a viable option if patients relapse. Most experiments are conducted with male rats, though an increasing amount of data has come to light on the differing effects of drugs on male and female rats (Mennenga and Bimonte-Nelson, 2014). Previous studies conducted through our lab have shown no difference in cocaine self-administration behavior across the estrous cycle phases with CP 94,253. It remains to be seen however, whether CP 94,253 would function dissimilarly in female rats than in male rats. This experiment studied the effects of CP 94,253 on post-abstinence and post-resumption cocaine self-administration in free-cycling female rats across two doses of cocaine. It was shown that CP 94,253 reduces cocaine intake both post-abstinence and post-resumption, suggesting that this pharmacotherapy would work in cases of relapse, and that there are no sex differences in its effects. While more studies should be conducted with locomotion and stress tests, thus far this experiment provides further evidence for the validity of CP 94,253 to be a promising pharmacotherapeutic option for future investigation.

ContributorsDoyle, Sophia Marie (Author) / Neisewander, Janet (Thesis director) / Olive, Foster (Committee member) / Scott, Samantha (Committee member) / School of Life Sciences (Contributor) / School of International Letters and Cultures (Contributor) / Barrett, The Honors College (Contributor)

Created2020-05