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.

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.

Cocaine is a powerful psychomotor stimulant that can affect serotonin (5HT), dopamine, and norepinephrine systems in the brain. Previous studies with 5HT1B receptor agonist, CP94253, have shown dose-dependent decreases in cocaine-self administration in male rats during maintenance. However, these studies do not take into consideration sex differences between male rats and female rats. Female rats introduce a new complexity because they constantly undergo an estrous cycle that consists of four phases, metestrus, diestrus, proestrus, and estrus. It was hypothesized that cocaine infusions and active lever response rates would greatly decrease during proestrus and estrus in comparison to metestrus and diestrus due to hormonal level differences of LH, FSH, progesterone, and estradiol. In this study, female rats were trained to self-administer a training dose of 0.75 mg/kg/infusion on a fixed progressive ratio (FR5). Rats were then pretreated with CP94253 to test the effects of this 5HT1B agonist on female rat cocaine self-administration during the estrous cycle. Results showed there was no three-way interaction between cycle phase, pretreatment, and cocaine dose on infusions or active lever responses. However, pretreatment with CP94253 decreased cocaine intake and active lever responses at high cocaine doses, regardless of cycle phase. Lastly, there was a two-way interaction between pretreatment and cycle phase in which active lever responses decreased during diestrus and proestrus. These results imply that CP94253 enhances cocaine's effect regardless of cycle phase. Future work can work with ovariectomized (OVX) female rats to observe cocaine self-administration during controlled cycle phases.

5-HT_1B receptors (5-HT_1BRs) modulate behavioral effects of cocaine. Here we examined the effects of the 5-HT_1BR agonist 5-propoxy-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-pyrrolo[3,2-b]pyridine (CP94253) on spontaneous and cocaine-induced locomotion and on cocaine-primed reinstatement of conditioned place preference (CPP) in male mice given daily repeated injections of either saline or cocaine (15 mg/kg, IP) for 20 days. In the locomotor activity experiment, testing occurred both 1 and 20 days after the final injection. In the CPP experiment, mice underwent conditioning procedures while receiving the last of their daily injections, which were given either during or ≥2 h after CPP procedures. The CPP procedural timeline consisted of baseline preference testing (days 12–13 of the chronic regimen), conditioning (days 14–19, 2 daily 30-min sessions separated by 5 h), CPP test (day 21), extinction (days 22–34; no injections), CPP extinction test (day 35), and reinstatement test (day 36). Mice that had not extinguished received additional extinction sessions prior to reinstatement testing on day 42.

On test days, mice were pretreated with either saline or CP94253 (10 mg/kg, IP). Testing began 30 min later, immediately after mice were primed with either saline or cocaine (5 mg/kg for locomotion; 15 mg/kg for reinstatement). We found that CP94253 increased spontaneous locomotion in mice receiving repeated injections of either saline or cocaine when tested 1 day after the last injection, but had no effect on spontaneous locomotion after 20 days abstinence from repeated injections. Surprisingly, cocaine-induced locomotion was sensitized regardless of whether the mice had received repeated saline or cocaine. CP94253 attenuated expression of the sensitized locomotion after 20 days abstinence. A control experiment in noninjected, drug-naïve mice showed that CP94253 had no effect on spontaneous or cocaine-induced locomotion. Mice reinstated cocaine-CPP when given a cocaine prime, and CP94253 pretreatment attenuated cocaine reinstatement. The findings suggest that stress from repeated saline injections and/or co-housing with cocaine-injected mice may cross-sensitize with cocaine effects on locomotion and that CP94253 attenuates these effects, as well as reinstatement of cocaine-CPP. This study supports the idea that 5-HT_1BR agonists may be useful anti-cocaine medications.