5-HT_1B receptor agonist attenuates cocaine self-administration after protracted abstinence and relapse in rats

Abstract

Background: The 5-HT1B receptor (5-HT1BR) agonist, CP94253, enhances cocaine intake during maintenance of self-administration (SA) but attenuates intake after 21 days of forced abstinence in male rats. Aims: We examined whether CP94253 attenuates cocaine intake in female rats after a period of abstinence, and if these attenuating effects persist or revert to enhancing cocaine intake during resumption (i.e. relapse) of daily cocaine SA. Methods: Male and female rats trained to lever press on a fixed ratio 5 schedule of cocaine reinforcement underwent ⩾21 days of forced abstinence. They were then tested for the effects of CP94253 (5.6 mg/kg, SC) or vehicle on cocaine SA. During the test session, rats had 1-h access to the training dose of cocaine (0.75 mg/kg, IV) followed by 1-h access to a lower cocaine dose (0.075 mg/kg, IV). Rats then resumed cocaine SA for 15 days to mimic relapse and were retested as done previously. Subsequently, rats underwent abstinence again (21–60 days) and were tested for CP94253 effects on locomotion and cue reactivity (i.e. responding for light/tone cues previously paired with cocaine infusions). Results: Regardless of sex, CP94253 decreased cocaine intake after abstinence and during resumption of SA and decreased cue reactivity while having no effect on locomotion. Conclusions: CP94253 decreases cocaine intake and cocaine seeking in both males and females even after resumption of cocaine SA. These findings suggest that the inhibitory effects of CP94253 observed after abstinence are long-lasting, and therefore, 5-HT1BR agonists may have clinical efficacy as anti-relapse medications for cocaine use disorders.

5-HT1B receptor agonist enhances breakpoint for cocaine on a progressive ratio (PR) schedule during maintenance of self-administration in female rats but reduces breakpoint for sucrose

“…cocaine under an FR5 schedule are enhanced in male rats during maintenance of cocaine SA but attenuated after prolonged forced abstinence (Pentkowski et al, 2014 ). Recently, we replicated the latter effect in both male and female rats and showed that the effect persists even when rats are tested after resuming sessions of daily access following abstinence (Scott et al, 2021 ). These same rats also showed a decrease in cocaine cue-reactivity in response to CP94253 when tested after either 21 or 60 days of abstinence (Scott et al, 2021 ).…”

“…Recently, we replicated the latter effect in both male and female rats and showed that the effect persists even when rats are tested after resuming sessions of daily access following abstinence (Scott et al, 2021). These same rats also showed a decrease in cocaine cue-reactivity in response to CP94253 when tested after either 21 or 60 days of abstinence (Scott et al, 2021). Collectively, the findings suggest that the functional effects of 5-HT 1B R agonists on cocaine reinforcement/motivation flip from facilitatory during maintenance of daily SA to inhibitory after prolonged abstinence in both males and females.…”

“…The ability of CP94253 to modulate cocaine reinforcement may depend on estrous cycle phase as rats in metestrus showed different dose-response functions for cocaine SA measures compared to other phases of the estrous cycle. Because previous findings suggest that 5-HT 1B agonists persistently attenuate motivation for cocaine after prolonged abstinence regardless of sex (Acosta et al, 2005;Pentkowski et al, 2009Pentkowski et al, , 2014Garcia et al, 2020;Scott et al, 2021), further research is needed to understand the mechanism underlying the switch in 5-HT 1B R agonist effects on cocaine SA during abstinence because their post-abstinence inhibition of cocaine SA suggests potential therapeutic effects for treating psychostimulant use disorders (Callahan and Cunningham, 1995;Fletcher and Korth, 1999;Miszkiel et al, 2011;Pentkowski et al, 2014;Garcia et al, 2017).…”

“…By contrast, after 21 days of forced abstinence, these manipulations shift the cocaine dose-response curve downward on a FR5 schedule, and decrease breakpoints and cocaine infusion rates on a PR schedule, suggesting a decrease in cocaine reinforcing effects and/or incentive motivation after abstinence (Pentkowski et al, 2012 , 2014 ). Additionally, 5-HT 1B R agonist decreases cocaine-reinforcing effects after abstinence and subsequent resumption of cocaine SA (i.e., relapse) regardless of sex (Scott et al, 2021 ). Moreover, 5-HT 1B R agonists decrease both cue-elicited and cocaine-primed reinstatement of extinguished cocaine-seeking behavior in male and female rats (Acosta et al, 2005 ; Pentkowski et al, 2009 , 2012 ; Scott et al, 2021 ).…”

“…Additionally, 5-HT 1B R agonist decreases cocaine-reinforcing effects after abstinence and subsequent resumption of cocaine SA (i.e., relapse) regardless of sex (Scott et al, 2021 ). Moreover, 5-HT 1B R agonists decrease both cue-elicited and cocaine-primed reinstatement of extinguished cocaine-seeking behavior in male and female rats (Acosta et al, 2005 ; Pentkowski et al, 2009 , 2012 ; Scott et al, 2021 ). Together the findings suggest that there is an abstinence-dependent switch in 5-HT 1B R modulation of cocaine SA in male rats from enhancement during maintenance to attenuation after a period of abstinence.…”