PRECLINICAL STUDY: Stimulation of 5‐HT_1B receptors enhances cocaine reinforcement yet reduces cocaine‐seeking behavior

Abstract

Paradoxically, stimulation of 5-HT 1B receptors (5-HT 1B Rs) enhances sensitivity to the reinforcing effects of cocaine but attenuates incentive motivation for cocaine as measured using the extinction/ reinstatement model. We revisited this issue by examining the effects of a 5-HT 1B R agonist, CP94253, on cocaine reinforcement and cocaine-primed reinstatement, predicting that CP94253would enhance cocaine-seeking behavior reinstated by a low priming dose, similar to its effect on cocaine reinforcement. Rats were trained to self-administer cocaine (0.75 mg/kg, i.v.) paired with light and tone cues. For reinstatement experiments, they then underwent daily extinction training to reduce cocaine-seeking behavior (operant responses without cocaine reinforcement). Next, they were pre-treated with CP94253 (3-10 mg/kg, s.c.) and either tested for cocaine-primed (10 or 2.5 mg/kg, i.p.) or cue-elicited reinstatement of extinguished cocaine-seeking behavior. For reinforcement, effects of CP94253 (5.6 mg/kg) across a range of self-administered cocaine doses (0-1.5 mg/kg, i.v.) were examined. Cocaine dose-dependently reinstated cocaine-seeking behavior, but contrary to our prediction, CP94253 reduced reinstatement with both priming doses. Similarly, CP94253 reduced cue-elicited reinstatement. In contrast, CP94253 shifted the self-administration dose-effect curve leftward, consistent with enhanced cocaine reinforcement. When saline was substituted for cocaine, CP94253 reduced response rates (i.e. cocaine-seeking behavior). In subsequent control experiments, CP94253 decreased open-arm exploration in an elevated plus-maze suggesting an anxiogenic effect, but had no effect on locomotion or sucrose reinforcement. These results provide strong evidence that stimulation of 5-HT 1B Rs produces opposite effects on cocaine reinforcement and cocaine-seeking behavior, and further suggest that 5-HT 1B Rs may be a novel target for developing medications for cocaine dependence.

Dopamine D3 and 5-HT1B receptor dysregulation as a result of psychostimulant intake and forced abstinence: Implications for medications development

“…However, in apparent contrast to these effects, we found that RU24969 (Acosta et al, 2005) and CP94253 (Pentkowski et al, 2009) dose-dependently decrease cue- and cocaine-primed reinstatement of extinguished cocaine-seeking behavior. The RU24969-induced decreases in reinstatement of cocaine seeking are reversed by the antagonist GR127935, suggesting that they are 5-HT 1B R-mediated.…”

“…As summarized in Table 5, Parsons et al (1998) subsequently showed that the more selective 5-HT 1B R agonists RU24969, CP94253 and CP93129 produce a similar effect on cocaine SA, and that the effect of CP94253 is reversed by the 5-HT 1B/1D R antagonist GR127935. These findings have been replicated by two other laboratories (Pentkowski et al, 2009; Przegalinski et al, 2007). Furthermore, we found that viral enhancement of 5-HT 1B R expression in terminals of medial NAc sh neurons shifts the dose– effect function for cocaine SA upward and to the left under a low demand reinforcement schedule (Pentkowski et al, 2012a).…”

“…Elevated 5-HT 1B R expression in terminals of the medial NAc sh also increases cocaine intake and breakpoints on a PR schedule (Pentkowski et al, 2012a). Collectively, the findings provide strong support for 5-HT 1B R-mediated enhancement of the reinforcing effects of psychostimulants during maintenance (Parsons et al, 1998; Pentkowski et al, 2009; Przegalinski et al, 2007). …”

“…Since 5-HT 1B R agonists enhance cocaine reinforcement, we initially thought that the effects of the agonists on cocaine-primed reinstatement (10 mg/kg, IP) resulted from a cocaine-like satiation effect (Acosta et al, 2005). Subsequently, however, we found that CP94253 (10 mg/kg, SC) reduces reinstatement by a lower cocaine priming dose (2.5 mg/kg, IP), which we had predicted would enhance seeking similar to a higher dose of cocaine (Pentkowski et al, 2009). These findings suggest that 5-HT 1B R agonists attenuate motivation for cocaine.…”

Administração prolongada do ácido 13-cis-retinóico (isotretinoína) em camundongos machos adolescentes: comportamentos emocionais e quantificação de transcritos de componentes do sistema serotoninérgico central.

“…Investigações utilizando técnicas farmacológicas e genéticas sugeriram envolvimento do receptor 5-HT 1B na vulnerabilidade ao abuso de drogas, como ingestão de etanol e cocaína, provavelmente através de uma ação indireta no sistema dopaminérgico (Hoplight, Sandygren e Neumaier, 2006;Pentkowski et al, 2009 (Aghajanian e Marek, 1999).…”