The 5-HT2C Receptor Agonist Ro60-0175 Reduces Cocaine Self-Administration and Reinstatement Induced by the Stressor Yohimbine, and Contextual Cues

Abstract

Previously, we showed that the 5-HT 2C receptor agonist Ro60-0175 reduces cocaine self-administration, and the ability of cocaine to reinstate responding after extinction of drug-seeking behavior. The present experiments extended these findings further by determining whether the effects of Ro60-0175 on self-administration were sustained with repeated treatment, and whether Ro60-0175 altered reinstatement induced by the pharmacological stressor yohimbine, or by the context in which self-administration occurred. In Experiment 1, Ro60-0175 (1 mg/kg, s.c.) reduced cocaine (0.25 mg/infusion) self-administration maintained by a progressive ratio schedule. This reduction was sustained over eight daily injections. In Experiment 2, rats self-administered cocaine in daily 2 h sessions for 15 days on a FR1 schedule. Following extinction, yohimbine (1 mg/kg, i.p.) reinstated responding, and this effect was reduced dose dependently by Ro60-0175 (0.3-3 mg/kg, s.c.). In Experiment 3, rats were trained to respond for cocaine on a FR1 schedule in a distinct environmental context (A); responding was then extinguished in a different context (B). Reinstatement tests occurred in either context A or B.Responding was reinstated only when rats were tested in the original self-administration context (A). This reinstatement was reduced dose dependently by Ro60-0175. All effects of Ro60-0175 were blocked by the 5-HT 2C receptor antagonist SB242084. Thus, Ro60-0175, acting via 5-HT 2C receptors, reduces cocaine self-administration and cocaine-seeking triggered by a stressor and by drug-associated cues. The effects of Ro60-0175 do not exhibit tolerance within the 8-day test period. These results indicate that selective 5-HT 2C receptor agonists may be a useful pharmacological strategy for treatment of drug abuse.

Contribution of a Mesocorticolimbic Subcircuit to Drug Context-Induced Reinstatement of Cocaine-Seeking Behavior in Rats

“…cocaine-seeking behaviors (Neisewander and Acosta, 2007;Fletcher et al, 2008). Therefore, it is significant that the effect of SCH23390 in the OFC could be overcome by co-administration of the D1-like receptor agonist, SKF81297 (Figure 2e left), at a dose that alone failed to reinstate cocaine-seeking behavior in rats that could exhibit reinstatement in response to cocaine priming (Figure 2e right).…”

Synergism Between a Serotonin 5-HT2A Receptor (5-HT2AR) Antagonist and 5-HT2CR Agonist Suggests New Pharmacotherapeutics for Cocaine Addiction

“…; Figure 9]. There was a main effect of treatment on latency to the first lever press during the reinstatement session versus VEH-COC [F (3,18) = 4.27; p < 0.05; data not shown]; a priori comparisons revealed that 1.5 mg/kg WAY163909 significantly increased latency to the first lever press versus VEH-COC (p < 0.05; data not shown). Neither 0.5 nor 1 mg/ kg of WAY163909 altered the latency to the first lever press versus VEH-COC (p < 0.05; data not shown).…”

Context-induced relapse to drug seeking: a review

“…Systemic injections of Ro 60-0175 (an agonist of 5-HT 2C serotonin receptors) or SR141716A (an antagonist of cannabinoid receptor 1, CB1) decrease drug priming-and discrete cue-induced reinstatement of drug seeking (Grottick et al 2000;De Vries et al 2001, 2003Burbassi & Cervo 2008). Based on these studies, Fletcher et al (2008) examined the effect of systemic injections of Ro 60-0175 on context-induced reinstatement of cocaine seeking, and Diergaarde et al (in press) examined the effect of systemic injections of SR141716A on context-induced reinstatement of nicotine seeking. They found that these injections decrease context-induced reinstatement.…”

“…During the reinstatement tests under extinction conditions, responding on the previously active lever leads to contingent presentations of the discrete drug cue but not the drug. Using variations of this procedure, we and others found context-induced reinstatement of heroin (Bossert et al , 2006(Bossert et al , 2007, cocaine (Crombag et al 2002a;Fuchs et al 2005Fuchs et al -2007Kearns & Weiss 2007;Fletcher et al 2008;Hamlin et al 2008), speedball (Crombag & Shaham 2002), alcohol Zironi et al 2006;Hamlin et al 2007;Marinelli et al 2007;Chaudhri et al 2008) and nicotine (Diergaarde et al in press) seeking (figure 1). In these studies, the magnitude of lever (or nose-poke) responding during tests for contextinduced reinstatement after extinction was similar to that observed on the first extinction session.…”