Attenuation of cocaine-induced reinstatement of drug seeking in squirrel monkeys by direct and indirect activation of 5-HT2C receptors

Abstract

Rationale 5-Hydroxytryptamine (5-HT) transport inhibitors can attenuate the abuse-related effects of cocaine and the mechanisms underlying this attenuation may involve activation of 5-HT2C receptors. Objectives We investigated the consequences of direct and indirect pharmacological activation of 5-HT2C receptors on reinstatement of cocaine-seeking behavior induced by cocaine priming and a cocaine paired stimulus. Methods Monkeys were trained to self-administer cocaine under a second-order schedule in which responding was maintained by i.v. cocaine injections and a cocaine-paired stimulus. Drug seeking was extinguished by replacing cocaine with vehicle and eliminating the cocaine-paired stimulus. During reinstatement tests, animals received a priming injection of cocaine along with restoration of the cocaine-paired stimulus, but only vehicle was available for self-administration. Results Pretreatment with either the 5-HT transport inhibitor fluoxetine (5.6 mg/kg) or the 5-HT2C receptor agonist Ro 60-0175 (1 mg/kg) attenuated reinstatement of drug seeking by cocaine priming. The reinstatement-attenuating effects of both drugs were reversed by the 5-HT2C receptor antagonist SB 242084 (0.03–0.56 mg/kg). Ro 60-0175 (1 mg/kg) attenuated cocaine-induced reinstatement of drug seeking regardless of whether priming injections were or were not accompanied by restoration of the cocaine-paired stimulus. Ro 60-0175 (0.56 mg/kg) was equally effective whether it was administered acutely or chronically. Finally, Ro 60-0175 (0.3–1 mg/kg) had observable behavioral effects suggestive of anxiolytic-like properties. Conclusions 5-HT2C receptor mechanisms play a key role in the modulation of cocaine-induced reinstatement by fluoxetine and Ro 60-0175. Direct activation of 5-HT2C receptors may offer a novel, tolerance-free therapeutic strategy for prevention of cocaine relapse.

Lorcaserin Reduces the Discriminative Stimulus and Reinforcing Effects of Cocaine in Rhesus Monkeys

“…It is unlikely that this suppression of cocaine self-administration reflects a leftward shift in the cocaine dose-response curve insofar as lorcaserin shifts the cocaine self-administration dose-response curve to the right in monkeys responding under a progressive ratio schedule (unpublished observations). Taken together, these findings are consistent with the acute effects of the 5-HT 2C receptor agonists WAY163909 and Ro60-0175 in rats and squirrel monkeys, respectively (Cunningham et al, 2011;Manvich et al, 2012;Rüedi-Bettschen et al, 2015), and provide further support for the notion that targeting 5-HT 2C receptors could provide an effective strategy for treating cocaine addiction.…”

“…Although 5-HT 2A receptor antagonists (e.g., ethoxy]amino}-3-(2-fluorophenyl)prop-2-en-1-ylidene]cyclohexa-2,5-dien-1-one) and M100907 [a-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenylethyl)]-4-piperidine methanol]) inhibit the effectiveness of noncontingent cocaine injections to reinstate extinguished responding for cocaine (cocaine-primed reinstatement) at doses that do not alter the ongoing self-administration of cocaine (Fletcher et al, 2002;Filip et al, 2005;Murnane et al, 2013), 5-HT 2C receptor agonists (e.g., Ro60-0175 [(S)-2(6-chloro-5-fluorindol-1-yl)-1-methylethylamine] and WAY163909 [(7bR, 10aR)-1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b] [1,4]diazepino [6,7,1hi]indole]) dose-dependently inhibit the effectiveness of cocaine primes and cocaine-associated stimuli (stimulus-induced reinstatement) to reinstate extinguished responding, as well as the direct reinforcing effects of cocaine in self-administration procedures (Grottick et al, 2000;Burmeister et al, 2004;Burbassi and Cervo, 2008;Cunningham et al, 2011;Manvich et al, 2012;Rüedi-Bettschen et al, 2015). These findings suggest that 5-HT 2C receptor-selective agonists might be effective for reducing cocaine abuse and for prolonging abstinence.…”

Effects of the serotonin 2C receptor agonist WAY163909 on the abuse-related effects and mesolimbic dopamine neurochemistry induced by abused stimulants in rhesus monkeys

“…Because of the regional distribution of serotonin 5-HT 2A and 5-HT 2C receptors in the brain, those receptors have been shown to exert opposing effects on cocaine self-administration and cocaine-induced reinstatement in nonhuman primates (Murnane et al 2013; Manvich et al 2012a). Particularly, activation of 5-HT 2C receptors has been shown to decrease cocaine self-administration, cocaine-induced reinstatement and dopamine overflow in the nucleus accumbens in both rodents (Grottick et al 2000; Neisewander and Acosta 2007; Burbassi and Cervo 2008; Fletcher et al 2008; Navailles et al 2008) and squirrel monkeys (Manvich et al 2012b; Rüedi-Bettschen et al 2015). However, the effects of receptor subtype-selective compounds and the extent of those findings to other stimulant drugs have yet to be systematically evaluated.…”

Serotonin antagonists fail to alter MDMA self-administration in rats

“…All of these studies point to a prominent role of DA in the maintenance of MDMA-taking and drug-seeking but a potential role of 5-HT has not been adequately addressed. The reinforcing effects of other drugs and drug-seeking following extinction of self-administration of other drugs are often decreased by selective 5-HT agonists as well as antagonists (Burmeister et al, 2004, Ruedi-Bettschen et al, 2015, Nic Dhonnchadha et al, 2009, Neisewander and Acosta, 2007, Peltier and Schenk, 1993. Therefore, the present study optimized conditions for observing decreases in MDMA self-administration and reinstatement of drug-seeking following administration of some 5-HT agonists and antagonists.…”