The Serotonin 2C Receptor Antagonist SB 242084 Exhibits Abuse-Related Effects Typical of Stimulants in Squirrel Monkeys

Abstract

Antagonists of the serotonin (5-hydroxytryptamine; 5-HT) type 2C receptor (5-HT 2C R) are being considered as potential pharmacotherapeutics for various affective disorders, but evidence suggests that these compounds enhance the effects of cocaine and related psychostimulants in rodents. However, the effects of selective 5-HT 2C R antagonists have not been evaluated in nonhuman primates. The present studies used operant-behavioral and in vivo microdialysis techniques to assess the impact of 5-HT 2C R antagonism on the behavioral and neurochemical effects of cocaine in squirrel monkeys. In subjects trained to lever-press on a fixed-interval schedule of stimulus termination, pretreatment with the highly selective 5-HT 2C R antagonist 6-chloro-2,3-dihydro-5-methyl-N-[6-[(2-methyl-3-pyridinyl) oxy]-3-pyridinyl]-1H-indole-1-carboxyamide dihydrochloride (SB 242084) (vehicle, 0.01-0.1 mg/kg) produced behavioralstimulant effects alone and interacted with cocaine in an apparently additive manner. In monkeys trained to selfadminister intravenous cocaine according to a second-order schedule of drug delivery, SB 242084 (vehicle, 0.03-0.1 mg/kg) modulated cocaine-induced reinstatement of previously extinguished responding and maintained selfadministration behavior when substituted for cocaine availability. These studies are the first to assess the direct reinforcing effects of a 5-HT 2C R-selective antagonist in any species. Finally, in vivo microdialysis studies revealed that pretreatment with SB 242084 (0.1 mg/kg) modulated cocaine-induced dopamine increases within the nucleus accumbens, but not the caudate nucleus, of awake subjects. Taken together, the results suggest that SB 242084 exhibits a behavioral profile that is qualitatively similar to other psychostimulants, although its efficacy is modest compared with cocaine. The observed interactions with cocaine and the substitution for cocaine self-administration may be indicative of some degree of abuse potential in humans.

Serotonin 5-HT2Receptor Interactions with Dopamine Function: Implications for Therapeutics in Cocaine Use Disorder

“…Systemic administration of the 5-HT 2C R agonist, Ro 60-0175, significantly attenuated cocaine-induced increases in extracellular DA in the NAc of conscious squirrel monkeys at a dose that attenuated cocaine self-administration and cocaineinduced reinstatement of previously-extinguished cocaine self-administration (Manvich et al, 2012a). Conversely, systemic administration of the selective 5-HT 2C R antagonist, SB 242084, enhanced cocaine-induced increases in NAc DA at a dose that enhanced cocaine-induced reinstatement and maintained self-administration when substituted for cocaine (Manvich et al, 2012b). The latter finding is consistent with a previous study demonstrating that systemic administration of SB 242084 enhanced cocaine-induced increases in DA in the NAc in rats .…”

“…Furthermore, by comparing the effects of a preferential agonist, m-chlorophenylpiperazine, with those of Ro 60-0175 on nondrug-maintained operant responding, the results indicated that increased pharmacological selectivity for the 5-HT 2C R confers a higher index of behavioral specificity, because Ro 60-0175 more potently altered cocaine-maintained versus nondrug-maintained behavior. In complete opposition to the behavioral effects of 5-HT 2C R agonist administration, pretreatment with the selective 5-HT 2C R antagonist SB 242084 induced modest behavioral-stimulant effects when administered alone, potentiated the behavioralstimulant effects of cocaine in an additive manner, and enhanced the reinstatement effects of cocaine in squirrel monkeys (Manvich et al, 2012b). The study also evaluated whether intravenous infusions of SB 242084 would maintain responding in squirrel monkeys when substituted for cocaine in self-administration sessions.…”

“…f Navarra et al, 2008Cunningham et al, 2011Cunningham et al, , 2013Anastasio et al, 2014a. g Katsidoni et al, 2011 h SB242084 alone supported self-administration in squirrel monkeys (Manvich et al, 2012b).…”

“…i Fletcher et al, 2002Fletcher et al, , 2006Fletcher et al, , 2008Winstanely et al, 2003;Frankel and Cunningham, 2004;Neisewander and Acosta, 2007;Burbassi and Cervo, 2008;Manvich et al, 2012b;Pennanen et al, 2013. j Filip and Cunningham, 2003. 188 Howell and Cunningham experimental conditions before conclusions about their reinforcing strength and abuse liability are drawn.…”

A short history of the 5-HT2C receptor: from the choroid plexus to depression, obesity and addiction treatment

“…Selective 5-HT2CR blockade produces opposite effects on self-administration of low doses of cocaine (Fletcher et al 2002a) and enhances cocaine-evoked reinstatement of drugseeking in rodents (Fletcher et al 2002a;Pelloux et al 2012). In non-human primates, 5-HT2CR agonism attenuated the stimulant, reinforcing and reinstatement effects of cocaine, which are blocked by the 5-HT2CR antagonist SB242084 (Manvich et al 2012a;2012b;Ruedi-Bettschen et al 2015). SB242084 itself may induce modest stimulant effects in primates (Manvich et al 2012a;2012b), although this data is open for discussion (RuediBettschen et al, 2015).…”