Article

Interaction of cocaine and dopamine transporter inhibitors on behavior and neurochemistry in monkeys

Yerkes National Primate Research Center, Emory University, 954 Gatewood Road NE, Atlanta, GA 30329, USA.
Pharmacology Biochemistry and Behavior (Impact Factor: 2.78). 04/2005; 80(3):481-91. DOI: 10.1016/j.pbb.2005.01.004
Source: PubMed

ABSTRACT

Drugs that target the dopamine transporter (DAT) have been proposed as pharmacotherapies to treat cocaine abuse. Accordingly, it is paramount to understand pharmacological interactions between cocaine and DAT inhibitors. The present study characterized acute interactions between cocaine and several DAT inhibitors (RTI-177, FECNT, RTI-112) that differed in selectivity for monoamine transporters on operant behavior and in vivo neurochemistry in squirrel monkeys. RTI-177 and FECNT, two DAT inhibitors with low affinity at norepinephrine transporters (NET), produced dose-dependent stimulant effects on behavior maintained by a fixed-interval schedule of stimulus termination. Compared to cocaine, RTI-177 and FECNT had a slower onset and longer duration of action. In vivo microdialysis in the caudate nucleus of awake monkeys confirmed dose-dependent increases in extracellular dopamine that corresponded to behavioral effects. Among the drugs characterized, RTI-112 is reportedly the least selective for binding to DAT, NET, and serotonin transporters (SERT). Interestingly, RTI-112 failed to produce significant behavioral-stimulant effects, and its effects on extracellular dopamine were highly variable across subjects. The results indicate that the pharmacological profile of DAT inhibitors may be influenced by actions at multiple monoamine transporters. Importantly, there was little evidence of additivity on behavioral or neurochemical measures when cocaine was administered in combination with behavioral-stimulant doses of the DAT inhibitors.

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    • "Daily enrichment was provided . Each animal had served in previous behavioral studies involving administration of compounds acting on monoaminergic and/or glutamatergic systems (Ginsburg et al., 2005; Kimmel et al., 2005, 2007, 2009; Banks et al., 2009; Bauzo et al., 2009; Fantegrossi et al., 2009). All studies were conducted in strict accordance with the "
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    ABSTRACT: Antagonists of the serotonin (5-hydroxytryptamine; 5-HT) type 2C receptor (5-HT2CR) 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-HT2CR 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-HT2CR 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-HT2CR 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 behavioral-stimulant effects alone and interacted with cocaine in an apparently additive manner. In monkeys trained to self-administer 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 self-administration behavior when substituted for cocaine availability. These studies are the first to assess the direct reinforcing effects of a 5-HT2CR-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.
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    • "NAC significantly attenuated cocaine-induced increases in extracellular dopamine in the caudate without an apparent alteration of basal extracellular dopamine. Acute systemic administration of NAC pretreatment did not completely abolish cocaine-induced increases in dopamine in this region, but decreased the effectiveness of cocaine such that the effects of 1.0 mg/kg cocaine following NAC pretreatment were equivalent to the effects of 0.3 mg/kg cocaine alone previously reported in squirrel monkeys (Bauzo et al., 2009a, Ginsburg et al., 2005). This lower dose of cocaine (0.3 mg/kg) is one that has induced behavioral-stimulant effects in nonhuman primates. "
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    • "Daily enrichment was provided via access to foraging devices, toys, and climbing/swing devices. Each animal had served in previous behavioral studies involving administration of compounds acting on monoaminergic and/or glutamatergic systems (Ginsburg et al., 2005; Kimmel et al., 2005, 2007, 2009; Banks et al., 2009; Bauzo et al., 2009; Fantegrossi et al., 2009). All studies were conducted in strict accordance with the "
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