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. 2009 Jan;91(3):333-8.
doi: 10.1016/j.pbb.2008.08.002. Epub 2008 Aug 8.

Effects of the monoamine uptake inhibitors RTI-112 and RTI-113 on cocaine- and food-maintained responding in rhesus monkeys

S S Negus  1 , N K Mello, H L Kimmel, L L Howell, F I Carroll
Affiliations

Effects of the monoamine uptake inhibitors RTI-112 and RTI-113 on cocaine- and food-maintained responding in rhesus monkeys

S S Negus et al. Pharmacol Biochem Behav. 2009 Jan.

Abstract

Cocaine blocks uptake of the monoamines dopamine, serotonin and norepinephrine, and monoamine uptake inhibitors constitute one class of drugs under consideration as candidate "agonist" medications for the treatment of cocaine abuse and dependence. The pharmacological selectivity of monoamine uptake inhibitors to block uptake of dopamine, serotonin and norepinephrine is one factor that may influence the efficacy and/or safety of these compounds as drug abuse treatment medications. To address this issue, the present study compared the effects of 7-day treatment with a non-selective monoamine uptake inhibitor (RTI-112) and a dopamine-selective uptake inhibitor (RTI-113) on cocaine- and food-maintained responding in rhesus monkeys. Monkeys (N=3) were trained to respond for cocaine injections (0.01 mg/kg/inj) and food pellets under a second-order schedule [FR2(VR16:S)] during alternating daily components of cocaine and food availability. Both RTI-112 (0.0032-0.01 mg/kg/hr) and RTI-113 (0.01-0.056 mg/kg/h) produced dose-dependent, sustained and nearly complete elimination of cocaine self-administration. However, for both drugs, the potency to reduce cocaine self-administration was similar to the potency to reduce food-maintained responding. These findings do not support the hypothesis that pharmacological selectivity to block dopamine uptake is associated with behavioral selectivity to decrease cocaine- vs. food-maintained responding in rhesus monkeys.

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Figures

Figure 1
Figure 1. Effects of treatment with RTI-112 and RTI-113 on responding maintained by 0.01 mg/kg/inj cocaine and food
Abscissae: Dose of test drug in mg/kg/hr, log scale. Ordinates: Percent control levels of cocaine- and food-maintained responding. All points show mean±SEM in 3 monkeys from the last 3 days of each 7-day treatment. The absence of error bars indicates that error bars were contained within the point. Filled points indicate a significant difference from control levels of cocaine- or food-maintained responding (p<0.05). There was not a significant effect of reinforcer type at any dose of either drug. ANOVA results for RTI-112. Main effect of dose: F(3,12)=27.17, p<0.0001. Main effect of reinforcer type: F(1,4)=8.09, p=0.047. Dose × reinforcer type interaction: F(3,12)=1.91, p=0.18. ANOVA results for RTI-113: Main effect of dose: F(4,16)=10.11, p=0.0003. Main effect of reinforcer type: F(1,4)=2.89, p=0.16. Dose × reinforcer type interaction: F(4,16)=0.66, p=0.63.
Figure 2
Figure 2. Time course of effects produced by treatment with saline, RTI-112 (0.01 mg/kg/hr) and RTI-113 (0.056 mg/kg/hr) on responding maintained by 0.01 mg/kg/inj cocaine and food
Abscissae: Consecutives days of treatment. All treatments were implemented for a period of 7 days. Ordinates: Percent control levels of cocaine- and food-maintained responding. All points show mean ± SEM in three monkeys. The absence of error bars indicates that error bars were contained within the point. There was not a significant difference in effects of RTI-112 or RTI-113 on cocaine- vs. food-maintained responding at any time during treatment. ANOVA results for saline treatment. Main effect of time: F(6,24)=0.89, p=0.39. Main effect of reinforcer type: F(1,4)=1.75, p=0.26. Time × reinforcer type interaction: F(6,24)=1.10, p=0.39. ANOVA results for 0.01 mg/kg/hr RTI-112 treatment. Main effect of time: F(6,24)=1.94, p=0.11. Main effect of reinforcer type: F(1,4)=1.46, p=0.29. Time × reinforcer type interaction: F(6,24)=1.00, p=0.45. ANOVA results for 0.056 mg/kg/hr RTI-113 treatment. Main effect of time: F(6,24)=5.08, p=0.0017. Main effect of reinforcer type: F(1,4)=1.22, p=0.33. Time × reinforcer type interaction: F(6,24)=0.24, p=0.96.
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