Effects of monoamine releasers with varying selectivity for releasing dopamine/norepinephrine versus serotonin on choice between cocaine and food in rhesus monkeys

Abstract

Monoamine releasers constitute one class of candidate medications for the treatment of cocaine abuse, and concurrent cocaine-versus-food choice procedures are potentially valuable as experimental tools to evaluate the efficacy and safety of candidate medications. This study assessed the choice between cocaine and food by rhesus monkeys during treatment with five monoamine releasers that varied in selectivity to promote the release of dopamine and norepinephrine versus serotonin (5HT) [m-fluoroamphetamine, (+)-phenmetrazine, (+)-methamphetamine, napthylisopropylamine and (±)-fenfluramine]. Rhesus monkeys (n=8) responded under a concurrent-choice schedule of food delivery (1-g pellets, fixed ratio 100 schedule) and cocaine injections (0-0.1 mg/kg/injection, fixed ratio 10 schedule). Cocaine choice dose-effect curves were determined daily during continuous 7-day treatment with saline or with each test compound dose. During saline treatment, cocaine maintained a dose-dependent increase in cocaine choice, and the highest cocaine doses (0.032-0.1 mg/kg/injection) maintained almost exclusive cocaine choice. Efficacy of monoamine releasers to decrease cocaine choice corresponded to their pharmacological selectivity to release dopamine and norepinephrine versus 5HT. None of the releasers reduced cocaine choice or promoted reallocation of responding to food choice to the same extent as when saline was substituted for cocaine. These results extend the range of conditions across which dopamine and norepinephrine-selective releasers have been shown to reduce cocaine self-administration.

Figure 1

Effects of continuous 7-day treatment with m-fluoroamphetamine (0.032–0.32 mg/kg/h) on choice between cocaine and food. Upper vertical axes: percent cocaine choice (left) or the number of choices completed per component (right) during treatment with saline (Baseline) or increasing doses of m-fluoroamphetamine. Upper horizontal axes: unit dose of cocaine in milligrams per kilogram per injection. Bottom panels show total choices, food choices, cocaine choices and cocaine intake during choice sessions before or during 7-day treatment with m-fluoroamphetamine. Lower left vertical axis: Number of choices per session. Lower right vertical axis: cocaine intake in mg/kg/day during choice sessions. Lower horizontal axes: experimental endpoint. All points and bars represent mean data ± SEM from four monkeys obtained during the last 3 days of each 7-day treatment. Filled symbols indicate significantly different (p < 0.05) from baseline conditions within a cocaine dose. Asterisk indicates significantly different (p < 0.05) from baseline conditions.

Figure 2

Effects of continuous 7-day treatment with (+)-phenmetrazine (0.032–0.32 mg/kg/hr) on choice between cocaine and food. Other details as in Fig. 1.

Figure 3

Effects of continuous 7-day treatment with (+)-methamphetamine (0.032–0.1 mg/kg/hr) on choice between cocaine and food. Other details as in Fig. 1.

Figure 4

Effects of continuous 7-day treatment with naphthylisopropylamine (0.1–1.0 mg/kg/hr) on choice between cocaine and food. Other details as in Fig. 1, except that 1.0 mg/kg/hr napthylisopropylamine was tested in only three monkeys.

Figure 5

Effects of continuous 7-day treatment with (±)-fenfluramine (0.1–0.32 mg/kg/hr) on choice between cocaine and food. Other details as in Fig. 1.

Figure 6

Effects of removing cocaine or food availability on choice. Horizontal axes in the upper panels show unit dose of cocaine available (during “Baseline” and “No Food” conditions), or unit dose of cocaine associated with the prevailing discriminative stimuli (during the “No Cocaine” condition). Other details as in Fig. 1.

Figure 7

Cocaine choice ED50 values in individual animals during each experimental manipulation. Horizontal axes: Experimental manipulation. Vertical axis: Cocaine choice ED50 value in mg/kg/inj (log scale). Different symbols represent individual animals. Horizontal line represents the mean for each condition. For the “No Cocaine” conditions, the ED50 value was based on the cocaine doses associated with the prevailing discriminative stimuli.

Figure 8

Effects of experimental manipulations on total, food and cocaine choices. Doses of each monoamine releaser were selected based on individual data as described in Results. Horizontal axis: Experimental endpoint. Vertical axis: Number of choices per session. Each bar shows mean±SEM from a group of 4 monkeys, except ”baseline,” which shows data from all 8 monkeys. Asterisk indicates significantly (p< 0.05) different from baseline within an experimental endpoint.