Interaction between behavioral and pharmacological treatment strategies to decrease cocaine choice in rhesus monkeys

Abstract

Behavioral and pharmacotherapeutic approaches constitute two prominent strategies for treating cocaine dependence. This study investigated interactions between behavioral and pharmacological strategies in a preclinical model of cocaine vs food choice. Six rhesus monkeys, implanted with a chronic indwelling double-lumen venous catheter, initially responded under a concurrent schedule of food delivery (1-g pellets, fixed-ratio (FR) 100 schedule) and cocaine injections (0-0.1 mg/kg/injection, FR 10 schedule) during continuous 7-day treatment periods with saline or the agonist medication phenmetrazine (0.032-0.1 mg/kg/h). Subsequently, the FR response requirement for cocaine or food was varied (food, FR 100; cocaine, FR 1-100; cocaine, FR 10; food, FR 10-300), and effects of phenmetrazine on cocaine vs food choice were redetermined. Decreases in the cocaine FR or increases in the food FR resulted in leftward shifts in the cocaine choice dose-effect curve, whereas increases in the cocaine FR or decreases in the food FR resulted in rightward shifts in the cocaine choice dose-effect curve. The efficacy of phenmetrazine to decrease cocaine choice varied systematically as a function of the prevailing response requirements, such that phenmetrazine efficacy was greatest when cocaine choice was maintained by relatively low unit cocaine doses. These results suggest that efficacy of pharmacotherapies to modulate cocaine use can be influenced by behavioral contingencies of cocaine availability. Agonist medications may be most effective under contingencies that engender choice of relatively low cocaine doses.

Figure 1

Effects of continuous 7-day treatment with phenmetrazine (0.032–0.32 mg/kg/h) on choice between cocaine and food under baseline FR conditions (Food FR 100/Coc FR 10) in rhesus monkeys (n=6), except for the 0.32 mg/kg/h phenmetrazine dose, which was tested in four monkeys. Numbers in parentheses indicate the number of subjects contributing to that data point for the 0.32/h phenmetrazine treatment; responding in the remaining monkey was eliminated. Abscissae: unit dose of cocaine in mg per kg per injection. Top ordinate: percent cocaine choice. Bottom ordinate: number of ratio requirements (choices) completed per component. All points represent mean data±SEM obtained during the last 3 days of each 7-day treatment. Filled symbols indicate statistically significant (p⩽0.05) compared with the saline condition within a given unit cocaine dose.

Figure 2

Effects of FR manipulations on the cocaine- or food-associated key on choice between cocaine and food in rhesus monkeys. Abscissae: unit dose of cocaine in mg per kg per injection. Top ordinates: percent cocaine choice. Bottom ordinates: the number of ratio requirements (choices) completed per component. All points represent mean data±SEM obtained during the 3 days preceding each phenmetrazine treatment. Filled symbols indicate statistically significant (p⩽0.05) compared with the baseline FR condition (cocaine FR 10, food FR 100) within a given unit cocaine dose.

Figure 3

Effects of continuous 7-day treatment with phenmetrazine (0.032–0.1 mg/kg/h) on choice between cocaine and food under different cocaine FR conditions. Abscissae: unit dose of cocaine in mg per kg per injection. Top ordinates: percent cocaine choice. Bottom ordinates: the number of ratio requirements (choices) completed per component. All points represent mean data±SEM obtained during the last 3 days of each 7-day treatment from four monkeys. Filled symbols indicate statistically significant (p⩽0.05) compared with the saline condition within a given unit cocaine dose. The graphs for the baseline FR manipulations are the same data as in Figure 1.

Figure 4

Effects of continuous 7-day treatment with phenmetrazine (0.032–0.1 mg/kg/h) on choice between cocaine and food under different food FR conditions. Abscissae: unit dose of cocaine in mg per kg per injection. Top ordinates: percent cocaine choice. Bottom ordinates: the number of ratio requirements (choices) completed per component. All points represent mean data±SEM obtained during the last 3 days of each 7-day treatment. The food FR 100 and FR 10 conditions represent data from six monkeys, whereas the food FR 300 condition represents data from five monkeys. Filled symbols indicate statistically significant (p⩽0.05) compared with the saline condition within a given unit cocaine dose. The graphs for the baseline FR manipulations are the same data as in Figure 1.

Figure 5

Effects of continuous 7-day phenmetrazine treatment (0.032–0.32 mg/kg/h) on total, food, and cocaine choices under different cocaine and food FR conditions. Abscissae: experimental end point. Ordinates: number of ratio requirements (choices) completed per session. All bars represent mean data±SEM obtained during the last 3 days of each phenmetrazine treatment or the 3 days preceding each phenmetrazine treatment. *p⩽0.05, significantly different from the saline condition.