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.

Effects of Environmental Manipulations and Treatment with Bupropion and Risperidone on Choice between Methamphetamine and Food in Rhesus Monkeys

“…Moreover, the small, nonsignificant shifts in methamphetamine choice in the present study when the response requirement for both reinforcers was an FR100 are in contrast to previous results with cocaine. Under similar choice procedures, cocaine vs food choice was significantly attenuated with the FR response requirement matched at either FR100 or FR10 (Banks et al, 2013;Negus, 2003). Overall, the results of the present study are consistent with the results from a human laboratory methamphetamine choice study and suggest that methamphetamine choice may be less sensitive to response requirement 'cost' manipulations than cocaine choice.…”

Effects of Phendimetrazine Treatment on Cocaine vs Food Choice and Extended-Access Cocaine Consumption in Rhesus Monkeys

“…A 12-h light-dark cycle was in effect (lights on from 0600 to 1800 hours). All monkeys had prior cocaine selfadministration histories (Banks et al, 2013b;Banks et al, 2013c). Animal research and maintenance were conducted according to the 8th edition of the Guide for the Care and Use of Laboratory Animals as adopted and promulgated by the National Institutes of Health.…”

“…Choice behavior was considered stable when the lowest unit-cocaine dose maintaining at least 80% cocaine vs food choice varied by p0.5 log units for 3 consecutive days. Experimental parameters (unit-cocaine dose and dose order, alternative food reinforcer magnitude, and ratio requirement on food-and cocaine-associated keys) of the choice session used in this study were based on extensive parametric manipulations reported previously (Negus, 2003) and are identical to parameters used to assess other candidate medications effects on cocaine choice (Banks et al, 2011(Banks et al, , 2013bBanks et al, 2013c;Negus, 2004;Negus and Mello, 2004). Consequently, with the parameters used in this study, we could detect both leftward and rightward shifts in the cocaine vs food choice dose-effect function that might result from manipulation of experimental variables.…”

“…The novel preclinical procedure employed in the present study was intended to model intensive 'heavy' cocaine use, and effects of PDM in this procedure extend the conditions under which monoamine releaser-based medications have decreased cocaine self-administration in nonhuman primate studies. For example, we have previously shown that dopamine-selective monoamine releasers, such as d-amphetamine and PM, are effective in decreasing cocaine choice under conditions that limit maximum daily cocaine intakes to approximately 1.2 mg/kg/day (Banks et al, 2011(Banks et al, , 2013bBanks et al, 2013c;Negus, 2003). Monoamine releaser-induced reductions in cocaine self-administration have also been demonstrated under other schedules of reinforcement associated with a broad range of daily cocaine intakes in both nonhuman primates (Czoty et al, 2010;Czoty et al, 2011;Negus and Mello, 2003a;Negus and Mello, 2003b) and rats (Chiodo and Roberts, 2009;Chiodo et al, 2008;Thomsen et al, 2013).…”

“…PDM is a low-potency monoamine-uptake inhibitor and a prodrug for the monoamine-releaser phenmetrazine (PM) (Banks et al, 2013a;Rothman et al, 2002). We have previously shown that continuous 7-day treatment with PM produces an amphetamine-like decrease in cocaine self-administration in rhesus monkeys under limited, 1-2 h, cocaine access conditions (Banks et al, 2011;Banks et al, 2013c;Negus et al, 2009); however, also like d-amphetamine, PM reliably maintains drug self-administration, and it is a schedule II controlled substance (Chait et al, 1987;Corwin et al, 1987;Rothman et al, 2002). By contrast, the prodrug PDM functioned as a reinforcer in one out of two drug selfadministration studies (Corwin et al, 1987;Griffiths et al, 1979), and this evidence for its lower abuse liability has contributed to its lower, schedule III, controlled-substance classification.…”