Effects of phendimetrazine treatment on cocaine vs food choice and extended-access cocaine consumption in rhesus monkeys

Abstract

There is currently no Food and Drug Administration-approved pharmacotherapy for cocaine addiction. Monoamine releasers such as d-amphetamine constitute one class of candidate medications, but clinical use and acceptance are hindered by their own high-abuse liability. Phendimetrazine (PDM) is a schedule III anorectic agent that functions as both a low-potency monoamine-uptake inhibitor and as a prodrug for the monoamine-releaser phenmetrazine (PM), and it may serve as a clinically available, effective, and safer alternative to d-amphetamine. This study determined efficacy of chronic PDM to reduce cocaine self-administration by rhesus monkeys (N=4) using a novel procedure that featured both daily assessments of cocaine vs food choice (to assess medication efficacy to reallocate behavior away from cocaine choice and toward choice of an alternative reinforcer) and 20 h/day cocaine access (to allow high-cocaine intake). Continuous 21-day treatment with ramping PDM doses (days 1-7: 0.32 mg/kg/h; days 8-21: 1.0 mg/kg/h) reduced cocaine choices, increased food choices, and nearly eliminated extended-access cocaine self-administration without affecting body weight. There was a trend for plasma PDM and PM levels to correlate with efficacy to decrease cocaine choice such that the monkey with the highest plasma PDM and PM levels also demonstrated the greatest reductions in cocaine choice. These results support further consideration of PDM as a candidate anti-cocaine addiction pharmacotherapy. Moreover, PDM may represent a novel pharmacotherapeutic approach for cocaine addiction because it may simultaneously function as both a monoamine-uptake inhibitor (via the parent drug PDM) and as a monoamine releaser (via the active metabolite PM).

Figure 1

Experimental procedure. (a) Following a baseline period during which cocaine self-administration was only available during daily 2 h cocaine –vs food choice sessions, monkeys were subsequently given daily access to cocaine during both choice sessions and ‘extended access' sessions lasting 20 h (noon to 0800 hours). During extended-access sessions, monkeys could respond for 0.1 mg/kg/injection cocaine under a FR 10/time out 15- min schedule of reinforcement. After 14 days of extended cocaine access, 0.32 mg/kg/h phendimetrazine (PDM) was continuously infused for 7 days, and then the PDM dose was increased to 1.0 mg/kg/h PDM for 14 days for a total of 21 consecutive days of PDM treatment. Extended-access conditions were continued for an additional 7 days following PDM treatment. (b) Following ‘baseline' cocaine vs food choice, saline was substituted for cocaine for a period of 14 days during both the choice session and 20 h self-administration conditions ‘no cocaine.' All cocaine-associated stimuli, including intravenous injections, were retained.

Figure 2

Effects of 20 h extended cocaine access on choice between cocaine and food in rhesus monkeys (n=4). Top abscissae: unit dose cocaine in mg/kg/injection. Top left ordinate: percent cocaine choice. Top right ordinate: percent food choice. Bottom abscissa: 4 h bins of the extended cocaine access session. Bottom ordinate: number of cocaine injections per each 4 h bin. All symbols represent mean±SEM of four monkeys from the last 3-day (days 5–7; 12–14) means of each experimental condition. Filled symbols indicate statistical significance (P<0.05) compared with choice session only conditions.

Figure 3

Effects of 21 days of continuous (+)-phendimetrazine (PDM) treatment on choice between cocaine and food and cocaine consumption during the 20-h extended cocaine access in rhesus monkeys (n=4; a, c). For comparison, the effects of 14 days of substituting saline ‘no cocaine' for cocaine in both the choice procedure and 20 h extended-access session in rhesus monkeys (n=3; b, d). Top abscissae: unit dose cocaine in mg/kg/injection or cocaine-associated stimuli. Top left ordinates: percent cocaine choice. Top right ordinates: percent food choice. Bottom abscissa: 4 h bins of the extended cocaine access session. Bottom ordinates: number of cocaine injections per each 4 h bin. All symbols represent mean±SEM of four monkeys from the last 3-day (days 5–7; 12–14; 19–21) means of each experimental condition. Filled symbols indicate statistical significance compared with ‘+ 20 h extended access—14 days' conditions for a and c and compared with ‘choice session alone' for b.

Figure 4

Recovery of cocaine vs food choice and cocaine consumption following termination of continuous (+)-phendimetrazine (PDM) treatment in rhesus monkeys (n=3). Top abscissae: unit dose cocaine in mg/kg/injection. Top left ordinate: percent cocaine choice. Top right ordinate: percent food choice. Bottom abscissa: 4 h bins of the extended cocaine access session. Bottom ordinate: number of cocaine injections per each 4 h bin. All symbols represent mean±SEM of three monkeys from the last 3-day means of each experimental condition. The fourth monkey lost catheter patency during the 7-day post-PDM period, and his data are excluded for this figure. Filled symbols indicate statistical significance (P<0.05) compared with ‘+ 20 h extended-access—14 days' conditions.