Effects of extended cocaine access and cocaine withdrawal on choice between cocaine and food in rhesus monkeys

Abstract

Chronic drug use may lead to sufficient drug intake to produce dependence and the emergence of abstinence signs during withdrawal. Although withdrawal can increase the reinforcing effects of some drugs (eg opioids), the impact of withdrawal on the reinforcing effects of stimulants like cocaine is less clear. This study used a novel cocaine vs food choice procedure to examine the relative reinforcing strength of cocaine before, during, and after exposure to graded levels of extended cocaine access. Responding in four rhesus monkeys was maintained by cocaine (0-0.1 mg/kg/injection) and food delivery under a concurrent-choice schedule during daily 2-h sessions. Under baseline conditions, cocaine maintained a dose-dependent increase in cocaine choice. Subsequently, subjects were exposed to and withdrawn from periods of extended cocaine access, which was accomplished by implementing daily 21-h supplemental sessions of cocaine self-administration in addition to daily choice sessions. During supplemental sessions, cocaine (0.1 mg/kg/injection) was available under a fixed-ratio 10/time-out X schedule, and the duration of the time-out was varied from 30 to 7.5 min. Cocaine intake increased 10-fold to >11 mg/kg/day during exposure to supplemental sessions with the shortest post-injection time-out. However, parameters of cocaine choice were not significantly affected either during or after extended cocaine access. These results do not support the hypothesis that cocaine withdrawal increases the reinforcing strength of cocaine. This differs from results with the opioid agonist heroin and suggests that withdrawal may have different functions in the maintenance of opioid and stimulant abuse.

Figure 1

Effects of extended cocaine access on cocaine choice in rhesus monkeys. Abscissae: unit dose cocaine (mg/kg/injection). Ordinate (top panel): % Cocaine choice. Ordinate (bottom panel): number of ratios completed per component (maximum=10 ratios per component). Extended cocaine access was accomplished by introducing daily, 21-h supplemental sessions of cocaine availability using 30, 15, and 7.5 min post-injection time-out periods. Baseline data show mean results from the 3 days preceding each 7-day period of extended access. Supplemental session data show mean results from the last 3 days of each 7-day period of extended access. All points show mean±SEM from four monkeys except the filled circles in the top panel (% cocaine choice during exposure to supplemental sessions with 7.5 min post-injection time-outs). These points show data for only 2–3 monkeys, because two monkeys failed to respond during most components and % cocaine choice could not be calculated.

Figure 2

Cocaine self-administration by individual rhesus monkeys during extended cocaine access (supplemental sessions of cocaine availability with post-injection time-outs of 30, 15, or 7.5 min). Abscissae: consecutive days of access. Ordinates: number of cocaine injections (0.1 mg/kg/injection) earned per experimental day. The identification number of each monkey is shown at the top of the panel. Each point shows data from a single determination in one monkey.

Figure 3

Cocaine intake during periods of extended cocaine access. Left panel: diurnal patterns of cocaine during supplemental sessions of cocaine availability with post-injection time-outs of 30, 15, or 7.5 min. Abscissa: Quintiles of the 21-h supplemental session (Quintile 1: 1:00–5:12 p.m.; Quintile 2: 5:12–9:24 p.m.; Quintile 3: 9:24 p.m.–1:36 a.m.; Quintile 4: 1:36–5:48 a.m.; Quintile 5: 5:48–10:00 a.m.). Ordinate: number of cocaine injections (0.1 mg/kg/injection) during each quintile. Each point shows mean±SEM from four monkeys during the last 3 days of exposure to each type of supplemental session. Right panel: daily cocaine intake at baseline and during access to supplemental sessions. Abscissa: duration of the post-injection time-out period during the supplemental sessions. The bar above ‘BL' shows baseline data when there were no supplemental sessions and cocaine was available only during choice sessions. Ordinate: daily cocaine intake in mg/kg. Baseline data show results from the 3 days preceding each 7-day period of extended access. Supplemental session data show results from the last 3 days of each 7-day period of extended access. All bars show mean±SEM in four monkeys. Asterisks indicate a significant difference from baseline. ^**p<0.01. Dashed bar above each supplemental session indicates total possible cocaine intake.

Figure 4

Effects of withdrawal from extended cocaine access on cocaine choice. Abscissae: unit dose cocaine in mg/kg/injection. Ordinates (top panels): percent cocaine choice. Ordinates (bottom panels). Number of ratios completed per component. Data are shown in the left, center, and right panels for supplemental sessions with 30, 15, and 7.5 min post-injection time-outs, respectively. In each panel, baseline data are indicated by a dotted gray line, and data obtained during access to supplemental sessions are shown by a solid gray line (identical to data shown in Figure 1). All points show mean±SEM data from four monkeys collected on days 1, 4, and 7 after termination of access to supplemental sessions.

Figure 5

Total choices, food choices, cocaine choices, and cocaine intake during choice sessions before, during, and after extended cocaine access. Abscissae: experimental endpoint. Left ordinates: number of choices per session. Right ordinates: cocaine intake in mg/kg/day during choice sessions. All bars show mean±SEM data from four monkeys. None of the parameters were significantly different from baseline either during or after extended cocaine access.

Figure 6

Effects of extended cocaine access +7 days of cocaine abstinence on cocaine choice. Abscissae: unit dose cocaine in mg/kg/injection. Ordinate (top panel): percent cocaine choice. Ordinate (bottom panel). Number of ratios completed per component. In each panel, baseline data are indicated by a dotted gray line, and data obtained during access to supplemental sessions (7.5 min post-injection time-outs) are shown by a solid gray line. All points show mean±SEM from three monkeys collected on days 1, 4, and 7 after the 7-day abstinence period (ie, days 8, 11, and 14 after termination of access to supplemental cocaine).