Influence of abstinence and conditions of cocaine access on the reinforcing strength of cocaine in nonhuman primates

Abstract

The development of addiction is marked by a transition from recreational to uncontrolled drug use. Investigators modeling this phenomenon in rodents observed increases in cocaine self-administration when conditions of drug access were altered as well as after abstinence. The present studies were designed to extend this research to nonhuman primates by examining whether the reinforcing strength of cocaine could be altered by changing conditions of cocaine availability or by introducing abstinence periods. Rhesus monkeys self-administered cocaine (0.03–0.3 mg/kg per injection) under a progressive-ratio (PR) schedule of reinforcement in evening sessions, with the number of injections earned serving as a measure of reinforcing strength. Alterations in the reinforcing strength of cocaine were assessed after additional access to cocaine under a fixed-ratio (FR) schedule was provided in morning sessions and following various periods of abstinence (3, 7 and 14 days) from regimens of self-administration that resulted in a range of cocaine intakes. Under baseline PR conditions, the maximum number of cocaine injections increased dose-dependently, peaking when 0.3 mg/kg per injection cocaine was available. No increases in the reinforcing strength of cocaine were observed under any condition. In contrast, a statistically significant decrease in the reinforcing strength of cocaine was observed following 14 days of abstinence under one condition. These results fail to support the views that increasing access to cocaine or abstinence enhances the reinforcing strength of cocaine.

Introduction

Intravenous drug self-administration techniques have demonstrated predictive validity in characterizing the abuse liability of centrally acting drugs (Griffiths et al., 1980, Ator and Griffiths, 2003) and have been used extensively to evaluate candidate pharmacotherapies for cocaine abuse (Mello and Negus, 1996, Carroll et al., 1999, Platt et al., 2002). Procedures typically used to examine self-administration involve limited daily access to cocaine, which results in stable rates of responding and patterns of cocaine intake. Such stable behavioral baselines have helped to elucidate the neurobiological mechanisms that mediate the reinforcing effects of cocaine (e.g., Ritz et al., 1987, Bergman et al., 1990). However, such procedures fail to address the progression from recreational to uncontrolled use that marks the development of addiction (Gawin and Ellinwood, 1988, Gawin, 1991, Dackis and O’Brien, 2001).

One approach to modeling uncontrolled drug use is to provide laboratory animals with unlimited access to cocaine. However, early studies demonstrated that unlimited access resulted in cocaine intakes sufficiently high to produce severe toxicity in rats and monkeys and death within as little as 5 days of exposure in monkeys (Deneau et al., 1969, Johanson et al., 1976, Aigner and Balster, 1978, Bozarth and Wise, 1985). Although the majority of subsequent studies have avoided toxicity by constraining cocaine availability, more recent studies in rodents have attempted to model “loss of control” over cocaine self-administration using conditions under which rats have extended access to cocaine under fixed-ratio (FR) schedules in the absence of toxic and/or lethal effects (e.g., Fitch and Roberts, 1993, Ahmed and Koob, 1988, Tornatzky and Miczek, 2000, Mantsch et al., 2003, Vanderschuren and Everitt, 2004). For example, Roberts and colleagues have developed a discrete-trials (DT) procedure in which rats have an opportunity to self-administer cocaine a variable number of times per hour, 24 h per day (Fitch and Roberts, 1993). Stable circadian patterns of self-administration were observed when rats had access to cocaine two or three times per hour. However, increasing the number of trials to four or five per hour (DT4, DT5) resulted in binge-like (i.e., non-circadian) responding and large daily cocaine intakes (Roberts et al., 2002).

During the transition from controlled drug use to addiction, cocaine presumably becomes a stronger reinforcer relative to other reinforcers in the abuser's environment. One method of assessing the reinforcing strength of a drug is to study self-administration using a progressive-ratio (PR) schedule (Hodos, 1961). Under PR schedules, the response requirement increases for successive presentations of a reinforcer until the subject stops responding. Several outcome measures are thought to reflect the strength of the reinforcer, including the total number of responses emitted, the total number of drug injections earned, or the ratio value completed (breaking point or BP) before responding ceases (Hodos, 1961, Katz, 1990, Stafford et al., 1998). Although BPs observed with cocaine are relatively stable over time (cf. Morgan and Roberts, 2004), they can be altered by experimental histories involving extended access to cocaine. For example, a procedure that results in escalation of cocaine intake in rodents during exposure to daily 6-h self-administration sessions (Ahmed and Koob, 1988) resulted in higher BPs for cocaine, suggesting an increased reinforcing strength (Paterson and Markou, 2003, but see Liu et al., 2005). A similar effect can be observed in rats after abstinence from extended-access self-administration of cocaine. For example, although Roberts et al. (2002) reported that 5 days of exposure to the DT4 or DT5 schedule shifted the cocaine dose–effect curve under a PR schedule rightward and/or down, suggesting a decrease in the reinforcing strength of cocaine (i.e., tolerance), BPs for cocaine were significantly increased after 7 days of abstinence from exposure to the DT4 schedule (Morgan et al., 2002, Morgan et al., 2005). In addition to highlighting the influence of conditions of drug access on patterns of drug self-administration, these data and others (e.g., Lu et al., 2004) support the view that, in rodents, a period of abstinence following cocaine self-administration is vital to enhancement of the reinforcing effects of cocaine, a phenomenon termed “incubation” (Grimm et al., 2001).

The goal of the present studies was to extend this line of research to nonhuman primates, using a within-subjects design, by investigating whether the reinforcing strength of cocaine could be altered by increasing access to cocaine or by imposing abstinence periods following cocaine exposure. Previous efforts in monkeys did not report changes in BP as a result of additional programmed injections of cocaine (Yanagita, 1976). However, using a concurrent schedule in monkeys, Negus (2003) found that following a brief abstinence period, cocaine choice was modestly decreased. In the present study, monkeys self-administered cocaine under a PR schedule during behavioral sessions conducted in the evening. The effects of four manipulations on the reinforcing strength of cocaine were assessed: (1) introducing abstinence periods from self-administration of cocaine under the PR schedule; (2) providing additional access to cocaine (0.03–0.3 mg/kg per injection) each morning under an FR 50 schedule; (3) introducing abstinence periods following twice-daily (0.1 mg/kg per injection morning FR 50 session, evening PR session) cocaine exposure; (4) introducing abstinence periods following exposure to high cocaine intakes, which were achieved by allowing monkeys to self-administer a high dose of cocaine (0.3 mg/kg per injection) twice per day under an FR 50 schedule.