A comparison of cocaine, GBR 12909, and phentermine self-administration by rhesus monkeys on a progressive-ratio schedule
Introduction
Ample evidence shows that cocaine can function as a positive reinforcer in nonhuman and human subjects, and the reinforcing effects of cocaine have been shown, under some conditions, to be greater than for other reinforcers. For example, Aigner and Balster (1978) found that rhesus monkeys reliably chose a 300 μg/kg injection of cocaine over five 1-g food pellets across eight days of testing. To the extent that marked preference of one option reflects that option's greater relative reinforcing efficacy (Johanson and Schuster, 1975, Markou et al., 1993) these data show that cocaine's reinforcing effects can be greater than those of competing reinforcers.
In other studies cocaine has been shown to support extremely persistent behavior. One way to measure behavioral persistence is by using a progressive-ratio (PR) schedule, under which reinforcers are delivered contingent upon the completion of a response requirement that increases across an experimental session. This continues until the subject stops responding or fails to complete the requirement within a pre-determined period of time. The largest response requirement completed by the subject or the total number of ratios completed have each been considered to be an indication of the relative effectiveness of that reinforcer (e.g. Hodos, 1961, Loh and Roberts, 1990, Depoortere et al., 1993); each has been termed the ‘breaking point’ by various investigators (in the present paper breaking point will refer to the number of ratios completed). Previous data have shown that larger magnitudes of food, drug, or other reinforcers maintain greater breaking points than do smaller reinforcer magnitudes (e.g. Hodos, 1961, Hodos and Kalman, 1963, Keesey and Goldstein, 1968, Yanagita, 1973). Further, breaking points maintained by food are increased with food deprivation (Hodos and Kalman, 1963). Taken together, these data provide support for the notion that breaking points can be interpreted as an index of relative reinforcing effectiveness. PR schedules have been used to compare behavior maintained by drug reinforcers within and across pharmacological classes (see Stafford et al., 1998, for a review). For example, it has been shown that cocaine maintained larger maximum breaking points than methylphenidate (Griffiths et al., 1975), nicotine (Risner and Goldberg, 1983), and procaine (Woolverton, 1995).
Recent animal research has identified drugs which may have potential to be developed as pharmacotherapeutic components of programs for the treatment of cocaine abuse. More specifically, pretreatment with the dopamine reuptake inhibitor GBR 12909 reduced cocaine self-administration at relatively small and mid-sized unit doses in rhesus monkeys without affecting food-reinforced responding occurring in different components of the same session (Glowa et al., 1995a, Glowa et al., 1995b). Pretreatment with the amphetamine analog phentermine has had mixed effects. In two studies using multiple fixed-ratio (FR) schedules of food and cocaine availability it selectively reduced cocaine self-administration (Glowa et al., 1997, Wojnicki et al., 1999), but in a third study using a PR schedule it did not (Stafford et al., 1999).
It is important to assess the abuse liability of these drugs with treatment potential. Rats and primates have been shown to self-administer both GBR 12909 (e.g. Roberts, 1993, Wojnicki and Glowa, 1996) and phentermine (e.g. Griffiths et al., 1976, Papasava et al., 1985a, Papasava et al., 1985b, Papasava et al., 1986). Patterns of responding maintained by these drugs, however, have sometimes differed from typical reports of cocaine self-administration. With regard to GBR 12909, Tella et al. (1996) found that rates of self-administration in rats on a FR schedule declined across sessions to a level that was no different than that maintained by vehicle. In rhesus monkeys, self-administration of small and mid-sized unit doses of GBR 12909 on FR schedules of reinforcement was enhanced following exposure to relatively large unit doses of GBR 12909 (Wojnicki and Glowa, 1996). With regard to phentermine, Papasava et al., 1985a, Papasava et al., 1985b, Papasava et al., 1986 found that self-administration was maintained only when rats were studied under food-deprivation conditions. In baboons, Griffiths et al. (1976) observed marked day-to-day variation in responding at the largest unit doses of phentermine examined (i.e. 1.0 mg/kg/inj) under an FR 160 schedule with 3-h post-infusion timeouts.
The purpose of the present experiment was to compare self-administration of various unit doses of cocaine, GBR 12909, and phentermine on a PR schedule in rhesus monkeys. The conceptual aim was to provide more data with which to assess the abuse liability of the latter two drugs in comparison with a ‘standard’ drug, cocaine, known to be abused in humans. The PR schedule of drug delivery was used to provide a measure of the relative reinforcing effects of GBR 12909 and phentermine in comparison with cocaine. A second aim was to assess whether previously reported differences in self-administration of these drugs by nonhumans under FR schedules would extend to behavior maintained by a PR schedule.
Section snippets
Subjects
Four individually housed, adult male rhesus monkeys (Macaca mulatta) weighing between 6.8 and 10.0 kg served as subjects (monkey numbers: 5L2, 44, 927, and 5KZ). Restricted food intake and post-session supplemental feedings of monkey chow (Harlan, Madison, WI) were used to maintain each subject at 90% of its free-feeding body weight. Food-restriction was employed to maximize the possibility that drugs would be self-administered robustly (e.g. Carroll, 1985, Papasava et al., 1985a, Papasava et
Results
Fig. 1 shows the average number of ratios completed per session as a function of unit dose of each self-administered drug. Each panel shows data from an individual monkey. All three monkeys tested with cocaine showed a similar pattern: the average number of ratios completed was small at relatively small unit doses (e.g. 1 μg/kg/inj for monkeys 44 and 927), increased to a peak across mid-sized unit doses, and decreased at the largest unit doses tested. Few or no ratios were completed when the
Discussion
The present data suggest that there are differences in self-administration of cocaine, phentermine, and GBR 12909 on a PR schedule of drug delivery. Cocaine was self-administered in a similar fashion by all the subjects tested. That is, the number of completed ratios increased from relatively small to intermediate-sized unit doses and decreased at the largest unit doses tested. We have obtained similar cocaine self-administration data using this PR schedule in prior experiments (e.g. Stafford
Acknowledgements
This research was supported by the National Institute on Drug Abuse (DA 09820). Procedures were conducted in accordance with the guidelines of the Animal Care and Use Committee of the Louisiana State University Medical Center in Shreveport. Portions of these data were presented at the Sixtieth Annual Meeting of the College on Problems of Drug Dependence in Scottsdale, AZ. The authors would like to thank Mary Kay Koch for her technical assistance.
References (28)
The role of food deprivation in the maintenance and reinstatement of cocaine-seeking behavior in rats
Drug Alcohol Depend.
(1985)- et al.
Parameters of self-administration of cocaine in rats under a progressive-ratio schedule
Pharmacol. Biochem. Behav.
(1993) - et al.
Self-administration of phentermine by naive rats: effects of body weight and a food delivery schedule
Pharmacol. Biochem. Behav.
(1985) - et al.
Intravenous self-administration of phentermine in food-deprived rats: effects of abrupt refeeding and saline substitution
Pharmacol. Biochem. Behav.
(1986) - et al.
Choice behavior in rhesus monkeys: cocaine versus food
Science
(1978) - et al.
Effects of dopamine reuptake inhibitors on food and cocaine maintained responding. I: Dependence on unit dose of cocaine
Exp. Clin. Psychopharm.
(1995) - et al.
Effects of dopamine reuptake inhibitors on food and cocaine maintained responding. II: Comparisons with other drugs and repeated administrations
Exp. Clin. Psychopharm.
(1995) - et al.
Phentermine/fenfluramine decreases cocaine self-administration in rhesus monkeys
NeuroReport
(1997) - et al.
Comparison of progressive ratio performance maintained by cocaine, methylphenidate and secobarbital
Psychopharmacologia
(1975) - et al.
Comparison of behavior maintained by infusions of eight phenylethylamines in baboons
Psychopharmacology
(1976)
The oral bioavailability and pharmacokinetics of soluble and resin-bound forms of amphetamine and phentermine in man
J. Pharmacokinet. Biopharm.
Progressive ratio as a measure of reward strength
Science
Effects of increment size and reinforcer volume on progressive ratio performance
J. Exp. Anal. Behav.
A choice procedure for drug reinforcers: cocaine and methylphenidate in the rhesus monkey
J. Pharmacol. Exp. Ther.
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