David Stafford

Progressive-ratio schedules of drug delivery in the analysis of drug self-administration: a review

Abstract Drugs, like other reinforcers, can vary in their relative abilities to support operant responding. Considerable research has been designed to obtain useful measures of a given drug’s or dose’s ”reinforcing efficacy” and to identify the ways in which a variety of behavioral and pharmacological variables impact these measures. Progressive-ratio schedules of drug delivery generate an index of a drug’s or dose’s reinforcing efficacy (the breaking point) and are being used increasingly as tools in the analysis of drug self-administration. Progressive-ratio schedules of drug delivery have been used to characterize the effects of pretreatment drugs, lesions, drug deprivation, physical dependence, and repeated non-contingent drug exposure on breaking points. Behavioral factors, including food restriction and electric shock, and organismic factors, including gender and strain, have also been investigated using progressive-ratio schedules of drug delivery. To the extent that breaking points provide an index of reinforcing efficacy, these studies demonstrate that a wide range of variables can influence the reinforcing efficacy of self-administered drugs. The objectives of this review are to critique existing research themes, outline potential limitations of progressive-ratio procedures, and to suggest potentially fruitful uses of these procedures in future research.

Preclinical research on cocaine self-administration: environmental determinants and their interaction with pharmacological treatment

It has been asserted that any comprehensive understanding of cocaine abuse and its treatment will require attention to both behavioral and pharmacological variables. Although the preclinical literature evaluating the effects of pharmacological variables on cocaine self-administration has been extensively reviewed, no comprehensive review of the effects of environmental variables on cocaine self-administration has been published. The present review summarizes and critiques the preclinical findings on environmental determinants of cocaine self-administration. The influence of environmental variables on the effects of pharmacological interventions on cocaine self-administration are also described. Several environmental variables have been shown to affect cocaine self-administration, including unit dose, schedule of cocaine delivery, schedules of nondrug stimuli, behavioral history, conditioned stimuli, food deprivation, exposure to stress, and rearing environment. Among these variables, unit dose, schedule of cocaine delivery, availability of alternative nondrug reinforcers, food deprivation, and rearing environment have also been shown to alter pharmacological treatment effects on cocaine self-administration. Thus, drug effects on cocaine self-administration are malleable and dependent upon the environmental context within which they occur. Suggestions for future research on the effects of these and other environmental variables on cocaine self-administration and its pharmacological treatment are presented.

A comparison of cocaine, GBR 12909, and phentermine self-administration by rhesus monkeys on a progressive-ratio schedule

The dopamine reuptake inhibitor GBR 12909 and the dopamine releaser phentermine may have potential for the treatment of cocaine abuse in humans. Pre-session treatment with either drug can decrease cocaine-maintained responding in rhesus monkeys while not affecting food-maintained responding. Both drugs are self-administered, but in some reports the patterns of responding they maintain differ from typical cocaine-reinforced responding. This study compared self-administration of cocaine (1--100 microg/kg/inj), GBR 12909 (3--100 microg/kg/inj), and phentermine (10--170 microg/kg/inj) in rhesus monkeys on a progressive-ratio schedule. Individual unit doses of each drug were available across several consecutive sessions. Cocaine self-administration was typical: the average number of ratios completed per session was a bitonic (increasing/decreasing) function of unit dose. Phentermine self-administration was variable across subjects (two of four monkeys self-administered reliably); one subject exhibited clear signs of behavioral toxicity. Self-administration of GBR 12909 was similarly variable across subjects. In the two subjects that self-administered GBR 12909 reliably, self-administration of small to mid-sized unit doses was enhanced following exposure to large unit doses. These data indicate that differences in self-administration of these drugs can be observed under progressive ratio procedures. Further, the data add to existing evidence suggesting that phentermine and GBR 12909 have at least moderate potential to be abused by humans.

Response requirements and unit dose modify the effects of GBR 12909 on cocaine-maintained behavior.

Previous studies found that GBR 12909 can decrease cocaine-maintained responding at doses that do not affect food-maintained responding. In this study, the effects of GBR 12909 (0.3-3.0 mg/kg) were further examined by varying the response requirement and unit dose of cocaine. Rhesus monkeys earned food or cocaine under a multiple fixed-ratio (FR) schedule. The FR for food was always 30, but the FR for cocaine was varied from 10-130 and the unit dose was varied from 5.6-56.0 microg/kg per injection. Doses of GBR 12909 were tested in an ascending order, for 5 consecutive sessions each. GBR 12909 selectively decreased cocaine-maintained responding in all monkeys in at least 1 condition. These effects were enhanced with large response requirements and/or small unit doses. The results demonstrate that environmental variables can influence the selectivity of GBR 12909s effects and contribute to a growing debate concerning the evaluation of potential pharmacotherapies for drug abuse.

Novel pharmacotherapies for cocaine abuse - 1995 to present

A new area in pharmaceutical development addresses the possibility that drug abuse can be treated with a medication. The advent of two successful treatments for drug abuse, nicotine patches and methadone, together with a growing cocaine abuse problem have sparked recent interest in developing a pharmacotherapy for cocaine abuse. Behavioural methods have been developed to the point where active compounds are likely to be identified, and a few potential agents have been found. Specific neurochemical effects of exposure to cocaine have suggested a number of additional targets, some of which have prompted the development of new ligands. Of those, drugs targeted at serotonergic, dopaminergic, GABAergic, opioid, and excitatory amino acid receptors have received the most attention. This article reviews recent advances in the development and testing of such agents, as well as patent applications (since 1995) for medications to treat drug abuse.