Fall 2001

Highlights of EBBS/EBPS Satellite Meeting

The Saturday SSPD paper session in Marseille, which immediately preceeded the start of the joint meeting of EBBS/EBPS, had a small, but devoted, audience. Each of the five presentations generated plenty of lively discussion. Titles and abstracts for each presentation are provided below for those who were unable to attend the meeting.

Abstracts from Marseille Meeting

Flipping biased coins: statistical analyses of quantal drug discrimination data

Results of drug discrimination tests are often classified as "full substitution", "no substitution", or "intermediate responding", but different criteria are used, and formal rules are lacking. To classify test results objectively, it may help to examine whether they are significantly different from the results obtained under training conditions. For quantal test data, this means comparing the proportion of subjects selecting the drug-appropriate response (DR) during a test with those during training, and assessing the statistical significance of differences among these proportions. Conventional statistical tests of such differences, however, make restrictive assumptions, and lack sensitivity. Sensitive statistical tests can, nevertheless, be developed by taking the performance of the discrimination, once acquired, into account. From this performance, the probabilities of DR selection after saline and after the training dose are estimated for each subject. Based on these probabilities, the statistical significance of differences between test results and training performance can be assessed analytically by applying binominal distributions, but can be examined also by means of Monte Carlo simulations consisting of Bernoulli trials. Unlike classical statistical approaches, Monte Carlo simulations and resampling methods do not restrict the design of drug discrimination tests. Moreover, they allow one to examine statistically not only the effects of individual doses, but also other aspects of drug discrimination test data. For example, they can be used to examine the shape of the dose-response curve (e.g., monotonic, biphasic), without requiring equally spaced doses and equal sample sizes. And they can be used to estimate 95% confidence limits of ED50 values, without the assumptions of the Litchfield and Wilcoxon method. It is hoped that these procedures, which can be carried out with Microsoft Excel, will be helpful to analyze and classify drug discrimination test results.

Bupropion: Is it a nicotine "replacement" therapy?

The antidepressant bupropion is commonly prescribed for tobacco cessation therapy. Investigation of the overlap in discriminative stimulus effects of bupropion and nicotine was initiated in the present study. In rats trained to discriminate 0.4 mg/kg (-)-nicotine from saline in a two lever drug discrimination procedure, both nicotine and bupropion dose-dependently substituted for the training dose. Whereas nicotine's discriminative stimulus effects were blocked by the noncompetitive nicotinic acetylcholine antagonist mecamylamine, those of bupropion were not. Previous work had shown that bupropion shares discriminative stimulus effects with other dopamine transport inhibitors, including cocaine and methamphetamine. The fact that nicotine's discriminative stimulus effects also partially overlap with those of cocaine and amphetamine suggests that bupropion may be producing its nicotine-like discriminative stimulus effects in part through its actions on dopaminergic neurotransmission. Further, these results suggest a dopaminergic component to the discriminative stimulus effects of nicotine. (Research supported by NIDA grant DA-05274).

Drug trace discrimination with nicotine, morphine and their antagonists

In typical drug discrimination experiments, subjects are exposed to psychoactive substances both prior to and during training sessions. To determine whether pre-session effects of drugs can serve as discriminative stimuli, rats were trained in a modified two-lever discrimination procedure with food reinforcers presented on a tandem VI-FR schedule. Five minutes after injection of nicotine (20 min pre-session) or saline, the nicotine antagonist mecamylamine was administered to block effects of nicotine during training sessions. Similarly, the action of morphine (30 min pre-session) was terminated by administering naloxone 10 min before training sessions. Stimulus control by drug states was acquired slowly and, typically, the accuracy of lever selection was no more than about 75% after 120 or more training sessions. Extinction tests confirmed stimulus control by nicotine in the presence of mecamylamine and by morphine in the presence of naloxone. However, mecamylamine and naloxone attenuated the response-rate reducing effects of nicotine and morphine respectively. The discriminative effect of nicotine, although weak, was related to the dose administered. A large dose of naloxone administered prior to the morphine blocked stimulus control. Drug effects present prior to training sessions may acquire stimulus control over behaviour, although other explanations of the data are possible. Stimulus control by drug states was less pronounced that in typical drug discriminations due to the time between termination of drug effects and training; the procedure may be analogous to classical conditioning with a CS-US interval that is excessively long (research supported by NIDA DA--5543).

Discriminative stimulus effects of ethanol in C57BL/6J and DBA/2J mice

No abstract available at press time.

Discrimination studies on BZ1 selective agonists and antagonists in rhesus monkeys

Gamma-hydroxybutyric acid (GHB), a naturally occurring metabolite of gamma-aminobutyric acid (GABA), has been used therapeutically and is also an emerging drug of abuse. The mechanisms that account for the therapeutic as well as the abuse-related effects of GHB are not fully understood. Discriminative stimulus effects of GHB have been assessed in several studies and are reported to comprise ethanol-like as well as GABAA and GABAB related components. The goal is the current study was to see whether stimulus control could be established and maintained with GHB in pigeons. Five pigeons received i.m. injections of vehicle or 100 mg/kg GHB 15 min prior to 15-min response periods during which food was available under a FR 20 schedule. Stimulus control was established after an average of 35 training sessions. Discriminative stimulus effects of the training dose of GHB were no longer evident 60 min after i.m. injection. Responding on the GHB-associated response key was dose-related with doses of 100 mg/kg and larger occasioning >80% drug-key responding. Up to a dose of 178.0 mg/kg, GHB did not systematically alter rates of key pecking. The GHB discriminative stimulus was not mimicked by the positive GABA-A modulator diazepam, up to doses of diazepam that eliminated responding. Small to moderate doses of 1,4 butanediol, purportedly a precursor of GHB, also failed to substitute fully for GHB. These results provide clear evidence for stimulus control with GHB in pigeons and further suggest that the mechanism of action of GHB under these conditions might be independent of GABA-A receptors. Supported, in part, by a NIH Research Career Development Award (DA00211) to CPF.