Donald E. McMillan - US grants

The objectives of this program are to study the role of both behavioral and pharmacological variables in drug discrimination processes and to determine the effects of both acute and chronic drug interactions on complex behavioral processes. The baseline schedule of reinforcement maintaining responding will be varied in drug discrimination experiments to compare stimulus control under different schedules of reinforcement and to bias responding toward or away from making the drug response. Response bias and discrimination sensitivity will be analyzed by signal detection and analysis. Attempts will be made to compare drug effects on exteroceptive stimulus control with effects of the same drugs on interoceptive stimulus control exerted by the training drug in drug discrimination experiments. We will also attempt to establish drug discrimination without errors to compare stimulus control with this procedure with that under traditional training methods. The training drugs in drug discrimination experiments will include phencyclidine, opioid drugs, Delta9-tetrahydrocannabinol, cocaine and benzodiazepines. Of particular interest will be drug interaction studies to determine how one drug modifies the stimulus control exerted by another drug. Interactions among Delta9-tetrahydrocannabinol, cocaine, morphine and diazepam will be emphasized. In experiments on drug effects on complex behavioral baselines, behavior will be maintained under delayed matching-to-sample, single alternation, temporally spaced responding, repeated acquisition and fixed-consecutive number schedules. The effects of acute and chronic drug administration on these baselines will be determined. The same drugs and drug combinations used in the drug discrimination experiments will be emphasized. These experiments should provide valuable information as to how both pharmacological and behavioral variables influence the stimulus control exerted by drugs which, in turn, contributes to both drug abuse and non-compliance problems. The experiments on complex behavior should provide clues as to the consequences of drug taking on specific behavioral processes.

There are conflicting opinions as to whether the use of "gateway" drugs, such as nicotine, ethanol and delta-9-tetrachydrocannabinol lead directly to the use of "harder" drugs, such as cocaine, amphetamines and opioids. Furthermore, there are few data available on the question of how the introduction of a second drug of abuse quantitatively affects the pattern of intake of a drug for which self administration is already well established. The present experiments are designed to answer such questions using a rat model of drug self-administration. Hopefully, the findings of the present experiments will provide important insights as to the emergence of polydrug abuse patterns in humans. In initial experiments, rats will be trained to consume 5% (w/v) ethanol with water freely available by using periods of limited access to a schedule of food-pellet presentation. Preliminary data show that the rats take almost all of their fluid as ethanol using this procedure. One food, water and ethanol intake stabilize, the effects of acute and chronic administration of nicotine, delta-9- tetrahydrocannabinol and cocaine will be determined. Subsequently, chronic administration of each of these drugs will be discontinued to determine the effects of their withdrawal on ethanol self administration. In another experiment, rats will be trained to self administer intravenously, cocaine, nicotine and if possible, delta-9-tetrahydrocannabinol to determine to what extent the "voluntary" use of a second drug influences ethanol self administration. subsequently, the opportunity to self administer these drugs will be discontinued to determine the effects of this type of withdrawal on ethanol self administration. In other experiments, comparisons will be made between rats with and without a history of ethanol administration in the acquisition of patterns of nicotine, cocaine and possibly delta-9- tetrahydrocannabinol self administration. These experiments should provide considerable useful information about drug interactions during the development of polydrug abuse patterns.

The objectives of this program are to study the role of behavioral and pharmacological variables in drug discrimination and to determine the effects of drug administration on complex behavioral processes. In drug discrimination experiments, we will use multiple schedules to extend the generality of our finding that fixed-ratio schedules produce steeper dose-effect curves than fixed-interval schedules during generalization tests. We will determine the effect of punishing incorrect responses on drug discrimination and will use concurrent variable-interval variable-interval schedules and concurrent fixed-ratio fixed-ratio schedules to determine if drug .discrimination behavior can be described in terms of the Matching Law. We also plan to begin to study the manner in which external environmental stimuli interact with interoceptive drug stimuli to produce stimulus control. The pigeon will be the primary subject, but some experiments will be replicated in rats to extend the generality of findings to another species. Phencyclidine will be the primary training drug, but some experiments will be replicated with methamphetamine to extend the generality of the findings to a second drug. The effects of substitution of other drugs for the training drug will be determined under most drug discrimination procedures. In addition to studying drugs of obvious pharmacological relevance to phencyclidine and methamphetamine, a number of other drugs will be tested for generalization to both training drugs for comparative purposes. In experiments on complex behavior, these same drugs will be studied for their effects on repeated acquisition, titrating matching-to sample, fixed-consecutive number (with and without an exteroceptive stimulus) and temporal discrimination. From these experiments important information should emerge to describe how schedule factors, environmental factors and organismic factors influence drug discrimination, as well as a description of the general pharmacology of phencyclidine, methamphetamine and related drugs. These data are relevant to both the abuse potential of these drugs and to describing the consequences of their use.

biomedical equipment purchase;

DESCRIPTION: (Applicant's Abstract) When an abused drug is self-administered it produces internal stimuli in the user of which the user is often aware. We refer to these effects in humans as the "subjective effects" of the drug. One way in which behavioral pharmacologists have studied these internal stimuli in animal models has been to establish them as discriminative stimuli. Responses can be scheduled to occur or not occur in the presence or absence of these internal drug stimuli by differentially reinforcing responding. These drug discrimination procedures have been used to study the behavioral consequences of a number of effects of drugs at the cellular level of the brain including receptor binding, neurotransmitter depletion, and many others. Despite the widespread usage of drug discrimination procedures, there are many questions about the procedure that have not been answered. For example, there are arguments about whether or not drug discrimination gradients are quantal or graded. It is not known if the discrimination between two different drugs differs from the discrimination between the presence and absence of a single drug. Although the experience of an organism with other drugs has been shown to be an important determinant of many drug effects, such historical factors have received little attention in drug-discrimination research. The ability of animals to learn complex drug discriminations has also received little attention and there are almost no studies in the literature that systematically compare the effects of drugs as discriminative stimuli with their effects on other behaviors. The proposed research would fill this gap by determining how reinforcement schedules and drug discrimination training history affect the discriminative stimulus properties of drugs. Experiments would also be conducted to develop new procedures for studying and interpreting complex drug discriminations and for comparing the effects of drugs as discriminative stimuli to their effects on animal models of anxiety, memory and other important behaviors. These experiments will provide fundamental new information about the drug discrimination process that should greatly add to our knowledge of how the stimulus properties of drugs contribute to their abuse.