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The search for a neurobiological substrate for the stimulant and reinforcing properties of cocaine has focused for some time on a particular part of the forebrain, the mesocorticolimbic dopamine (DA) system. This mesocorticolimbic DA system innervates the region of the nucleus accumbens (NACC) (ventral striatum) in the anterior part of the basal forebrain and appears to play a critical role in mediating the acute reinforcing effects of cocaine and amphetamine. This chapter reviews the role of mesocorticolimbic DA in the reinforcing properties of psychomotor stimulants as measured by intravenous (IV) drug self-administration in rats. In addition, the primary neuropharmacological mechanism for cocaine reinforcement provides a rich substrate for studying nondopaminergic modulation of the reinforcing actions of cocaine.

I would like to stress several major points. The first is that CNS pharmacology is important in drug self-administration. In the case of cocaine, the necessary effect seems to be blockade of reuptake of DA rather than blockade of reuptake of NE or 5-HT or local anesthetic effects. An action of that DA on the D2 subtype of DA receptors appears to play an important role. The second point is that increased DA in synapses in the CNS is not sufficient to explain drug-maintained behavior. The schedule of reinforcement critically determines rates and patterns of drug-maintained behavior. Barrett (this volume) has presented convincing evidence that behavioral history, i.e., the sequential exposure to alternative behavioral conditions, can dramatically alter drug effects. What I hope to have made clear is that the simultaneous opportunity to engage in other behaviors can dramatically alter the reinforcing effects of drugs. Indeed, under appropriate conditions, a drug can function as both a positive and a negative reinforcer simultaneously in the same animal. The drug-choice studies I have described emphasize the dynamic nature of the interaction between behavioral and pharmacologic variables. The frequency of choosing to self-administer cocaine varied with the magnitude of the dose of cocaine (a pharmacologic variable) and the magnitude of an alternative positive reinforcer that was available (a behavioral variable). Increasing the magnitude of the alternative reinforcer decreased cocaine choice, but increasing the magnitude of the cocaine dose reestablished drug preference. In a sense, this is not a surprising result. The rhetoric of the times, however, would have it that drug self-administration, particularly cocaine self-administration, is somehow a different class of behavior that is not subject to the usual laws governing the behavior of organisms. As our understanding of drug self-administration evolves, however, that position will become increasingly untenable. These experimental findings challenge simple neurobiological assumptions about the determinants of drug self-administration. Clearly, a reinforcing effect, like any other behavioral effect of a drug, is not simply an immutable effect of a pharmacologic property of the drug. Given the pivotal role of reinforcing effects in drug abuse, this realization is critical to a comprehensive understanding of drug abuse. Any complete neurobiological model of drug abuse will have to account for these effects. Apparently, increasing the concentration of DA in synapses in the brain is not sufficient to account for drug-maintained behavior.(ABSTRACT TRUNCATED AT 400 WORDS)

Self-injection of 12 sedative-anxiolytics was examined in baboons. Intravenous injections and initiation of a 3-h time-out were dependent upon completion of a fixed-ratio schedule requirement, permitting eight injections per day. Before testing each dose of drug, self-injection performance was established with cocaine. Subsequently, a test dose was substituted for cocaine. At some doses, all five of the benzodiazepines examined (alprazolam, bromazepam, chlordiazepoxide, lorazepam, triazolam) maintained rates (number of injections per day) of drug self-injection above vehicle control in each of the baboons tested. Maximum rates of benzodiazepine self-injection were generally submaximal. Of the benzodiazepines examined, triazolam maintained the highest rates of self-injection. Among the three barbiturates tested, methohexital generally maintained high rates of self-injection in contrast to hexobarbital and phenobarbital, which only maintained low rates. Of the four non-benzodiazepine non-barbiturate sedatives examined, both chloral hydrate and methyprylon occasionally maintained high rates of self-injection. Although there were differences within and across animals, baclofen maintained intermediate rates of self-injection. The novel anxiolytic buspirone maintained only low rates of self-injection that were not different from vehicle. This study further validates the self-injection methodology for assessing sedative-anxiolytic abuse liability and provides new information about drug elimination rate as a determinant of drug self-administration.

The data presented point to the importance of studying drug effects under conditions similar to those in which drugs are taken outside of the laboratory. Interactions between the reinforcing and other direct effects of these drugs, as well as their interactions with ongoing environmental events can only be evaluated under such conditions. These data support the utility of a residential research facility for the investigation of substance use and its effects under conditions which approximate those in which people live outside of the laboratory. This unique laboratory, designed for continuous observation of human behavior over extended periods of time, provides a controlled environment with the flexibility for establishing a range of subject behaviors, and the ability to simultaneously monitor a wide range of individual and social behavior patterns. We can study regulation of drug intake and its effects, both within a day and over days, assessing the effects of experimental manipulations on the patterning of self-administration behavior as well as the performance of a range of other behaviors as a function of drug self-administration. The design of such studies is a logical extension of basic preclinical research, as well as more traditional human behavioral pharmacology research. Although little data are yet available on drug-related "hangovers" or "morning after" effects, it should be clear that this residential laboratory would provide ideal experimental conditions for such research. We have shown that subjects will exhibit stable patterns of drug self-administration which are sensitive to systematic manipulation of variables. Therefore, we are in the position of being able to evaluate longer term effects on performance of drug-taking behavior as it occurs under conditions approximating the natural ecology. The examples of data collected in the laboratory have demonstrated that drug effects are not a unitary phenomenon, but instead depend on ongoing behaviors as well as pharmacological variables such as drug and dose. If we are going to evaluate drugs and the way in which they affect workplace behavior, we must carry out our evaluation under conditions which approximate those in which people might be using them, while at the same time controlling extraneous variables and protecting the participants from possible deleterious effects. We have shown that drugs, such as marijuana and amphetamine, have divergent effects that are influenced by both situational and behavioral factors. A thorough evaluation of the effects of any drug on behavior is, therefore, dependent on the evaluation of the drug's effects under the conditions in which it is likely to be taken.