Reward Pathways and Drugs
REWARD PATHWAYS AND DRUGS
The observation that animals would work in order to receive electrical stimulation to discrete brain areas was first described by Olds and Milner (1954). In this paper, they stated, "It is clear that electrical stimulation in certain parts of the brain, particularly the septal area, produces acquisition and extinction curves which compare favorably with those produced by conventional primary reward." This phenomenon is usually referred to as brain-stimulation reward (BSR), intracranial self-stimulation (ICSS), or intracranial stimulation (ICS).
Most abused substances increase the rate of response (lever pressing) for rewarding ICS, and this has been interpreted as an increase in the reward value of the ICS. Because changes in rate of response could also be a function of the effects of the drug on motor performance, a number of methods have been developed that control for the confounding nonspecific effects of the drugs under study, at least in part. The three most commonly used procedures are phase shifts (Wise et al., 1992), two-level titration (Gardner et al., 1988), and the psychophysical discrete-trial procedure (Kornetsky & Porrino, 1992). Using these threshold methods for determining the sensitivity of an animal to BSR, there is general agreement that most of the commonly abused substances do in fact increase the sensitivity of animals to the rewarding action of the electrical stimulation and this action is independent of any motor effects of the substances.
In this method, rates of response are determined at various intensities of stimulation. Data are usually presented as rate-intensity (rate-frequency) functions. If a drug shifts the rate-intensity function to the left, it is interpreted as an increase in sensitivity of the animal to the rewarding stimulation. A shift to the right is interpreted as a decrease in sensitivity. Threshold (sometimes called locus of rise ) is defined as the intensity that yields half the maximum rate of response for the animal. If the maximum rate becomes asymptotic at approximately the same stimulus intensity as observed after saline, it is assumed that any phase shift is a direct effect of the drug on the reward value of the stimulation, not the result of a nonspecific motor effect of the drug.
In this procedure, rats are placed in a chamber with two levers; pressing one of the levers results in rewarding stimulation, but at the same time the response attenuates the intensity of stimulation by a fixed amount. A response on the second lever resets the intensity to the original level. The threshold is defined as a mean intensity at which the reset response is made.
PSYCHOPHYSICAL DISCRETE TRIAL METHOD
A wheel manipulandum is usually used, although the method has been employed using a response lever. In this method, discrete trials are used, each demanding only a single response by the rat in order to receive the rewarding stimulation. A trial consists of an experimenter-delivered (non-contingent) stimulation. If the animal responds by turning the manipulandum within 7.5 seconds, it receives a second stimulation at the identical stimulation intensity as the first stimulus. Current intensities are varied in a stepwise fashion or descending and ascending order. This yields a response-intensity function, with the threshold defined as the intensity at which the animal responds to 50 percent of the trials. Of the methods currently used, this is the only one that does not make use of the response rate as an integral part of the procedure for the determination of the reward threshold—thus it is independent of the rate of response and the possible confounding motor effects of the drug.
DOPAMINE AND ICS
Although most abused drugs lower the threshold for ICS for some drugs, the findings have not always been consistent, particularly with Hallucinogens and the Sedative-Hypnotics, including Alcohol (ethanol). For the most part, the threshold-lowering effects caused by the abused substances are compatible with the hypothesis that facilitation of Dopamine is involved in their rewarding effects. Drugs that increase dopamine availability at the synapse facilitate ICS, and those that block dopamine transmission decrease ICS (i.e., they raise the threshold—or the amount of current—needed to produce rewarding effects).
Because abused substances clearly enhance the rewarding value of the intracranial stimulation and not simply cause a general increase in motor behavior, the brain-stimulation-reward model directly allows for the study of the neuronal mechanisms involved in the rewarding effects of abused substances. Although this is not as homologous a model of drug-taking behavior as is the self-administration model, it predicts as well as the self-administration model the Abuse Liability of compounds, and it readily lends itself to analysis of the mechanisms involved in the rewarding effects of abused substances.
(See also: Research, Animal Model )
Gardner, E. L., et al. (1988). Facilitation of brain stimulation reward by Δ9-tetrahydrocannabinol, Psychopharmacology; 96, 142-144.
Kornetsky, C., & Porrino, L. J. (1992). Brain mechanisms of drug-induced reinforcement. In C. P. O'Brien & J. H. Jaffe (Eds.), Addictive States. New York: Raven Press.
Olds, J., & Milner, P, (1954). Positive reinforcement produced by electrical stimulation of septal area and other regions of rat brain. Journal of Comparative Physiology and Psychology; 47, 419-427.
Wise, R. A., et al. (1992). Self-stimulation and drug reward mechanisms. In P. W. Kalivas & H. H. Samson (Eds.), The neurobiology of drug and alcohol addiction. New York: Annals of the New York Academy of Sciences, Vol. 654.
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