Action of drugs of abuse on brain reward systems

Abstract

The finding that animals will work for electrical stimulation of some but not all parts of the brain has prompted the view that there are specialized brain circuits which subserve reward function. Two synaptic links in this circuitry have been partially identified. Studies of the effective stimulation parameters indicate that the directly activated fibers are usually high-frequency-sensitive, fast-conducting, myelinated fibers. Pharmacological studies suggest that all reward sites tested are afferent to a critical dopaminergic synapse; the myelinated, reward-relevant fiber of the medial forebrain bundle may synapse directly on the dopamine link. Dopamine blockers block self-stimulation regardless of electrode placement, and dopamine agonists are rewarding in their own right; thus the critical dopaminergic synapse plays both a necessary and (with its normal efferents) a sufficient role in reward function. Several drugs of abuse can facilitate self-stimulation, and it is hypothesized that they do so by a direct action on the same neural substrate. Amphetamine and cocaine seem to act directly in the critical dopamine synapse. Opiates might act at the dopamine synapse or cell bodies, or might act on dopamine afferents. Ethanol, barbiturates and benzodiazepines have not been extensively explored, but if their reported facilitations of self-stimulation are reliable they might be suggested to cause them by a naloxone-reversible inhibition of noradrenergic function, which disinhibits rather than directly excites the dopamine reward link. These suggestions as to the possible sites of interaction of drugs of abuse with brain stimulation reward circuitry are speculative, and are advanced as potentially heuristic working hypotheses.