1) It is assumed that depression, whether in the normal or the mentally ill, results from insufficient positive reinforcement or reward. The depressed patient, however, despairs even if the environment supplies a normal amount of rewarding stimulation. This failure of rewarding stimulation to exert its usual energizing effect is attributed, at least in some types of depression, to a biochemical defect in the hypothalamic reward mechanism. 2) Self-stimulation studies made it possible to investigate the pharmacology of the reward mechanism in experimental animals. It was concluded that the reward mechanism is directly or indirectly activated by a catecholamine, probably norepinephrine, on the following evidence: a) Chemical analyses show that self-stimulation structures are unusually rich in norepinephrine. b) Self-stimulation is selectively inhibited by chlorpromazine, which antagonizes norepinephrine centrally, and by reserpine, which depletes the brain of norepinephrine. c) Self-stimulation is selectively facilitated by amphetamine, which resembles norepinephrine closely in chemical structure, and which appears to produce its stimulating effect by liberating norepinephrine from stores in the reward system. Other potent releasers of norepinephrine, like α-methyl-meta-tyrosine and tetrabenazine (in combination with a mono-amine oxidase inhibitor) selectively facilitate self-stimulation too. 3) It is therefore suggested, on this and other evidence, that at least some types of depression result from an insufficient synthesis or utilization of norepinephrine in the reward system, and that antidepressive drugs probably act by the following mechanisms: a) Monoamine oxidase inhibitors relieve depression by building up levels of norepinephrine in the reward system. b) Imipramine and related drugs relieve depression by elevating the level of free norepinephrine in the reward system, probably by blocking its uptake into storage sites. c) Amphetamine sometimes provides temporary relief from depression by releasing norepinephrine from stores in the reward system.
