Effects and interactions of imipramine, chlorpromazine, reserpine and amphetamine on self-stimulation: possible neurophysiological basis of depression.

Neural theorizing about the affective disorders has been given substance by recent discoveries of brain systems for positive and negative reinforcement. Brain loci for negative motivation were demonstrated by Delgado, Roberts, and Miller [1] in experiments that followed up the early work of Hess [2]. These investigators showed that electrical stimulation of certain thalamic and hippocampal sites in the cat could be substituted for painful stimulation for the motivation of several forms of learning, including the conditioning of anxiety. Shortly thereafter, Olds and Milner [3] reported that electrical stimulation of the septal region and parts of the hypothalamus had the effect of a powerful reward. This was ingeniously demonstrated by a “self-stimulation” experiment in which rats with permanent electrodes were trained to stimulate their own brains thousands of times per hour by pressing a lever. These findings have been generalized to a number of species and have been extended even to man. In the human studies, subjective reports of pleasure and pain have been obtained after electrical stimulation of specific subcortical regions [4].