1 Center for Studies in Behavioral Neurobiology, Department of Psychology, Concordia University, Montreal, QC, Canada.

Deep-brain stimulation of the medial forebrain bundle (MFB) can provide effective, enduring relief of treatment-resistant depression. Panksepp provided an explanatory framework: the MFB constitutes the core of the neural circuitry subserving the anticipation and pursuit of rewards: the "SEEKING" system. On that view, the SEEKING system is hypoactive in depressed individuals; background electrical stimulation of the MFB alleviates symptoms by normalizing activity. Panksepp attributed intracranial self-stimulation to excitation of the SEEKING system in which the ascending projections of midbrain dopamine neurons are an essential component. In parallel with Panksepp's qualitative work, intracranial self-stimulation has long been studied quantitatively by psychophysical means. That work argues that the predominant directly stimulated substrate for MFB self-stimulation are myelinated, non-dopaminergic fibers, more readily excited by brief electrical current pulses than the thin, unmyelinated axons of the midbrain dopamine neurons. The series-circuit hypothesis reconciles this view with the evidence implicating dopamine in MFB self-stimulation as follows: direct activation of myelinated MFB fibers is rewarding due to their trans-synaptic activation of midbrain dopamine neurons. A recent study in which rats worked for optogenetic stimulation of midbrain dopamine neurons challenges the series-circuit hypothesis and provides a new model of intracranial self-stimulation in which the myelinated non-dopaminergic neurons and the midbrain dopamine projections access the behavioral final common path for reward seeking via separate, converging routes. We explore the potential implications of this convergence model for the interpretation of the antidepressant effect of MFB stimulation. We also discuss the consistent finding that psychomotor stimulants, which boost dopaminergic neurotransmission, fail to provide a monotherapy for depression. We propose that non-dopaminergic MFB components may contribute to the therapeutic effect in parallel to, in synergy with, or even instead of, a dopaminergic component.