Relapse continues to be a major problem for stimulant use disorder. Neuromodulation with tools like deep brain stimulation (DBS) is currently being explored as a potential treatment [1]. Since it was FDA-approved for the treatment of Parkinson’s disease more than two decades ago, DBS has emerged as a promising approach for otherwise intractable neuropsychiatric illnesses [2]. DBS currently has a humanitarian device exemption status from the FDA for the treatment of compulsive disorders like refractory obsessive-compulsive disorder and Tourette’s syndrome [2]. This suggests that DBS may also become a valuable tool in treating substance use disorders (SUDs) [1].

Preclinical studies show that DBS of the ventral striatum inhibits relapse to cocaine seeking. However, the underlying biological mechanism of this effect on drug seeking is not clear. Classical DBS involves high-frequency electrical stimulation, which is non-specific and can affect not only neuronal cell bodies near the electrode, but also glial cells and axons from distant sites passing by or terminating in the vicinity, which results in orthodromic or antidromic stimulation of distant brain areas. In the ventral striatum, DBS likely stimulates the major striatal cell types—D1 and D2 medium spiny neurons (MSNs)—as well as GABAergic and cholinergic interneurons, and various axons terminating in or passing through the ventral striatum. It is not clear whether ventral striatum DBS’ effects on drug seeking are mediated by one or more cell types which are normally interconnected and together modulate the ultimate behavioral outcome. Now that DBS can be deployed to selectively affect different neuronal populations [3], and given the different roles of D1 and D2 MSNs in regulating drug-seeking behaviors, understanding the role of the different ventral striatum cell types, especially D1 and D2 MSNs, in DBS’s effects on drug seeking is of high importance.

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