Role of accumbens medium spiny neurons subtypes in reinstatement to ketamine cues in male and female Long Evans rats.

Ketamine is approved for treatment-resistant depression and is being tested for substance use disorder and PTSD, but its addictive potential raises safety concerns. The nucleus accumbens (NAc), a brain reward hub, is involved in how drug-related cues become salient. The NAc contains two types of medium spiny neurons (MSNs): those expressing dopamine 1 receptors (D1R) and those expressing dopamine 2 receptors (D2R). Using DREADD technology in transgenic rats, the authors found that D1R-expressing MSNs, but not D2R-expressing ones, play a key role in reinstatement of seeking behavior triggered by ketamine-associated cues. This identifies a cell-type specific mechanism in ketamine's addictive properties.

Study at a glance

Abstract

Ketamine, a non-competitive N-Methyl-D-Aspartate receptor antagonist, was approved for use with Treatment-Resistant Depression (TRD) and is currently in clinical trials for treating substance use disorder (SUD), and Post Traumatic Stress Disorder. However, ketamine is an addictive drug, and thus we need to better understand ketamine's mechanism of action in addiction to reliably assess the safety of repeated use as a treatment for several psychopathologies. The nucleus accumbens (NAc), the brain's major reward hub, plays an important role in the salience of drug-related cues. The NAc is comprised of 90-95% GABAergic medium spiny neurons (MSNs) and consists of the Core and Shell. MSNs consist of two distinct subpopulations: Dopamine 1 receptor (D1R) and dopamine 2 receptor (D2R) expressing MSNs that roughly positively and negatively regulate behavior, respectively. However, the cell-type specific role of D1R/D2R-containing MSNs in the NAc and the underlying circuitry mediating ketamine reinstatement remains unknown. To this end, we used Designer Receptors Exclusively Activated by Designer Drugs (DREADD, hM4Di) in Drd1a-iCre and Drd2-iCre transgenic rats to assess the roles of the two distinct NAc MSNs during ketamine cue-induced reinstatement. Our results showed an important role of D1R, but not D2R, NAc MSNs in reinstatement to ketamine cues. Future work will focus on identifying the underlying circuit driving cue-induced reinstatement and roles of the direct and indirect pathways.