The ins and outs of the striatum: role in drug addiction

Abstract

Addiction is a chronic relapsing disorder characterized by the loss of control over drug intake, high motivation to obtain the drug, and a persistent craving for the drug. Accumulating evidence implicates cellular and molecular alterations within cortico-basal ganglia-thalamic circuitry in the development and persistence of this disease. The striatum is a heterogeneous structure that sits at the interface of this circuit, receiving input from a variety of brain regions (e.g., prefrontal cortex, ventral tegmental area) to guide behavioral output, including motor planning, decision-making, motivation and reward. However, the vast interconnectivity of this circuit has made it difficult to isolate how individual projections and cellular subtypes within this circuit modulate each of the facets of addiction. Here, we review the use of new technologies, including optogenetics and DREADDs (Designer Receptors Exclusively Activated by Designer Drugs), in unraveling the role of the striatum in addiction. In particular, we focus on the role of striatal cell populations (i.e., direct and indirect pathway medium spiny neurons) and striatal dopaminergic and glutamatergic afferents in addiction-related plasticity and behaviors.

Keywords: DREADDs; addiction; basal ganglia; cortex; optogenetics; striatum.

Fig. 1

Simplified schematic view of striatal inputs and outputs. The striatum receives glutamatergic inputs (denoted in green) from the cortex, amygdala, hippocampus and thalamus and dopaminergic inputs (denoted in blue) from the VTA and SNc. Direct pathway striatal neurons (dMSNs) project monosynaptically to the GPi/SNr whereas indirect pathway striatal neurons (iMSNs) project to the GPi/SNr via the GPe/VP and STN. Red dashed lines denote GABAergic inhibitory projections.