The striatal balancing act in drug addiction: distinct roles of direct and indirect pathway medium spiny neurons

Abstract

The striatum plays a key role in mediating the acute and chronic effects of addictive drugs, with drugs of abuse causing long-lasting molecular and cellular alterations in both dorsal striatum and nucleus accumbens (ventral striatum). Despite the wealth of research on the biological actions of abused drugs in striatum, until recently, the distinct roles of the striatum's two major subtypes of medium spiny neurons (MSNs) in drug addiction remained elusive. Recent advances in cell-type-specific technologies, including fluorescent reporter mice, transgenic, or knockout mice, and viral-mediated gene transfer, have advanced the field toward a more comprehensive understanding of the two MSN subtypes in the long-term actions of drugs of abuse. Here we review progress in defining the distinct molecular and functional contributions of the two MSN subtypes in mediating addiction.

Keywords: D1+ MSNs; D2+ MSNs; addiction; cell-type-specific; cocaine; dopamine; medium spiny neurons; nucleus accumbens.

Figure 1

All drugs of abuse increase dopamine signaling in striatum, which can differentially modulate glutamatergic activity in the two MSN subtypes. In particular, cocaine binds to the dopamine transporter preventing dopamine reuptake into the terminals of VTA dopamine neurons. Activation of G_s/_olf coupled D₁ receptors enhances PKA activity and alters Ca²⁺ and K⁺ conductances to enhance the glutamate mediated "up-state" in these MSNs. In contrast, activation of G_i/G_o D₂-receptors diminishes PKA activity and alters Ca²⁺, Na⁺, and K⁺ conductances to diminish the glutamate mediated “up-state.” This shifts these MSNs back to their resting “down-state.”