The Striatal Balancing Act in Drug Addiction: Distinct Roles of Direct and Indirect Pathway Medium Spiny Neurons

Mary Kay Lobo,Eric J Nestler

doi:10.3389/fnana.2011.00041

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.

Highlights

Drugs of abuse exert potent molecular and cellular alterations in both dorsal striatum and ventral striatum, and many of these changes occur in medium spiny neurons (MSNs), the principal projection neurons in dStr and NAc, which account for 90–95% of all neurons in these regions
The two MSN subtypes are differentiated by their enrichment of dopamine receptor 1 (D1) or dopamine receptor 2 (D2) as well as several other genes (Gerfen and Young, 1988; Gerfen et al, 1990; Le Moine et al, 1990, 1991; Bernard et al, 1992; Ince et al, 1997; Lobo et al, 2006, 2007; Heiman et al, 2008; gensat.org) and by their distinct projections through the cortico-basal ganglia pathway
Future research should evaluate how modulation of these glutamate receptor subunits in the two MSN subtypes affects the structural synaptic changes observed in NAc after drugs of abuse (Dietz et al, 2009; Russo et al, 2010), the dendritic alterations observed after cocaine exposure selectively in the D1+ MSNs (Lee et al, 2006; Kim et al, 2011) which may be associated with the increase in miniature excitatory postsynaptic currents observed in D1+ MSNs (Kim et al, 2011)

Summary

Introduction

Drugs of abuse exert potent molecular and cellular alterations in both dorsal striatum (dStr) and ventral striatum (nucleus accumbens, NAc), and many of these changes occur in medium spiny neurons (MSNs), the principal projection neurons in dStr and NAc, which account for 90–95% of all neurons in these regions. The latter findings showed that loss of TrkB (the receptor for BDNF) in D2+ MSNs results in similar behavioral responses to cocaine as total TrkB knockout from the NAc, showing for the first time a selective dominant role for a molecular pathway in D2+ MSNs in mediating the effects of drugs of abuse.

Results

Conclusion