The addicted synapse: mechanisms of synaptic and structural plasticity in nucleus accumbens

Addictive drugs cause persistent restructuring of several neuronal cell types in the limbic regions of brain thought to be responsible for long-term behavioral plasticity driving addiction. Although these structural changes are well documented in nucleus accumbens medium spiny neurons, little is known regarding the underlying molecular mechanisms. Additionally, it remains unclear whether structural plasticity and its synaptic concomitants drive addictive behaviors or whether they reflect homeostatic compensations to the drug not related to addiction per se. Here, we discuss recent paradoxical data, which either support or oppose the hypothesis that drug-induced changes in dendritic spines drive addictive behavior. We define areas where future investigation can provide a more detailed picture of drug-induced synaptic reorganization, including ultrastructural, electrophysiological and behavioral studies.

Introduction

Drug addiction is marked by long-lasting changes in behavior, such as craving and relapse. Correlated with these stable behavioral abnormalities is the persistent restructuring of many neuronal cell types in limbic regions of the brain. Two general types of structural plasticity have been observed: changes in the size of cell bodies [1] and changes in dendritic arborizations or spine morphology [2]. With regard to the latter, depending upon the class of addictive substance, nature of the drug administration paradigm (e.g. experimenter versus self-administered), and neuronal cell type examined, drugs of abuse can alter the complexity of dendritic branching, as well as the number and size of dendritic spines on neurons in several brain regions (Table 1). Correlative evidence suggests that certain morphological changes are important mediators of addictive behaviors. For example, morphine and cocaine alter the density of dendritic spines on medium spiny neurons (MSNs) in nucleus accumbens (NAc), a key brain reward region, to a greater extent in animals self-administering the drug, compared with animals given the drug by the investigator, suggesting that volition can be important for key aspects of plasticity (reviewed in Ref. [3]). Additionally, cocaine-induced changes in NAc dendritic structure are tightly correlated with the induction of behavioral sensitization [4]: doses and drug administration paradigms that induce sensitization reliably increase dendritic spines and branching. Despite this evidence, however, the behavioral relevance of structural plasticity is still uncertain. Several recent studies using viral-mediated gene transfer and other methods to better understand the behavioral relevance and molecular basis of cocaine-induced changes in dendritic structure of MSNs have produced conflicting results, with two publications supporting the hypothesis that cocaine-induced increases in dendritic spine density mediate behavioral sensitization and two other publications diametrically opposing it 5, 6, 7, 8. In this review, we discuss current paradoxical experimental data and formulate areas for future investigation. We detail key themes, starting with the types of synaptic plasticity induced by drugs of abuse and signaling pathways that mediate drug-induced structural plasticity, and progressing to more detailed discussions of spine morphometry and the functional role of actin reorganization in addiction.