Integrating synaptic plasticity and striatal circuit function in addiction (2011)

Curr Opin Neurobiol. 2012 Jun;22(3):545-51. doi: 10.1016/j.conb.2011.09.009.

Grueter BA, Rothwell PE, Malenka RC.



Nancy Pritzker Laboratory, Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA 94305, United States.


Exposure to addictive drugs causes changes in synaptic function within the striatal complex, which can either mimic or interfere with the induction of synaptic plasticity. These synaptic adaptations include changes in the nucleus accumbens (NAc), a ventral striatal subregion important for drug reward and reinforcement, as well as the dorsal striatum, which may promote habitual drug use. As the behavioral effects of drugs of abuse are long-lasting, identifying persistent changes in striatal circuits induced by in vivo drug experience is of considerable importance. Within the striatum, drugs of abuse have been shown to induce modifications in dendritic morphology, ionotropic glutamate receptors (iGluR) and the induction of synaptic plasticity. Understanding the detailed molecular mechanisms underlying these changes in striatal circuit function will provide insight into how drugs of abuse usurp normal learning mechanisms to produce pathological behavior.


The development, progression, and persistence of drug addiction are thought to involve dynamic alterations in synaptic transmission within the striatum and related basal ganglia circuits. Synapses in these regions exhibit various forms of long-term synaptic plasticity, which appear to be aberrantly engaged by exposure to addictive drugs. These forms of plasticity include strengthening of synaptic connectivity, or long-term potentiation (LTP), as well as its weakening, or long-term depression (LTD). These synaptic changes often manifest themselves as changes in the number and function of iGluRs, including AMPA receptors (AMPARs) and NMDA receptors (NMDARs). Thus, it is of great interest to elucidate the mechanisms of synaptic plasticity in the striatal circuitry that underlie important aspects of addiction related behaviors.

Conclusion and future directions

By outlining recent developments in the area of striatal synaptic plasticity and addiction, we have highlighted several emerging trends. A number of studies using a variety of approaches have provided convergent evidence regarding the time course of synaptic adaptations in the NAc, following both acute and repeated cocaine exposure, withdrawal/extinction, and re-exposure/reinstatement (Figure 1). However, we are just beginning to understand synaptic adaptations in dorsal striatal subregions, which may be particularly important for late stages of addiction involving habitual drug-seeking. The past several years of research have also greatly advanced our understanding of synaptic plasticity in specific neuronal populations of the striatum, particularly MSNs of the direct and indirect pathway, and the role of these particular cell types in behavioral responses to drugs of abuse. An important next step will be to expand these approaches to models of reinstatement and relapse – one of the most challenging problems in clinical treatment of addiction. Finally, optogenetic techniques have made it possible to dissect the function of different inputs to the striatum

an approach that should illuminate how synapses formed by these various inputs may be differentially modulated by drugs of abuse. In conclusion, the striatal complex should be examined in terms of its functionally distinct components, at the level of individual neuronal pathways in order to fully understand the cellular and behavioral mechanisms that underlie motivated behaviors, drug abuse and addiction.