Glutamatergic synaptic plasticity in the mesocorticolimbic system in addiction

Abstract

Addictive drugs remodel the brain's reward circuitry, the mesocorticolimbic dopamine (DA) system, by inducing widespread adaptations of glutamatergic synapses. This drug-induced synaptic plasticity is thought to contribute to both the development and the persistence of addiction. This review highlights the synaptic modifications that are induced by in vivo exposure to addictive drugs and describes how these drug-induced synaptic changes may contribute to the different components of addictive behavior, such as compulsive drug use despite negative consequences and relapse. Initially, exposure to an addictive drug induces synaptic changes in the ventral tegmental area (VTA). This drug-induced synaptic potentiation in the VTA subsequently triggers synaptic changes in downstream areas of the mesocorticolimbic system, such as the nucleus accumbens (NAc) and the prefrontal cortex (PFC), with further drug exposure. These glutamatergic synaptic alterations are then thought to mediate many of the behavioral symptoms that characterize addiction. The later stages of glutamatergic synaptic plasticity in the NAc and in particular in the PFC play a role in maintaining addiction and drive relapse to drug-taking induced by drug-associated cues. Remodeling of PFC glutamatergic circuits can persist into adulthood, causing a lasting vulnerability to relapse. We will discuss how these neurobiological changes produced by drugs of abuse may provide novel targets for potential treatment strategies for addiction.

Keywords: addiction; dopamine; drugs of abuse; glutamate; nucleus accumbens; prefrontal cortex; synaptic plasticity; ventral tegmental area.

Figure 1

Working model of the role of drug-induced synaptic plasticity in the mesocorticolimbic system in drug addiction. Simplified schematic of the mesocorticolimbic brain areas known to be affected by drug-induced plasticity, important synaptic modifications that occur in these brain areas and the behavioral consequences of these modifications. AMG, amygdala; NAc, nucleus accumbens; (m)PFC, (medial) prefrontal cortex; VTA, ventral tegmental area.