Drug-evoked synaptic plasticity causing addictive behavior.

Introduction The clinical manifestations of drug addiction are the subject of medical literature and fiction alike. In Novel with Cocaine, first published almost 80 years ago under a pseudonym and only recently rediscovered, Mark Levi provides a disturbing account of a young Russian man becoming addicted to cocaine. Vadim, the novel’s antihero reflects: “Before I came in contact with cocaine I assumed that happiness was an entity, while in fact all human happiness consists of a clever fusion of two elements: the physical feeling of happiness, and the external event providing the psychic impetus for that feeling.” This statement eloquently describes a core element of the addiction process. An initially neutral stimulus becomes attractive when associated with drug consumption, and even after prolonged periods of abstinence this cue may trigger craving and cause the subject to relapse (Stewart et al., 1984; Childress et al., 1988). The risk for relapse remains high after years of abstinence, which constitutes a major challenge for treating drug addiction. Therefore, many researchers have argued that the secret to understanding addiction lies in the elucidation of the “memory trace” that links the cue to the compulsive drug use. The implicit underlying hypothesis is that addictive drugs generate an inappropriate learning signal that leads to the encoding of a unique trace, which, when reactivated, has a strong behavioral impact(Redishetal.,2008;Schultz, 2011). Here we will review emerging evidence that the cellular correlates of the drug memory trace are the various forms of synaptic plasticity, mainly of glutamatergic transmission, in the circuits of the mesolimbic system, which we have previously called “drug-evoked synaptic plasticity” (Lüscher and Malenka, 2011). We will review the literature reporting drugevoked synaptic plasticity in animal models of addiction and argue for a staged remodeling of the mesolimbic circuitry (Kalivas and O’Brien, 2008) that is eventually responsible for relapse and compulsive drug use.