Synaptic plasticity and addiction

Key Points A major problem in the treatment of addiction is relapse, which is often caused by the powerful and long-lasting memories of the drug experience. Drugs of abuse can hijack or impair specific synaptic plasticity mechanisms in the mesolimbic dopamine system, which is central to reward processing in the brain. Drugs of abuse or acute stress elicit long-term potentiation (LTP) at excitatory synapses on dopamine cells in the ventral tegmental area (VTA). Morphine prevents a novel form of LTP at inhibitory synapses on the same dopamine cells. Both changes are likely to increase dopamine cell firing. Orexin, a neuropeptide implicated in arousal and feeding, enhances N -methyl- D -aspartate (NMDA) receptor-mediated synaptic responses in dopamine cells leading to LTP of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-mediated responses. The actions of orexin in the VTA might be important for several of the behavioural adaptations caused by cocaine and, perhaps, other drugs of abuse. At excitatory synapses on medium spiny neurons in the nucleus accumbens, cocaine causes a form of long-term depression (LTD) that is due to the removal of synaptic AMPA receptors. It also impairs endocannabinoid-mediated LTD. In contrast, during withdrawal from chronic cocaine administration, there appears to be an increase in excitatory synaptic transmission. Further work is necessary to determine whether other drugs of abuse have the same effects. Other key brain areas in which drugs of abuse affect synaptic function and plasticity include the bed nucleus of the stria terminalis and the amygdala. There may be important differences in the effects of drugs of abuse on synaptic function and plasticity depending on whether the drug is self-administered or not. It will be important in future work to use animal models that more closely mimic the behaviour of human substance abusers. Drugs of abuse alter synaptic plasticity mechanisms in key brain circuits. Kauer and Malenka review the drug-induced synaptic modifications that take place in the mesolimbic dopamine system, which is central to reward processing and contributes to addiction. Addiction is caused, in part, by powerful and long-lasting memories of the drug experience. Relapse caused by exposure to cues associated with the drug experience is a major clinical problem that contributes to the persistence of addiction. Here we present the accumulated evidence that drugs of abuse can hijack synaptic plast