Hallmark behaviors of addiction

     Drug addiction is a chronically relapsing brain disease. In fact, environmental conditioned cue associations with drug experience are significant factors in the ongoing cycle of relapse in addiction (Hsiang et al, 2014). Relapse to drug addiction can occur even after prolonged abstinence and is often precipitated by exposure to drug-associated cues that provoke drug craving.  For example, it has been observed that in current abstinent, former-cocaine users, mere exposure to environmental cues present at the time of previous cocaine use may evoke powerful memories of the rewarding properties of cocaine, induce drug craving, and facilitate relapse to cocaine seeking and consumption. Similarly, recall of a cocaine related memory may be sufficient to induce relapse to cocaine-seeking and/or cocaine taking in drug-free rodents with a history of cocaine administration. 

The incubation of drug craving, a phenomenon characterized by the progressive potentiation of cue-induced drug cravings after withdrawal, is partially mediated by drug-induced accumulation of GluA2-lacking, calcium permeable AMPA receptors in the nucleus accumbens (NAc) (Bossert et al., 2013; Kalivas et al., 2009). However, the molecular events involved are unknown. In order to shed light on this question, Lee et al., 2013 studied silent or immature synapses in the  basolateral amygdala (BLA) to NAc projection on rodents. Silent or immature synapses express stable NMDA receptors and are abundant during early developmental; and subsequently mature into fully functional synapses by recruiting AMPA receptors. The researchers found that cocaine self-administration generates these silent synapses, and as the withdrawal period progressed, these silent synapses become unsilenced, a process involving synaptic insertion of calcium-permeable AMPA receptors. Moreover, by using in vivo optogenetic stimulation to conduct a long term depression (LTD) protocol on withdrawal day 45 that would internalize the newly inserted AMPA receptors, a re-silencing of some of the previously silent synapses was observed. This event correlated with a significant reduction in cocaine craving incubation. Taken altogether, these results suggest that this synapse-based reorganization is critical for persistent cocaine craving and relapse after withdrawal.

     References: 

     Bossert JM, Marchant NJ, Calu DJ, Shaham Y. (2013). The reinstatemt model of drug relapse: recent neurobiological findings, emerging research topics, and translational research. Psychopharmacology, 229(3): 453-76.

      Kalivas PW. (2009). The glutamate homeostasis hypothesis of addiction. Nature reviews Neuroscience, 10:561-572.