Regulation of Synaptic Connectivity With Chronic Cocaine

In animal models of addiction, repeated exposure to drugs of abuse, such as cocaine, amphetamines, and nicotine, increases the number of dendritic spines ( panel A ) in the nucleus accumbens (NAc), a key brain region involved in reward, pleasure, and motivation. Dendritic spines are the primary anatomical sites of excitatory synapses. Many scientists deem that this long-lasting increase in synaptic connectivity in the NAc may underlie the similarly persistent behaviors of drug taking and drug seeking associated with drug addiction and relapse. Although this concept is appealing, the functional relationship between increased synaptic connectivity in the NAc and addiction-related behaviors is poorly understood. Our recent findings shed some important light on this issue.

We recently found that cocaine regulates myocyte enhancer factor 2 (MEF2) transcription factors in the NAc to control the observed increase in synaptic connectivity. During development, MEF2 sculpts mature brain circuits by promoting activity-dependent synapse elimination. Excitatory synaptic activity and subsequent calcium signaling events stimulate MEF2 activity. However, after chronic cocaine exposure or activation of dopamine receptor signaling, we observed a decrease in MEF2 activity in the striatum and found that decreasing MEF2 activity in the NAc promoted an increase in dendritic spine density. We also found that chronic cocaine and dopamine signaling reduced MEF2 activity in the striatum through novel signaling pathways involving the regulator of calmodulin signaling (RCS), calcineurin (CaN), and Cdk5 ( panel B ). Reducing MEF2 is required for cocaine-induced dendritic spine plasticity in vivo. On the other hand, we observed that expression of a hyperactive MEF2 in the NAc, the condition that blocked dendritic spine changes, increased behavioral responses to repeated cocaine exposure. This suggests that the increased spine density in the NAc is not required for cocaine-induced behavioral plasticity and that increased synaptic connections during chronic drug use may actually limit behavioral changes associated with drug addiction rather than support them. Together with the previous literature, our findings suggest that the increased density of synapses may be a compensatory response to decreased activity of these brain reward regions. Therefore, a focus on enhancing synaptic contacts and neuronal activity in the NAc may be therapeutic in drug addiction.