The Necessity of Gap Junction Communication in Extinction of a Cocaine Seeking Memory

Astrocytes, a type of glial cell, have a wide variety of functions such as regulation of neurotransmitters and detoxification of the central nervous system. Emerging evidence, however, has demonstrated that they also mediate neuronal communication at the synapse and are capable of cellular communication via gap junctions (GJs). GJs are specialized membrane structures between closely apposed cells that permit limited cytoplasmic continuity. GJs between astrocytes and neurons may therefore participate in the coupling of astrocyte and neuron physiology. Despite this, very little work has been done to determine how astroglial communication utilizing GJs contributes to experience-dependent neuronal plasticity. Drugs of abuse, such as cocaine, can alter the brain resulting in compulsive drug seeking. Craving and relapse are mediated by cues associated with drug use. Reducing cue reactivity through extinction, or learning that the cues no longer predict drug, could reduce relapse rates. Thus, we investigated the role of astroglial GJs during extinction of cocaine seeking. We first examined the necessity of astroglial communication in both the infralimbic (IL) and prelimbic (PrL) medial prefrontal cortex using a cocaine conditioned place preference (CPP) paradigm. In this model, rats are conditioned to associate one chamber but not another with cocaine. We found that a bilateral IL microinfusion of a non-specific GJ antagonist (Carbenoxolone; CBX) prior to the CPP test resulted in persistent CPP expression across trials. Conversely, a single bilateral PrL microinfusion of CBX persistently disrupted expression of a CPP. Thus, astroglial GJs in the IL are necessary for extinction of a CPP, whereas astroglial communication in PrL is necessary for expression of a CPP. Taken together, these results indicate that the IL and PrL possess dissociable roles in CPP learning and extinction. Future experiments aim to discern these modalities more clearly, as it is thought that PrL mediates expression of drug seeking through memory retrieval. Experiments are underway to dissociate the effects of GJ inhibition on extinction and retrieval, and will be utilized to ascertain definitive evidence regarding the dissociation between enhanced extinction and impaired retrieval in the IL and PrL. The results of these experiments will provide new insight into the functions of glial cells during drug-associated learning, and their regulation may constitute new avenues for the treatment of drug addiction