Imbalances in prefrontal cortex Homer 2 versus Homer 1 signaling : A molecular maladaptation mediating cocaine-seeking behavior ?

The Homer family of proteins play an active role in regulating various aspects of glutamate transmission within the prefrontal cortex (PFC) and nucleus accumbens (NAC)– two brain regions exhibiting abnormal glutamate transmission in animal models of addiction. Recent immunoblotting studies indicated that both self-administered cocaine and repeated, non-contingent cocaine treatment increases the expression of Homer2a/b relative to Homer1b/c in the PFC. To determine the functional relevance of this neuroadaptation, we assessed the behavioral and neurochemical effects of PFC Homer2b over-expression in mice. PFC Homer2b over-expression: (1) enhanced cocaine-seeking behavior in a conditioned place-preference paradigm, without influencing cocaine-induced motor hyperactivity or any other measure of motor behavior, emotionality, cognitive or sensorimotor processing; (2) elevated PFC basal glutamate content and reduced cocaine-induced glutamate release in the PFC, in a manner consistent with earlier data from Homer1 knockout mice; and (3) reduced NAC basal glutamate content and enhanced cocaine-induced glutamate release within this region, in a manner consistent with data from cocaine-sensitized rodents. Thus, elevated PFC Homer2 signaling is sufficient to “pre-sensitize” the accumbens glutamate system(s) to cocaine and to promote drug-seeking behavior. More recently, we have shown that PFC knock-down of Homer1c also enhances cocaine-seeking in mice, furthering the notion that idiopathic or drug-induced imbalances in the relative amount of Homer2 vs. Homer1 signaling within the PFC is a pathological state which renders one more vulnerable to the addictive properties of cocaine. Key-Words: Homer proteins, prefrontal cortex, drug-seeking, cocaine, glutamate