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Phosphatidylinositide 3-kinases (PI3Ks) are intracellular signal transducer enzymes that recruit protein kinase B (aka Akt) to the cell membrane, the subsequent activation of which regulates many cellular functions. PI3K/Akt activity is up-regulated within mesocorticolimbic structures in animal models of alcoholism, but less is known regarding PI3K/Akt activity in animal models of cocaine addiction. Given that prefrontal cortex (PFC) is grossly dysregulated in addiction, we studied how cocaine affects protein indices of PFC PI3K/Akt activity in rat and mouse models and examined the relevance of PI3K activity for cocaine-related learning. Immunoblotting of mouse medial PFC at 3 weeks withdrawal from a cocaine-sensitization regimen (seven injections of 30 mg/kg, intraperitoneal [IP]) revealed increased kinase activity, as did immunoblotting of tissue from the ventral PFC of rats with a history of long-access intravenous cocaine self-administration (0.25 mg/0.1 mL infusion; 10 days of 6 h/d cocaine access). Interestingly, increased Akt phosphorylation was observed in rat ventromedial PFC at both 3- and 30-day withdrawal only in animals re-exposed to cocaine-associated cues. A conditioned place-preference paradigm in mice and a cue-elicited drug-seeking test in rats were conducted to determine the functional relevance for elevated PI3K activity for addiction-related behavior. In both cases, an intra-PFC infusion of the PI3K inhibitor wortmannin (50μM) reduced drug-seeking behavior. Taken together, this cross-species, interdisciplinary, study provides convincing evidence that cocaine history produces an enduring increase in PI3K/Akt-dependent signaling within the more ventral aspect of the PFC that is relevant to behavioral reactivity to drug-associated cues/contexts. As such, PI3K inhibitors may well serve as an effective strategy for reducing drug cue reactivity and craving in cocaine addiction.

An interaction exists between stress and alcohol in the etiology and chronicity of alcohol use disorders, yet a knowledge gap exists regarding the neurobiological underpinnings of this interaction. In this regard, we employed an 11-day unpredictable, chronic, mild stress (UCMS) procedure to examine for stress-alcohol cross-sensitization of motor activity as well as alcohol consumption/preference and intoxication. We also employed immunoblotting to relate the expression of glutamate receptor-related proteins within subregions of the nucleus accumbens (NAC) to the manifestation of behavioral cross-sensitization. UCMS mice exhibited a greater locomotor response to an acute injection of 2 g/kg alcohol than unstressed controls and this cross-sensitization extended to alcohol intake (0-20 percent), as well as to the intoxicating and sedative properties of 3 and 5 g/kg alcohol, respectively. Regardless of prior alcohol injection (2 g/kg), UCMS mice exhibited elevated NAC shell levels of mGlu1α, GluN2b and Homer2, as well as lower phospholipase Cβ within this subregion. GluN2b levels were also lower within the NAC core of UCMS mice. The expression of stress-alcohol locomotor cross-sensitization was associated with lower mGlu1α within the NAC core and lower extracellular signal-regulated kinase activity within both NAC subregions. As Homer2 regulates alcohol sensitization, we assayed also for locomotor cross-sensitization in Homer2 wild-type (WT) and knock-out (KO) mice. WT mice exhibited a very robust cross-sensitization that was absent in KO animals. These results indicate that a history of mild stress renders an animal more sensitive to the psychomotor and rewarding properties of alcohol, which may depend on neuroplasticity within NAC glutamate transmission.