1. PI3K activation within ventromedial prefrontal cortex regulates the expression of drug-seeking in two rodent species.
- Author
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Szumlinski, Karen K., Ary, Alexis W., Shin, Christina B., Wroten, Melissa G., Courson, Justin, Miller, Bailey W., Ruppert‐Majer, Micaela, Hiller, John W., Shahin, John R., Ben‐Shahar, Osnat, Kippin, Tod E., Ruppert-Majer, Micaela, and Ben-Shahar, Osnat
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PREFRONTAL cortex , *PROTEIN kinase B , *COCAINE abuse , *RODENTS , *DRUG-seeking behavior , *FRONTAL lobe , *BIOLOGICAL models , *ANIMAL behavior , *SUBSTANCE abuse , *PHOSPHOTRANSFERASES , *DESIRE , *LEARNING , *RATS , *SELF medication , *TRANSFERASES , *COCAINE , *RESEARCH funding , *DOPAMINE uptake inhibitors , *COMPULSIVE behavior , *PHOSPHORYLATION , *MICE , *ANIMALS , *PROMPTS (Psychology) , *PHARMACODYNAMICS - Abstract
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. [ABSTRACT FROM AUTHOR]
- Published
- 2019
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