1. PI3K activation within ventromedial prefrontal cortex regulates the expression of drug‐seeking in two rodent species
- Author
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John W. Hiller, John R. Shahin, Osnat Ben-Shahar, Melissa G. Wroten, Bailey W. Miller, Justin Courson, Alexis W. Ary, Tod E. Kippin, Karen K. Szumlinski, Micaela A. Ruppert-Majer, and Christina B. Shin
- Subjects
Medicine (miscellaneous) ,Self Administration ,Pharmacology ,PI3K ,Medical and Health Sciences ,Wortmannin ,Mice ,Phosphatidylinositol 3-Kinases ,chemistry.chemical_compound ,0302 clinical medicine ,Cocaine ,Dopamine Uptake Inhibitors ,Medicine ,Phosphorylation ,Prefrontal cortex ,Craving ,Phosphoinositide-3 Kinase Inhibitors ,Behavior, Animal ,Substance Abuse ,incubation ,conditioned place preference ,Psychiatry and Mental health ,wortmannin ,medicine.anatomical_structure ,Cues ,Drug-Seeking Behavior ,Ventromedial prefrontal cortex ,Prefrontal Cortex ,Article ,Cocaine-Related Disorders ,03 medical and health sciences ,Animals ,Learning ,Kinase activity ,Protein kinase B ,PI3K/AKT/mTOR pathway ,Behavior ,Animal ,business.industry ,Psychology and Cognitive Sciences ,Conditioned place preference ,Rats ,030227 psychiatry ,Disease Models, Animal ,chemistry ,Cue reactivity ,Disease Models ,business ,Proto-Oncogene Proteins c-akt ,030217 neurology & neurosurgery - 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 3weeks withdrawal from a cocaine-sensitization regimen (seven injections of 30mg/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 (0.25mg/0.1mL infusion; 10days of 6h/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.
- Published
- 2018