Akt1 signaling in dopamine‐dependent behaviors (LB116)

Abstract

Background: One biochemical change acquired following induction of depression‐like behavior and exposure to drugs of abuse is decreased phosphorylation of the Akt1 serine‐threonine kinase.Methods: To examine the relevance of intact Akt signaling, we used Akt1‐mutant mice as genetic model. By combining biochemical, pharmacological, genetic and behavioral approaches, we examined if altered Akt signal transduction affects behavioral responses in experimental paradigms related to mesolimbic/nigrostriatal dopamine function.Results: Loss‐of‐function Akt1‐mutant mice exhibited a phenotype of increased susceptibility in the learned helplessness paradigm. In this experimental model for acquired behavioral depression, the exposure to inescapable electric foot shocks (IES) disrupts the subject’s escape to subsequent noxious stimuli. While no significant differences were observed between sham‐treated control mice depending on genotypes, IES‐treated Akt1‐mutant mice showed increased latencies of crossing and a higher number of escape failures when compared to IES‐treated wild‐type mice. In further support of the importance of intact Akt signaling in dopamine‐dependent behavioral responsiveness, Akt1‐mutant mice displayed enhanced responses to acute cocaine, diminished sensitization to chronic cocaine exposure and altered conditional place preference for cocaine.Western blotting and immunohistochemical analyses after IES training revealed genotype‐dependent changes in Akt phosphorylation and regulation of its substrates following IES training. These biochemical changes phenocopied differences in behavioral outputs when comparing wild‐type and Akt1‐mutant mice.Discussion: Several mechanisms have been proposed to explain increased excitability of DA neurons after drug exposure. One that is increasingly attractive involves dephosphorylation and inhibition of the serine/threonine kinase Akt. Reduced Akt kinase activity is frequently observed in psychiatric disorders with high comorbidity for substance use. By exploring Akt1‐dependent stress responses in the mesolimbic system using genetic models, we gain novel insights into the role of Akt signaling in regulating critical brain circuitry involved in motivation, decision‐making and reward.Grant Funding Source: Supported by NIH DA032280