Isoform‐selective PI3‐kinase Inhibition Confers Partial Resilience to Cocaine Cessation‐induced Anxiety‐like Behavior

Abstract

Phosphoinositide 3‐kinase (PI3K) is a multi‐subunit signaling complex that phosphorylates phosphoinositides, membrane‐embedded second messengers that are critical for synaptic and structural plasticity of neurons. Cocaine potentiates PI3K‐Akt‐mTOR cascade activity, and this activation persists beyond the period of drug exposure. The PI3K p110β isoform is neuronally enriched and able to control PI3K signal propagation, allowing for manipulation of PI3K activity in a more targeted manner than broad‐spectrum PI3K inhibition. Cessation of cocaine use triggers anxiety‐like behavior in humans and rodent models, and anxiety can be a causal factor in relapse. Here, we used viral‐mediated gene silencing to reduce expression of p110β in the dorsomedial prefrontal cortex (dmPFC). Isoform‐selective PI3K inhibition mitigated anxiety‐like behavior triggered by acute cocaine. Interestingly, however, a history of repeated cocaine exposure occluded this resilience, presenting an opportunity to compare immediate‐early gene expression between cocaine‐vulnerable and cocaine‐resilient mice. We examined 22 brain regions and found that resilient mice – those displaying less anxiety‐like behavior – displayed lower immediate‐early gene expression in the claustrum and lateral hypothalamus. We next found that chemogenetic stimulation of the claustrum induced anxiety‐like behavior. Future studies will determine whether suppressing p110β in the dmPFC combats anxiety‐like behavior via connections with the claustrum. Our findings suggest that isoform‐selective PI3K inhibition mitigates cocaine cessation‐elicited anxiety‐like behavior, likely via coordinated brain regions and circuits.