The PI3-Kinase p110 beta Isoform Controls Severity of Cocaine-Induced Sequelae and Alters the Striatal Transcriptome

• Type of Material: Article
• Authors: Lauren P Shapiro, Emory University; Elizabeth G Pitts, Emory University; Dan C Li, Emory University; Britton R Barbee, Emory University; Elizabeth A Hinton, Emory University; Gary Bassell, Emory University; Christina Gross, Cincinnati Children’s Hospital Medical Center; Shannon Gourley, Emory University
• Language: English
• Date: 2021-05-03
• Publisher: ELSEVIER SCIENCE INC
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021 Society of Biological Psychiatry.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.biopsych.2021.01.008
• Title of Journal or Parent Work: BIOLOGICAL PSYCHIATRY
• Volume: 89
• Issue: 10
• Start Page: 959
• End Page: 969
• Grant/Funding Information: The Emory Viral Vector Core is supported by an NINDS Core Facilities grant, P30 NS055077.; The Yerkes National Primate Research Center is supported by NIH OD011132.; This work was supported by PHS MH103748, GM008602, and DA044297; the Georgia Research Alliance; and the Marcus Foundation and Children’s Healthcare of Atlanta.
• Keywords: EXPRESSION; D-2 RECEPTORS; ADDICTION; DOPAMINE D-1; Science & Technology; BEHAVIORAL SENSITIZATION; SUBUNIT; Neurosciences & Neurology; Life Sciences & Biomedicine; PI3 KINASE; MEDIAL PREFRONTAL CORTEX; Neurosciences; Psychiatry; NUCLEUS-ACCUMBENS; NEURONS

Abstract

Background: The PI3-kinase (PI3K) complex is a well-validated target for mitigating cocaine-elicited sequelae, but pan-PI3K inhibitors are not viable long-term treatment options. The PI3K complex is composed of p110 catalytic and regulatory subunits, which can be individually manipulated for therapeutic purposes. However, this possibility has largely not been explored in behavioral contexts. Methods: Here, we inhibited PI3K p110β in the medial prefrontal cortex (mPFC) of cocaine-exposed mice. Behavioral models for studying relapse, sensitization, and decision-making biases were paired with protein quantification, RNA sequencing, and cell type–specific chemogenetic manipulation and RNA quantification to determine whether and how inhibiting PI3K p110β confers resilience to cocaine. Results: Viral-mediated PI3K p110β silencing reduced cue-induced reinstatement of cocaine seeking by half, blocked locomotor sensitization, and restored mPFC synaptic marker content after exposure to cocaine. Cocaine blocked the ability of mice to select actions based on their consequences, and p110β inhibition restored this ability. Silencing dopamine D2 receptor–expressing excitatory mPFC neurons mimicked cocaine, impairing goal-seeking behavior, and again, p110β inhibition restored goal-oriented action. We verified the presence of p110β in mPFC neurons projecting to the dorsal striatum and orbitofrontal cortex and found that inhibiting p110β in the mPFC altered the expression of functionally defined gene clusters within the dorsal striatum and not orbitofrontal cortex. Conclusions: Subunit-selective PI3K silencing potently mitigates drug seeking, sensitization, and decision-making biases after exposure to cocaine. We suggest that inhibiting PI3K p110β provides neuroprotection against cocaine by triggering coordinated corticostriatal adaptations.