Akt and its phosphorylation in nucleus accumbens mediate heroin‐seeking behavior induced by cues in rats

Abstract

Akt is initially identified as one of the downstream targets of phosphatidylinositol‐3 kinase (PI3K) and is involved in morphine reward and tolerance. However, whether phospholyration of Akt (p‐Akt) mediates heroin relapse remains unclear. Here, we aimed to explore the role of p‐Akt in the nucleus accumbens (NAc) in cue‐induced heroin‐seeking behaviors after withdrawal. First, rats were trained to self‐administer heroin for 14 days, after which we assessed heroin‐seeking behaviors induced by a context cue (CC) or by discrete conditioned cues (CS) after 1 day or 14 days of withdrawal. We found that the active responses induced by CC or CS after 14 days of withdrawal were higher than those after 1 day of withdrawal. Meanwhile, the expression of p‐Akt in the NAc was also greatest when rats were exposed to the CS after 14 days of withdrawal. Additionally, a microinjection of LY294002, an inhibitor of PI3K, into the NAc inhibited the CS‐induced heroin‐seeking behaviors after 14 days of withdrawal, paralleling the decreased levels of p‐Akt in the NAc. Finally, Akt1 or β‐arrestin 2 was downregulated via a lentiviral injection to assess the effect on heroin seeking after 14 days of withdrawal. CS‐induced heroin‐seeking behavior was inhibited by downregulation of Akt1, but not β‐arrestin 2, in the NAc. These data demonstrate that Akt phosphorylation in the NAc may play an important role in the incubation of heroin‐seeking behavior, suggesting that the PI3K/Akt pathways may be involved in the process of heroin relapse and addiction.

A comparison of reinforcing effectiveness and drug-seeking reinstatement of 2-fluorodeschloroketamine and ketamine in self-administered rats

“…Dopamine receptor D2 functions through the Akt/GSK-3β signaling cascade (Rosen et al, 2016 ; Wang et al, 2019 ). The present results showed upregulation of the Akt/mTOR/GSK-3β pathway, which is consistent with the previous reports (Zhu et al, 2021 ). Ketamine self-administration decreased the expression of GSK-3β in the NAc (Huang et al, 2015 ).…”

Identification and Verification of Potential Hub Genes in Amphetamine-Type Stimulant (ATS) and Opioid Dependence by Bioinformatic Analysis

“…Some studies indicated that the PI3K/Akt signaling pathway played an essential role in neuronal survival ( Dudek et al, 1997 ) and neurodegeneration ( Wu et al, 2010 ; Chen et al, 2012 ). Qiao et al reported that drugs (e.g., alcohol, heroin, morphine, and METH) could activate the PI3K/Akt signaling pathway in the cortex, and contribute to addiction ( Qiao et al, 2018 ; Li et al, 2020 ; Meng et al, 2020 ; Zhu et al, 2021 ). The Akt phosphorylation in the NAc was related to heroin-seeking behavior ( Zhu et al, 2021 ).…”

“…Qiao et al reported that drugs (e.g., alcohol, heroin, morphine, and METH) could activate the PI3K/Akt signaling pathway in the cortex, and contribute to addiction ( Qiao et al, 2018 ; Li et al, 2020 ; Meng et al, 2020 ; Zhu et al, 2021 ). The Akt phosphorylation in the NAc was related to heroin-seeking behavior ( Zhu et al, 2021 ). Furthermore, we detected that the PI3K and Akt mRNA levels in BV2 cells treated with METH and heroin significantly increased than those of controls.…”

Insights into the Promising Prospect of G Protein and GPCR-Mediated Signaling in Neuropathophysiology and Its Therapeutic Regulation

“…Based on the reorganized dopamine hypothesis of psychosis [ 122 ], antipsychotics that block D2Rs were thought to simply reverse striatal hyperdopaminergic activity. So, the antipsychotic drug should simultaneously activate and inhibit dopamine signalling according to the brain region [ 197 ]. Antipsychotic medication might benefit from the discovery that D2Rs are capable of signaling not just through standard G protein pathways but also through noncanonical pathways that induce the creation of a signaling complex involving protein phosphatase2 (PP2A), GSK3 β , 5AKT, and β arr2.…”