Chaperone heat shock protein 70 in nucleus accumbens core: a novel biological target of behavioural sensitization to morphine in rats

Abstract

Drug addiction is a major public health issue, yet the underlying adaptation of neural networks by drugs of abuse is not fully understood. We have previously linked chaperone heat shock protein 70 (Hsp70) to drug-induced adaptations. Focusing on the NAc core and shell, the present study aims to provide further findings for our understanding of the relation between behavioural sensitization to morphine and Hsp70 at transcriptional and functional levels in rats. Firstly, we delineated the characteristics of behavioural sensitization induced by a single morphine exposure (1-10 mg/kg, s.c.). Secondly, Hsp70 protein expression in the NAc core was time- and dose-relatedly induced during the development of behavioural sensitization to a single morphine exposure in rats, and Pearson analysis indicated a positive correlation between behavioural sensitization and Hsp70 expression in NAc core. Thirdly, at the transcriptional level, intra-NAc core injection of the specific heat shock factor-I (HSF-I) inhibitor N-Formyl-3,4-methylenedioxy-benzylidine-γ-butyrolactam (KNK437) suppressed Hsp70 expression and the development of behavioural sensitization, while the HSF-I specific inducer geranylgeranylacetone (GGA) promoted both of them. Interestingly, intra-NAc shell injection of KNK437 or GGA did not affect the development of behavioural sensitization. Finally, both the functional inhibition of Hsp70 ATPase activity by methylene blue (MB), and the antagonism of Hsp70 substrate binding site (SBD) activity by pifithrin-μ (PES) impaired the development of behavioural sensitization when they were microinjected into the NAc core. Taken together, the critical involvement of chaperone Hsp70 in behavioural sensitization to morphine identifies a biological target for long-lasting adaptations with relevance to addiction.

Interruption of Continuous Opioid Exposure Exacerbates Drug-Evoked Adaptations in the Mesolimbic Dopamine System

“…These gene expression changes could be related to opioid-induced temperature fluctuations in the nucleus accumbens (88), though they may also indicate a general response to cellular stress that is independent of temperature. Striatal expression of heat shock proteins is tied to psychomotor sensitization, withdrawal, and other behavioral responses to opioids (85,(89)(90)(91)(92)(93)(94), supporting functional relevance of the transcriptional changes we observe.…”

The role of TXNDC5 in castration-resistant prostate cancer—involvement of androgen receptor signaling pathway

“…Previous studies suggested that HSP70 is a stress-inducible HSP that promotes survival and invasion of PCa, and inactivation of HSP70 leads to the loss of invasion in various cancer cell types. 24 Although the HSP70 inhibitor KNK437 produced no visible effects on the function of TXNDC5 overexpression in PCa cells ( Supplementary Figures 5a and b), silencing HSP70 ( Supplementary Figure 5c) or KNK437 treatment ( Supplementary Figures 5d and e), which has been shown to interfere with transcriptional activation of HSP70, 25 could decrease TXNDC5 protein expression through reducing the half-time of TNXDC5 protein ( Supplementary Figure 5f). Their interaction further supports the pro-metastasis function of TXNDC5.…”

Drug Dependent Stress and Heat Shock Protein Response

“…The research reports a correlation between behavioral sensitization to morphine and Hsp70 as evidenced by Hsp70 inhibition of Hsp70. The study suggested that Hsp70 is a target for adaptations with relevance to addiction [11].…”