Inhibition of Receptor Protein Tyrosine Phosphatase β/ζ Reduces Alcohol Intake in Rats

다국어 초록 (Multilingual Abstract)

Pleiotrophin (PTN) and midkine (MK) are cytokines that are up‐regulated in the prefrontal cortex (PFC) after alcohol administration and have been shown to reduce alcohol intake and reward. Both cytokines are endogenous inhibitors of receptor protein tyrosine phosphatase (RPTP) β/ζ (a.k.a. PTPRZ1). Recently, a new compound named MY10 was designed with the aim of mimicking the activity of PTN and MK. MY10 has already shown promising results regulating alcohol‐related behaviors in mice.
We have now tested the effects of MY10 on alcohol operant self‐administration and Drinking In the Dark‐Multiple Scheduled Access (DID‐MSA) paradigms in rats. Gene expression of relevant genes in the PTN/MK signaling pathway in the PFC was analyzed by real‐time PCR.
MY10, at the highest dose tested (100 mg/kg), reduced alcohol consumption in the alcohol operant self‐administration paradigm (p = 0.040). In the DID‐MSA paradigm, rats drank significantly less alcohol (p = 0.019) and showed a significant decrease in alcohol preference (p = 0.002). We observed that the longer the exposure to alcohol, the greater the suppressing effects of MY10 on alcohol consumption. It was demonstrated that the effects of MY10 were specific to alcohol since saccharin intake was not affected by MY10 (p = 0.804). MY10 prevented the alcohol‐induced down‐regulation of Ptprz1 (p = 0.004) and anaplastic lymphoma kinase (Alk; p = 0.013) expression.
Our results support and provide further evidence regarding the efficacy of MY10 on alcohol‐related behaviors and suggest the consideration of the blockade of RPTPβ/ζ as a target for reducing excessive alcohol consumption.
Pleiotrophin (PTN) is an endogenous inhibitor of RPTPβ/ζ that diminishes alcohol behavioral responses. PTN induces the dimerization of RPTPβ/ζ. As a result, PTN inhibits the phosphatase activity of RPTPβ/ζ causing increases in the phosphorylation of its substrates, some of which are relevant for alcohol effects such as ALK and Fyn. MY10 is a small‐molecule inhibitor targeting the active domain of RPTPβ/ζ. Treatment with MY10 reduces alcohol consumption, possibly through its capacity to prevent the downregulation of ALK induced by alcohol.