UC San Diego
Endostatin reduces relapse to ethanol seeking in dependent rats: Regulation by PECAM-1 and oligodendrocytes
- Author(s): Xing, Nancy Yuanyuan
- Advisor(s): Mandyam, Chitra D
- et al.
Alcohol use disorder (AUD) produces a variety of mental damage; AUD is a serious public health issue. Current FDA approved medications to treat AUD are partially effective, warranting the need for better therapies. Animal models of AUD are currently used to discover new therapies due to their robust face and predictive validity. Previous studies suggested that rats with AUD had higher ethanol seeking behavior during abstinence that correlated with enhanced expression of platelet endothelial cell adhesion molecules (PECAM-1; angiogenesis marker), increased number of oligodendrocyte progenitor cells (OPCs) and altered neuronal activation in medial prefrontal cortex (mPFC). However, it is unclear whether PECAM-1 directly promotes ethanol seeking behavior by reducing neuronal activity and increasing proliferating OPCs. Thus, to investigate the role of PECAM-1 in alcohol-dependent rats, we used endostatin, a broad-spectrum angiogenesis/PECAM-1 inhibitor. Results from behavior studies showed that in alcohol-dependent female rats, endostatin significantly reduced alcohol seeking during relapse. Postmortem tissue analysis using quantitative immunohistochemistry in the mPFC demonstrated that reduced seeking correlated with reduced PECAM-1, OPCs and neuronal activation. Western blotting analysis revealed that endostatin enhanced the activity of calcium calmodulin dependent kinase II (CaMKII), which could assist with normalizing the altered neuronal activity during abstinence. In conclusion, our analyses confirmed that the angiogenesis of PECAM-1 is responsible for enhancing ethanol seeking behavior by altering neuronal activation and oligodendrogenesis in female rat mPFC. Our research provided a possible mechanism to inhibit ethanol seeking and prevent the glial and neuronal damage caused by increased accumulation of PECAM-1 from alcohol drinking.