GLRB variants regulate nearby gene expression in human brain tissues.

A recent genome-wide association study (GWAS) identified four genetic variants rs78726293, rs191260602, rs17035816 and rs7688285 in GLRB gene to be associated with panic disorder (PD) risk. In fact, GWAS is an important first step to investigate the genetics of human complex diseases. In order to translate into opportunities for new diagnostics and therapies, we must identify the genes perturbed by these four variants, and understand how these variant functionally contributes to the underlying disease pathogenesis. Here, we investigated the effect of these four genetic variants and the expression of three nearby genes including PDGFC, GLRB and GRIA2 in human brain tissues using the GTEx (version 6) and Braineac eQTLs datasets. In GTEx (version 6) dataset, the results showed that both rs17035816 and rs7688285 variants could significantly regulate PDGFC and GLRB gene expression. In Braineac dataset, the results showed that rs17035816 variant could significantly regulate GLRB and GRIA2 gene expression. We believe that these findings further provide important supplementary information about the regulating mechanisms of rs17035816 and rs7688285 variants in PD risk.

The phosphodiesterase-4 inhibitor roflumilast decreases ethanol consumption in C57BL/6J mice.

RATIONALE: Alcohol use disorders have become one of the most damaging psychiatric disorders in the world; however, there are no ideal treatments in clinic. Phosphodiesterase-4 (PDE4), an enzyme that specifically hydrolyzes intracellular cyclic AMP (cAMP), has been involved in alcohol use disorders. Roflumilast is the first PDE4 inhibitor approved for treatment of chronic obstructive pulmonary diseases in clinic. It was of particular interest to researchers to determine whether roflumilast altered ethanol consumption. OBJECTIVES: The present study tried to determine the effects of roflumilast on ethanol intake and preference. METHODS: We used the two-bottle choice paradigm to assess ethanol intake and preference in C57BL/6J mice treated with roflumilast (1, 3, or 10 mg/kg) or rolipram (0.5 mg/kg; positive control). The effect of roflumilast was verified using the ethanol drinking-in-dark (DID) test. Locomotor activity was examined using the open-field test. Intake of sucrose or quinine was also tested to determine whether natural reward preference and aversive stimuli were involved in the effect of PDE4 inhibitors. RESULTS: Similar to rolipram, roflumilast decreased ethanol intake and preference in two-bottle choice and DID tests in a dose-dependent manner, with significant changes at the dose of 10 mg/kg; in contrast, roflumilast did not affect sucrose or quinine drinking, although it decreased locomotor activity at the high dose within 3 h of treatment. CONCLUSIONS: These data provide novel demonstration for the effect of roflumilast on ethanol consumption and suggest that roflumilast may be beneficial for treatment of alcoholism.