Comparison of phosphodiesterase 7 expres⁃sion in brain striatum of C57BL/6J and DBA/2J mice and association with ethanol drinking behavior

摘要

OBJECTIVE Cyclic adenosine monophosphate(cAMP)-protein kinase A(PKA)signaling has been shown to regulate alcohol consumption.The phosphodiesterase 7(PDE7)enzyme is one of the PDE families responsible for controlling intracellular levels of cAMP.However,the role of PDE7 in alcohol consump⁃tion remains unknown.C57BL/6J(B6)mice innately consume larger amounts of alcohol while DBA/2J(DBA)mice do the opposite,ie,they drink little alcohol.In the present study,we evaluated whether PDE7 plays a role in regulat⁃ing alcohol intake using adult B6 and DBA mice.METHODS Adult male B6 and DBA mice were tested for ethanol(7%and 10%,V/V)intake and preference using the two-bottle choice task.In addition,a separate set of B6 and DBA mice was examined for PDE7 expression in the striatum,a brain region critical for ethanol drinking,using Western blotting.Further,PDE7 subtype expres⁃sion in the striatum of B6 mice in response to ethanol drinking was examined.Finally,the effect of the PDE7 inhibitor BRL-50481 on etha⁃nol consumption was examined in B6 mice.RESULTS①Comparison of ethanol drinking behavior between B6 and DBA mice.Compared to DBA mice,B6 mice had significantly higher ethanol intake and preference,without altering sucrose intake and preference or quinine intake and preference.②Comparison of the expres⁃sion of PDE7 subtypes in the brain striatum of B6 and DBA mice.Compared to DBA mice,naive B6 mice showed significant lower expres⁃sion of PDE7A(P<0.01),but not PDE7B in the striatum.③PDE7A in the striatum of naive and ethanol-drinking B6 mice.After ethanol drinking for 10 d,B6 mice showed significant increases in expression of PDE7A in the striatum(P<0.01)relative to naive controls,but no changes in PDE7B.④Effect of BRL-50481 on ethanol drinking behavior in B6 mice.BRL-50481(0.3-3 mf·kg-1)reduced ethanol intake(P<0.01 for 0.3 and 1 mg·kg-1;P<0.05 for 3 mg·kg-1)and preference(P<0.05 for all doses)without altering the total fluid intake in B6 mice.CON⁃CLUSION PDE7A expression is relatively high in the striatum of alcohol preferring mice such as B6 and can be further increased following etha⁃nol drinking.PDE7A is an important player in the regulation of alcohol consumption.Drugs inhibiting PDE7A can be novel treatments for alcoholism.