Glycogen synthase kinase‐3 β in the ventral tegmental area mediates diurnal variations in cocaine‐induced conditioned place preference in rats

Cocaine sensitization and reward are reported to be under the influence of diurnal rhythm. However, no previous studies have reported brain areas that play a role as modulators and underlie the mechanism of diurnal variations in cocaine reward. We examined (1) the diurnal rhythm of glycogen synthase kinase‐3 β ( GSK ‐3 β ) activity in the suprachiasmatic nucleus ( SCN ) and reward‐related brain areas in naive rats; (2) the effect of day and night on the acquisition of cocaine‐induced conditioned place preference ( CPP ); (3) the influence of cocaine‐induced CPP on GSK ‐3 β activity in the SCN and reward‐related brain areas; and (4) the effect of the GSK ‐3 β inhibitor SB 216763 microinjected bilaterally into the ventral tegmental area ( VTA ) on cocaine‐induced CPP . A significant diurnal rhythm of GSK ‐3 β activity was found in the SCN and reward‐related brain areas, with diurnal variations in cocaine‐induced CPP . GSK ‐3 β activity in the SCN and reward‐related brain areas exhibited marked diurnal variations in rats treated with saline. GSK ‐3 β activity in rats treated with cocaine exhibited distinct diurnal variations only in the prefrontal cortex and VTA . Cocaine decreased the expression of phosphorylated GSK ‐3 β (i.e. increased GSK ‐3 β activity) only in the VTA in rats trained and tested at ZT 4 and ZT 16. SB 216763 microinjected into the VTA bilaterally eliminated the diurnal variations in cocaine‐induced CPP , but did not affect the acquisition of cocaine‐induced CPP . These findings suggest that the VTA may be a critical area involved in the diurnal variations in cocaine‐induced CPP , and GSK ‐3 β may be a regulator of diurnal variations in cocaine‐induced CPP .