Comparison of the effects of dopamine D 1 and D 2 receptor antagonists on nerve growth factor mRNA expression

Abstract

Regulation of the expression of the nerve growth factor (NGF) gene has been reported previously to be mediated by the interaction of c- fos with an activator protein-1 (AP-1) binding site present in the first intron on the NGF gene. Using an RNase protection assay and in situ hybridization, we examined the effects of dopamine D 1 and D 2 receptor antagonists on NGF mRNA. Haloperidol (0.1–8 mg/kg) and (−)-sulpiride (10–100 mg/kg), induced NGF mRNA in a dose-dependent fashion in the hippocampus, piriform cortex, striatum and nucleus accumbens. The haloperidol (1 mg/kg)- and (−)-sulpiride (20 mg/kg)-induced NGF mRNA expression attained a maximum level 120 min after injection and returned to control levels 24 h later. Prior administration of the protein synthesis inhibitor cycloheximide blocked the haloperidol- and (−)-sulpiride-mediated induction of NGF mRNA. In contrast, R-(−)-8-chloro-2,3,4,5-tetrahydro-3,1-methyl-5-phenyl-11-3-benzyoepine-7-ol (SCH23390) did not induce NGF mRNA expression in either a dose-dependent or time-dependent manner. Our previous studies have shown that haloperidol and (−)-sulpiride induce the expression of c- fos and c- jun mRNAs and increase their AP-1 DNA binding activities. Thus, the data suggest that neuroleptics induce NGF gene expression by increasing AP-1 DNA binding activity.