Dopaminergic and glutamatergic blocking drugs differentially regulate glutamic acid decarboxylase mRNA in mouse brain

Abstract

Dopaminergic and glutamatergic inputs play an important role in regulating the activity of GABAergic neurons in basal ganglia. To understand more fully the biochemical interactions between these neurotransmitter systems, the effects of blocking dopamine and glutamate ($\text{N-}\text{methyl-}\text{d}\text{-aspartate}$) (NMDA) receptors on the expression of glutamic acid decarboxylase (GAD) mRNA were examined. Persistent blockade of dopamine receptors was achieved by daily injections of EEDQ, a relatively non-selective irreversible D₁ and D₂ dopamine receptor antagonist, or FNM, a relatively selective irreversible D₂ dopamine receptor antagonist. Persistent blockade of NMDA receptors was achieved by continuously infusing dizocilpine (MK-801), a non-competitive NMDA receptor antagonist. The levels of GAD mRNA in mouse brain were measured by in situ hybridization histochemistry following treatment with these agents. Repeated administration of EEDQ increased the levels of GAD mRNA in corpus striatum and frontal and parietal cortex; the first significant effects were seen after 4 days of treatment. Treatment with FNM elicited effects similar to those produced by EEDQ, except FNM also significantly increased GAD mRNA in nucleus accumbens. Neither EEDQ nor FNM produced significant effects on GAD mRNA in olfactory tubercle or septum. Infusion of MK-801 produced a rapid and marked decrease in the levels of GAD mRNA in corpus striatum, nucleus accumbens, olfactory tubercle, septum and frontal and parietal cortex; significant changes were seen as early as 2 days of treatment. No significant effects were seen in globus pallidus. Cellular analysis of emulsion autoradiograms from corpus striatum revealed that MK-801 reduced the amount of GAD mRNA in individual cells as well as the proportion of cells expressing high levels of GAD mRNA. These results suggest that dopamine, though its interaction with D₂ dopamine receptors, exerts an inhibitory effect on the expression of GAD mRNA, and that glutamate, though its interaction with NMDA receptors, exerts a stimulatory effect on GAD mRNA expression. They show further that the regulation of gene expression by dopamine receptors or NMDA receptors is different in different regions of the brain.