Effects of antipsychotics on GABA neurons in the basal ganglia of the rat

Abstract: Antipsychotics are used in the treatment of psychosis and, based on their propensities to induce extrapyramidal side effects (EPS), are divided into typical (haloperidol) and atypical (clozapine) subtypes. The incidence of EPS, arises from an imbalance in the neurotransmission between two majorGABAergic pathways of the basal ganglia that connect the striatum directly to the entopeduncular nucleus (EP) and the substantia nigra reticulata or indirectly via the globus pallidus and the subthalamic nucleus. The striatonigral/EP neurons express dopamine D1-receptors and preprodynorphin (PPD) while striatopallidal neurons contain D2-receptors and preproenkephalin (PPE).The GABA neurons contain glutamic acid decarboxylase (GAD, the rate limiting enzyme of GABA synthesis), which exists in two isoforms-- GAD65 and GAD67. In situ hybridization and receptor autoradiographic methods were used in rats. It was shown that the modulation of basal ganglia D1-receptor binding by a typical antipsychotic (fluphenazine) was primarily due to the blockade of D1-receptors. In the EP, GAD65 and GAD67 mRNAs were most abundant in the rostra1 limbic and the caudal motor subregions, respectively. Subchronic administration of clozapine increased D1-receptor binding and GAD65 mRNA levels; haloperidol enhanced both GAD65 and GAD67 mRNA expression in the rostra1 and caudal EP. Both drugs induced vacuous chewing movements (VCMs). The glutamate receptor (NMDA) antagonist, MK-801, which excerted a week effect on VCMs, increased GAD67 mRNA in both EP subregions. Whereas haloperidol only increased PPE mRNA expression, MK-801 enhanced both PPE and PPD mRNA levels in the striatum.The biochemical differences between haloperidol and clozapine in the EP may be linked to their different clinical profiles of the two antipsychotics. The modulation of GAD65 mRNA expression in the EP may play a role in the display of VCMs. Whereas haloperidol primarily influenced the indirect pathway, MK-801 activated both thedirect and indirect pathways.