CHRONIC TREATMENT WITH A CLASSICAL NEUROLEPTIC ALTERS EXCITATORY AMINO-ACID AND GABAERGIC NEUROTRANSMISSION IN SPECIFIC REGIONS OF THE RAT-BRAIN

The purpose of the following experiments was to describe some of the n eurochemical changes that occur in the basal ganglia of rats exposed c hronically to a classical neuroleptic, fluphenazine, and to relate the se changes to extrapyramidal motor dysfunction. For these studies a co mbination of behavioural, receptor autoradiographic and in situ hybrid ization methods were employed. Preliminary pharmacological studies on GABA receptors showed that incubation in Tris-acetate rather than Tris -citrate buffer increased the number of binding sites labelled by [H-3 ]muscimol by over 120% without affecting binding affinity or selectivi ty. The results of experiments with fluphenazine showed that treatment for six months increased the frequency of vacuous chewing movements c ompared to controls. In the striatum, changes in GABA transmission wer e observed in fluphenazine-treated rats with increases in glutamate de carboxylase mRNA levels in the caudate nucleus, dorsal shell and core of the accumbens and decreases in [H-3]muscimol binding in the caudate and dorsal shell regions. These data suggest that fluphenazine treatm ent increased GABA transmission in specific subregions of the caudate and accumbens nuclei. In addition, glutamate decarboxylase mRNA levels were elevated in the entopeduncular nucleus of fluphenazine-treated a nimals. Autoradiographic analysis of excitatory amino acid binding sho wed that fluphenazine exposure decreased lpha-amino-3-hydroxy-5-methyl isoxazole-4-propionic acid binding in entopeduncular nucleus and in th e ventrolateral thalamic nucleus and decreased [H-3]dizocilpine maleat e binding in the medial geniculate nucleus. These experiments show tha t in addition to altering GABA transmission, chronic neuroleptic expos ure alters excitatory amino acid transmission in specific regions of t he basal ganglia-thalamocortical motor system. The neuroleptic depende nt increases in glutamate decarboxylase mRNA levels in the entopeduncu lar nucleus may reflect changes in neurotransmission in the indirect p athway connecting the major input and output nuclei of the basal gangl ia. Changes in some of these brain regions may be related to the occur rence of extrapyramidal motor disturbances.