Increased striatal glutamate decarboxylase after lesions of the nigrostriatal pathway

Abstract

The neurotransmltter 7-aminobutyric acid (GABA) is synthesized in brain by the enzyme glutamic acid decarboxylase (GAD). The basal ganglia, particularly the globus pallidus and substantia nigra (SN), have been shown to contain high levels of GAD activity1,4,26, aS, and the existence of a GABAergic pathway from the globus pallidus (GP) or caudal striatum to the SN is now well established. Thus, lesions of the GP have been shown to result m a loss of GAD activity in the SN6,7,1°, 19,24, where GAD has been immunocytochemically localized in nerve terminals z2. A system of GABA interneurons is also thought to exist in the striatum21,22,3'L Interest in the GABA systems of the basal ganglia has been greatly sttmutated by the changes which have been observed in this system in various extrapyramidal disorders. For example, decreased GAD activity has been found m the striatum and SN of patients dying with Huntington's disease 3,18,2z,z6. Also, although the most striking aspect of Parkinson's disease is the marked decrease in SN and striatal dopamine (DA) levels, a consistent decrease in GAD activity in these structures has also been observed 8,x8,24. This decrease in GAD activity has been reported to be reversed by chromc L-DOPA therapy 16,zz. Also, normal rats treated chronically with L-DOPA have been reported to have increased striatal GAD activity 16. These results suggest an mteraction between the nigrostriatal DA system and the GAD-containing cells of the striatum. In the present study the effects of lesions of the nigrostriatal pathway on GAD activity have been investigated to further elucidate possible mteractions of these two systems. Male Wistar rats weighing 300-350 g received a unilateral stereotaxic injection of 6-hydroxydopamine (6-OHDA, Regis Chemicals: 4 #g/2 #1 in 10 rain; 0.2 mg/ml ascorbic acid) into the nigrostriatal bundle (NSB) (A -t-4.4, L q1.8, DV ---2.4 mm) ~1 at the level of the lateral hypothalamus while under Nembutal anesthesia (50 mg/kg, i.p.). Twenty-five days following surgery the rats were sacrificed by cervical fracture and the SN and anterior one-third of the striatum were dissected on ice. In a separate