The Regulation of Gaba and Benzodiazepine Receptors Following Neurotoxin-Induced Striatal and Medial Forebrain Bundle Lesions.

GABA, a major inhibitory transmitter, is used by many projection neurons of the striatum. To investigate the role of GABA in striatal function, the GABA receptor complex was studied after lesions of the striatum or the nigrostriatal neurons. Quantitative receptor autoradiography using thaw-mounted tissue slices was developed for the study of GABA and benzodiazepine (BDZ) receptors. Using this technique, binding of ('3)H muscimol to GABA receptors and ('3)H flunitrazepam to BDZ receptors were found to be specific, to be of high affinity, to show distinct regional distributions and to have pharmacological profiles similar to those found in behavioral and clinical studies. With the technique established, binding to GABA and BDZ receptors after unilateral striatal kainate lesions was examined. In the primary striatal projection areas--globus pallidus (GP), entopeduncular nucleus (EPN) and substantia nigra pars reticulata (SNr)--binding to both receptors increased. ('3)H Muscimol binding was decreased in the secondary striatal projection areas, the anteroventrolateral and ventromedial thalamus (which receive GABAergic input from EPN and SNr, respectively). Subsequently, changes in GABA and BDZ receptors were studied following the destruction of dopaminergic nigrostriatal cells by unilateral 6-hydroxydopamine lesion of the medial forebrain bundle. Decreased GABA and BDZ receptors were found in striatum and GP, but increased receptors were found in EPN and SNr. In all lesioned animals, the GABA and BDZ receptor alterations were due to changes in receptor numbers, and the response of BDZ receptors was slower than that of GABA receptors. In summary, quantitative receptor autoradiography allowed the detection of GABA and BDZ receptor changes in multiple small areas in each lesioned brain. This technique made it feasible to carry out kinetic, saturation and competition studies using less than 1 mg of tissue. The data suggest that dopamine is functionally inhibitory on striatopallidal neurons but is functionally excitatory on striatoentopeduncular and striatonigral cells which in turn inhibit the thalamus. This quantitative autoradiographic technique can be generalized to study other transmitter receptors and can be combined with 2-deoxyglucose uptake studies.Ph.D.Mental healthUniversity of Michiganhttp://deepblue.lib.umich.edu/bitstream/2027.42/160579/1/8512484.pd