This research will use an integrated approach to examine the adaptations in CNS function which occur with the prolonged use of CNS depressants, and to understand the mechanisms by which their chronic use alters CNS inhibitory/excitatory tone. Converging lines of evidence, including recent findings from this laboratory, suggest that the substantia nigra pars reticulata (SNpr) is a major subcortical regulatory center of CNS excitability and of basal ganglia motor output and is an ideal location in which to attempt to correlate alterations in receptor function with their behavioral consequences. The SNpr is a major site of benzodiazepine receptor downregulation following chronic benzodiazepine treatment. Further, the inhibitory GABA syste, prominent in SNpr, is also altered by chronic benzodiazepine treatment. Preliminary studies indicate an alteration in behavioral sensitivity in SNpr to locally applied GABA and benzodiazepine agonists following chronic benzodiazepine treatment. The first major goal of this research is to use both standard and autoradiographic binding techniques to quantitate and localize changes in GABA receptor number after chronic benzodiazepine administration. The time course of changes in the GABA receptor system will be compared to those already known for the benzodiazepine system. The second major goal is to use SNpr function as a substrate to evaluate the extent of tolerance and dependence to the benzodiazepines and its relationship to altered GABA and benzodiazepine receptor number, and to altered function of the GABA-benzodiazepine-chloride ionophore complex. SNpr function will be measured by the motor response following local microinjection of benzodiazepine receptor agonists and antagonists, GABA receptor agonists and an antagonists and picrotoxin. The results of this proposal may have bearing on the differential tolerance which has been observed to occur to the benzodiazepines in man. This system may provide a behavioral assay for the benzodiazepine """"""""antagonist"""""""" Ro15-1788 by evaluation of the effects of microinjection of Ro15-1788 into SNpr. Ro15-1788 can precipitate abstinence signs following chronic benzodiazepine treatment and so may prove a valuable tool for examining dependence. This SNpr system will be useful for exploring the molecular and functional correlates of tolerance and dependence to other CNS depressants e.g., barbiturates and ethanol, whose mechanisms have well established links with alterations in GABA systems and should also be useful for evaluating the role of other drug or neuro-transmitter systems in the mechanisms underlying tolerance and dependence.
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