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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA004075-01
Application #
3209108
Study Section
(DABA)
Project Start
1986-07-01
Project End
1989-06-30
Budget Start
1986-07-01
Budget End
1987-06-30
Support Year
1
Fiscal Year
1986
Total Cost
Indirect Cost
Name
University of Toledo
Department
Type
Schools of Medicine
DUNS #
807418939
City
Toledo
State
OH
Country
United States
Zip Code
43614
Xiang, K; Tietz, E I (2008) Chronic benzodiazepine-induced reduction in GABA(A) receptor-mediated synaptic currents in hippocampal CA1 pyramidal neurons prevented by prior nimodipine injection. Neuroscience 157:153-63
Xiang, Kun; Earl, Damien E; Davis, Kathleen M et al. (2008) Chronic benzodiazepine administration potentiates high voltage-activated calcium currents in hippocampal CA1 neurons. J Pharmacol Exp Ther 327:872-83
Das, Paromita; Lilly, Scott M; Zerda, Ricardo et al. (2008) Increased AMPA receptor GluR1 subunit incorporation in rat hippocampal CA1 synapses during benzodiazepine withdrawal. J Comp Neurol 511:832-46
Xiang, Kun; Tietz, Elizabeth I (2007) Benzodiazepine-induced hippocampal CA1 neuron alpha-amino-3-hydroxy-5-methylisoxasole-4-propionic acid (AMPA) receptor plasticity linked to severity of withdrawal anxiety: differential role of voltage-gated calcium channels and N-methyl-D-aspartic acid re Behav Pharmacol 18:447-60
Song, Jun; Shen, Guofu; Greenfield Jr, L John et al. (2007) Benzodiazepine withdrawal-induced glutamatergic plasticity involves up-regulation of GluR1-containing alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors in Hippocampal CA1 neurons. J Pharmacol Exp Ther 322:569-81
Lilly, S M; Alvarez, F J; Tietz, E I (2005) Synaptic and subcellular localization of A-kinase anchoring protein 150 in rat hippocampal CA1 pyramidal cells: Co-localization with excitatory synaptic markers. Neuroscience 134:155-63
Van Sickle, Bradley J; Xiang, Kun; Tietz, Elizabeth I (2004) Transient plasticity of hippocampal CA1 neuron glutamate receptors contributes to benzodiazepine withdrawal-anxiety. Neuropsychopharmacology 29:1994-2006
Lilly, Scott M; Zeng, X J; Tietz, E I (2003) Role of protein kinase A in GABAA receptor dysfunction in CA1 pyramidal cells following chronic benzodiazepine treatment. J Neurochem 85:988-98
Chen, S; Huang, X; Zeng, X J et al. (1999) Benzodiazepine-mediated regulation of alpha1, alpha2, beta1-3 and gamma2 GABA(A) receptor subunit proteins in the rat brain hippocampus and cortex. Neuroscience 93:33-44
Tietz, E I; Huang, X; Chen, S et al. (1999) Temporal and regional regulation of alpha1, beta2 and beta3, but not alpha2, alpha4, alpha5, alpha6, beta1 or gamma2 GABA(A) receptor subunit messenger RNAs following one-week oral flurazepam administration. Neuroscience 91:327-41

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