Benzodiazepines (BZs) are useful clinically, however tolerance to many of their actions occurs with prolonged administration. Investigations of GABA-A receptors (GABARs) in rats chronically treated with flurazepam have shown significant decreases of inhibitory function in hippocampus and have uncovered changes in excitatory amino acid receptor (EAAR)-mediated activity. Preliminary studies of NMDA and AMPA receptors detected changes in subunit mRNA and protein, consistent with the hypothesis that impaired GABAR-mediated inhibition leads to compensatory changes in EAARs. Electrophysiological studies suggest that functional EAAR-mediated transmission may be altered affecting synaptic plasticity as well. From these findings, three hypotheses were developed and will be tested by 3 Specific Aims: 1) is to characterize changes in NMDA and AMPA receptor protein and receptor number using i) quantitative immunohistochemistry, ii) Western analysis and iii) autoradiographic binding studies; 2) is to examine changes in functional EAAR-mediated transmission using whole cell recordings from CA1 pyramidal cells to measure i) characteristics of mEPSCs, ii) properties of stimulus- and agonist-evoked EPSCs and iii) shifts in dose-response curves of evoked events by the NR2B-selective antagonist ifenprodil; 3) is to assess changes in synaptic plasticity by examining i) expression of Thr286-phosphorylated CaMKII by Western analysis, ii) kinase activity of CaMKII and iii) the frequency-response function of LTP in BZ tolerant hippocampus. Tolerance occurs with many drugs of abuse, so a better understanding of EAAR regulation after chronic BZ may have broader implications in the area of drug abuse research.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30DA006041-02
Application #
6378478
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Babecki, Beth
Project Start
2001-06-01
Project End
Budget Start
2001-06-15
Budget End
2002-05-31
Support Year
2
Fiscal Year
2001
Total Cost
$31,923
Indirect Cost
Name
University of Toledo
Department
Physiology
Type
Schools of Medicine
DUNS #
807418939
City
Toledo
State
OH
Country
United States
Zip Code
43614
Shen, Guofu; Van Sickle, Bradley J; Tietz, Elizabeth I (2010) Calcium/calmodulin-dependent protein kinase II mediates hippocampal glutamatergic plasticity during benzodiazepine withdrawal. Neuropsychopharmacology 35:1897-909
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