We have recently observed that 2-amino-7-phosphonoheptanoic acid (APH), a excitatory amino acid (EAA) antagonist with selectively for N-methyl-D-aspartate (NMDA) receptors, virtually eliminates the spontaneous convulsions which occur following the abrupt withdrawal of barbital from barbiturate dependent rats. These convulsions represent the most serious behavioral manifestation of this potentially life threatening syndrome which has been estimated to be more severe than opiate withdrawal. Most importantly, these data provide the first direct evidence for an involvement of EAA pathways in the manifestation of this abstinence syndrome. The major objective of this renewal proposal is to identify the brain regions which contain NMDA receptors involved in the propagation of these abstinence related convulsions. Alzet minipumps attached to intracerebral cannula will infuse APH into select brain regions and the potential ameliorative effects on spontaneous convulsions will be determined. The amygdala (AMY) and hippocampus (HIPPO), sites where more than 50 percent of these convulsions appear to originate as well as major sites of NMDA receptor concentration, will be the initial regions investigated. Other experiments will explore a potential key involvement of chronic barbiturate- induced adaptations in EAA pathways in the development of barbiturate dependence. In particular, we will extensively investigate an apparent hyperresponsiveness to kainate in barbital dependent rats. Collectively, these studies will test the hypothesis that EAA pathways play a key role in the development of and the manifestation of barbiturate dependence.
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