The objectives of this application are (a) to provide the candidate with further training and experience in several research techniques which will not only enhance the present investigations but also provide a broad base from which the candidate may pursue his long term goals in the study of mental illness, and (b) to investigate in further detail three separate but related aspects of certain """"""""excitotoxic"""""""" molecules which are structurally and pharmacologically similar to the putative mammalian neurotransmitter glutamic acid (Glu). Several lines of evidence suggest that Glu [and/or aspartic acid (Asp)] is the excitatory transmitter in many brain regions, including some major pathways in the """"""""limbic system."""""""" In the last few years the potent Glu agonist kainic acid (KA) has been used as an axon-sparing lesioning tool to study structure-function relationships within the CNS. Other Glu agonists such as N-methyl aspartic acid (NMA) may be equally, if not better suited for such studies. Recently it has been demonstrated by the candidate that the neurotoxic activity of KA can be enhanced by morphine and suppressed by diazepam, suggesting an interaction between the glutamergic system and psychoactive drugs which are significantly involved in both therapy and abuse. A major focus of this proposal is to study the mechanism(s) underlying this interaction. In addition to a variety of neurohistologic approaches to be used in these studies, the candidate will learn and employ the neurochemical techniques used to investigate high-affinity uptake and receptor bindings. *Other investigators have reported an age-dependent susceptibility of striatal neurons to the toxic action of KA, concluding that a mature and intact glutamergic pathway is required for this toxin to be effective. The applicant proposes to study the toxic effect of Glu, KA and other Glu analogs in relation to the development of specific pathways in rat brain. The olfactory cortex and other limbic areas will be focused upon with systemic administration as well as direct injection of these """"""""excitotoxic"""""""" amino acids. During the implementation of these studies the applicant will learn methods of autoradiography in order to
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