The long-term goals of this proposal are to characterize alterations in dopamine-glutamate interactions in limbic motor circuits that are likely to have a profound effect on the neural substrates that translate motivationally salient stimuli into adaptive motor responses. The first research objective is to identify whether or not kappa opiate receptors in the striatum or substantia nigra regulate basal extracellular dopamine and glutamate levels as detected by in vivo microdialysis. The second objective is to identify the conditions which promote dopamine agonist- induced increases in extracellular glutamate levels in the dorsal striatum and substantia nigra. It is expected that an increase in extracellular glutamate levels in caudate and/or substantia nigra neurons will be large after repeated administration of a direct dopamine D1/D2 receptor agonist than after a single administration. Such an increase in extracellular glutamate is hypothesized to underlie long-term adaptations in neuronal sensitivity to dopamine receptor stimulation (sensitization). The role of endogenous modulators, which are turned on in response to augmented dopamine-glutamate receptor stimulation. would be to attenuate dopamine/glutamate activity in order to maintain homeostasis. It has emerged that kappa opiate receptor stimulation suppresses dopamine release in the striatum and blocks the initial locomotor stimulating and behavioral sensitizing effects of dopamine agonists. Therefore, a third objective of this proposal is to investigate whether kappa receptor- stimulated attenuation of glutamate release occurs in the striatonigral system in response to acute or repeated dopamine receptor stimulation. Because induction of behavioral sensitization has been linked to D1 receptor stimulation in the substantia nigra and VTA, the ventral mesencephalon is a major candidate for a site where kappa receptors reside on glutamatergic terminals. Thus, a fourth objective of this proposal is to map kappa opiate receptor immunoreactivity at the light and electron microscopic level using polyclonal antisera raised against a unique peptide sequence in the newly cloned kappa opiate receptor. Development of double labeling for kappa receptors and other neurotransmitter markers at the ultrastructural level will allow direct evaluation of whether or not kappa receptors reside in/on glutamatergic (and dopaminergic) terminals, and, if so, where this colocalization occurs in limbic motor circuitry. These multidisciplinary studies are planned to contribute fundamental information about opiate-glutamate-dopamine interactions in the striatonigral system. Furthermore, data generated by these studies should advance our understanding of the role of endogenous opioid peptide/receptor systems in the modulation of dopamine-glutamate interactions which underlie the actions of abused drugs.
