Dopamine and opioid receptors in the nucleus accumbens are, at least partially, responsible for increases in locomotor activity following the administration of cocaine or opioids. Although the opioid system does not depend upon dopamine for its actions, the depletion of dopamine will augment opioid-induced locomotor activity. The neurochemical basis for this peptide-amine interaction has not yet been elucidated. The coupling of dopamine and opioid receptors in the same postsynaptic neurons may result in an upregulation of opioid receptors in response to dopamine depletion. Preliminary data support this hypothesis. The anatomical localization of any increases in opioid receptor affinity or number will be analyzed by quantitative receptor autoradiography. Another hypothesis is that the dopamine and opioid receptors share a second messenger or ion channel whose activity is enhanced by the dopamine depletion. Modification in the number of Ca+2-activated K+ channels, guanine nucleotide binding proteins or alterations in the opioid inhibition of dopamine-stimulated adenylate cyclase after dopamine depletion might enhance the response of the cell to opioids. The number of Ca+2-activated K+ channels will be determined by specific binding of the bee venom toxin, [125I]apamin. The number of guanine nucleotide binding (Go or Gi) proteins will be measured by [32P]ADP-ribosylation in the presence of pertussis toxin. Opioid agonist inhibition of dopamine-sensitive adenylate cyclase will be analyzed in plasma membrane fractions from nucleus accumbens. If alterations in these neurochemical parameters occur 10 days after the dopaminergic lesion,, then a time course of dopamine depletion will be correlated with the neurochemical alterations. To further evaluate the behavioral role of the Ca+2-activated K+ channels and of guanine nucleotide binding proteins, the opioid-induced augmentation in locomotor activity after dopamine depletion will be evaluated after apamin or pertussis toxin injections into the nucleus accumbens. Understanding the neurochemical basis for these dopamine-opioid interactions will provide mechanistic information in drug abuse situations where the use of cocaine and opioids has been combined.
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