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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National Institute on Drug Abuse (NIDA)
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Drug Abuse Biomedical Research Review Committee (DABR)
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Washington State University
Schools of Veterinary Medicine
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Churchill, L; Kalivas, P W (1999) The involvement of the mediodorsal nucleus of the thalamus and the midbrain extrapyramidal area in locomotion elicited from the ventral pallidum. Behav Brain Res 104:63-71
Churchill, L; Swanson, C J; Urbina, M et al. (1999) Repeated cocaine alters glutamate receptor subunit levels in the nucleus accumbens and ventral tegmental area of rats that develop behavioral sensitization. J Neurochem 72:2397-403
Churchill, L; Klitenick, M A; Kalivas, P W (1998) Dopamine depletion reorganizes projections from the nucleus accumbens and ventral pallidum that mediate opioid-induced motor activity. J Neurosci 18:8074-85
Lu, X Y; Churchill, L; Kalivas, P W (1997) Expression of D1 receptor mRNA in projections from the forebrain to the ventral tegmental area. Synapse 25:205-14
Johnson, K; Churchill, L; Klitenick, M A et al. (1996) Involvement of the ventral tegmental area in locomotion elicited from the nucleus accumbens or ventral pallidum. J Pharmacol Exp Ther 277:1122-31
Churchill, L; Roques, B P; Kalivas, P W (1995) Dopamine depletion augments endogenous opioid-induced locomotion in the nucleus accumbens using both mu 1 and delta opioid receptors. Psychopharmacology (Berl) 120:347-55
Napier, T C; Mitrovic, I; Churchill, L et al. (1995) Substance P in the ventral pallidum: projection from the ventral striatum, and electrophysiological and behavioral consequences of pallidal substance P. Neuroscience 69:59-70
Churchill, L; Kalivas, P W (1994) A topographically organized gamma-aminobutyric acid projection from the ventral pallidum to the nucleus accumbens in the rat. J Comp Neurol 345:579-95
Churchill, L; Austin, M C; Kalivas, P W (1992) Dopamine and endogenous opioid regulation of picrotoxin-induced locomotion in the ventral pallidum after dopamine depletion in the nucleus accumbens. Psychopharmacology (Berl) 108:141-6
Churchill, L; Cross, R S; Pazdernik, T L et al. (1992) Patterns of glucose use after bicuculline-induced convulsions in relationship to gamma-aminobutyric acid and mu-opioid receptors in the ventral pallidum--functional markers for the ventral pallidum. Brain Res 581:39-45

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