Effects of cocaine on release and uptake of dopamine in vivo: Differentiation by mathematical modeling

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Abstract

Although considerable effort has been invested trying to distinguish between the effects of cocaine in dopamine (DA) uptake and release in both in vitro and in vivo experiments, disagreement over the specific actions of cocaine remains. The results obtained by combining experimental extracellular DA data with a mathematical model of the dopaminergic neuron allow examination of the cocaine uptake inhibition/release question. The extracellular DA concentration profile observed following a 30 mg/kg IP cocaine injection can be modeled if both pre- and postsynaptic uptake are competitively inhibited by cocaine with or without an enhanced DA release effect. However, if cocaine elicits enhanced DA release, modeling predicts a 40% increase over basal levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and a 30% increase in homovanillic acid (HVA) at 60 minutes following a 30 mg/kg IP cocaine injection. Reported DOPAC and HVA data for similar cocaine doses indicate little change in either DOPAC or HVA. These data agree best with modeled metabolite predictions for little or no cocaine-enhanced DA release.

References (57)

  • M.L. McKenna et al.

    The role of dopamine in the discriminative stimulus properties of cocaine

    Neuropharmacology

    (1980)
  • A.C. Michael et al.

    Mechanisms contributing to the recovery of striatal releaseable dopamine following mfb stimulation

    Brain Res.

    (1987)
  • V.H. Morgenroth et al.

    Dopaminergic neurons-alterations in the kinetic properties of tyrosine hydroxylase after cessation of impulse flow

    Biochem. Pharmacol.

    (1976)
  • L.C. Nicolaysen et al.

    Extracellular cocaine and dopamine are linearly related in rat striatum

    Brain Res.

    (1988)
  • J.A. Nielsen et al.

    Differential effects of d-amphetamine, 8-phenylethylamine, cocaine and methyl-phenidate on the rate of dopamine synthesis in terminals of nigrostriatal and mesolimbic neurons and on the efflux of dopamine metabolites into cerebroventricular perfusates of rats

    Life Sci.

    (1983)
  • R.L. Patrick et al.

    Potentiation by cocaine of the stimulus-induced increase in dopamine synthesis in rat brain striatal synaptosomes

    Neuropharmacology

    (1977)
  • E.W. Pelton et al.

    Dopamine and norepinephrine uptake and metabolism by astroglial cells in culture

    Life Sci.

    (1981)
  • J. Peris et al.

    One injection of cocaine produces a long-lasting increase in [3H]dopamine release

    Pharmacol. Biochem. Behav.

    (1987)
  • D.K. Pitts et al.

    Cocaine modulation of central monoaminergic neurotransmission

    Pharmacol. Biochem. Behav.

    (1987)
  • M.E.A. Reith et al.

    Structural requirements for cocaine congeners to interact with dopamine andserotonin uptake sites in mouse brain and to induce stereotyped behavior

    Biochem. Pharmacol.

    (1986)
  • D.C.S. Roberts et al.

    On the role of ascending catecholaminergic systems in intravenous self-administration of cocaine

    Pharmacol. Biochem. Behav.

    (1977)
  • D.C.S. Roberts et al.

    Extinction and recovery of cocaine self-administration following 6-hydroxydopamine lesions of the nucleus accumbens

    Pharmacol. Biochem. Behav.

    (1980)
  • B.H.C. Westerink et al.

    Turnover of acid dopamine metabolites in striatal and mesolimbic tissue of the rat brain

    Eur. J. Pharmacol.

    (1976)
  • R.A. Wise

    Catecholamine theories of reward: a critical review

    Brain Res.

    (1978)
  • J.J. Woodward et al.

    Dopamine uptake during fast-phase endogenous dopamine release from mouse striatal synaptosomes

    Neurosci. Lett.

    (1986)
  • K.A. Zito et al.

    Disruption of cocaine and heroin self-administration following kainic acid lesions of the nucleus accumbens

    Pharmacol. Biochem. Behav.

    (1985)
  • S.P. Bagchi

    Multiple actions of cocaine with opposing effects on brain 3,4-dihydroxyphenylacetic acid level

    Soc. Neurosci. Abstr.

    (1986)
  • P.A. Baumann et al.

    Is drug inhibition of dopamine uptake a misinterpretation of in vitro experiments?

    Nature

    (1976)
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