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Correlation between drug-induced supersensitivity of dopamine dependent striatal mechanisms and the increase in striatal content of the Ca2+ regulated protein activator of cAMP phosphodiesterase

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Summary

Rats were injected daily with 1.3 μmol/kg of haloperidol s.c. for 10 days. From the second to the ninth day after haloperidol withdrawal the rats developed supersensitivity to the behavioral affects of apomorphine. Concomitantly, the K a of dopamine for the activation of striatal adenylate cyclase was lowered and the striatal content of the Ca2+ dependent protein that activates cAMP phosphodiesterase was increased. This activator protein is stored in striatal membranes and can be released by membrane phosphorylation in cytosol. This protein increases the activity of the high K m phosphodiesterase (Uzunov et al., 1976) but when it is bound to striatal membranes it facilitates the activation of striatal adenylate cyclase by dopamine (Gnegy et al., 1976 b). The increase in protein activator content of striatal membranes caused by haloperidol could be a primary factor in causing supersensitivity to the biochemical and behavioral effects of dopamine receptor agonists.

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Authors and Affiliations

  1. Laboratory of Preclinical Pharmacology, National Institute of Mental Health, Saint Elizabeths Hospital, 20032, Washington, D.C., USA

    M. E. Gnegy, A. Lucchelli & E. Costa

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  1. M. E. Gnegy
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  2. A. Lucchelli
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  3. E. Costa
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Gnegy, M.E., Lucchelli, A. & Costa, E. Correlation between drug-induced supersensitivity of dopamine dependent striatal mechanisms and the increase in striatal content of the Ca2+ regulated protein activator of cAMP phosphodiesterase. Naunyn-Schmiedeberg's Arch. Pharmacol. 301, 121–127 (1977). https://doi.org/10.1007/BF00501426

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  • DOI: https://doi.org/10.1007/BF00501426

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