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Dopamine receptor supersensitivity: An outcome and index of neurotoxicity

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Abstract

The characteristics feature of neurotoxicity is a definable lesion which can account for observed deficits, corresponding to loss of nuclei or axonal fibers normally comprising a specific pathway or tract. However, with ontogenetic lesions, the operative definition fails. In rats lesioned as neonates with 6-hydroxydopamine (6-OHDA), near-total destruction of dopamine-(DA-) containing nerves is produced, and this itself is definable. However, the most prominent feature of rats so-lesioned is the DA receptor supersensitivity (DARSS) that develops and then persists throughtout the lifespan. DA D1 receptors show overt supersensitivity to agonists producing vacuous chewing movements (VCMs), while D1 receptors associated with locomotor activity have a latent supersensitivity that must be unmasked by repeated D1 or D2 agonist treatments — a ‘priming’ phenomenon. This D1 DARSS is not usually associated in either a change in D1 receptor number (Bmax) or affinity (Kd). In contrast to D1 DARSS, D2 receptors are not so predictably supersensitized by a lession of DA neurons. In reality, the permanently exaggerated response to an agonist by supersensitized receptors isper se a manifestation of neurotoxicity. Despite dramatic behavioral responses mediated by supersensitized receptors, DARSS has not been easy to correlate with enhanced production of second messengers or early response genes. Altered signaling (i.e., neuronal cross-talk) in defined pathways may represent the mechanism that produces so-called receptor supersensitization. Longlived agonist-induced behavioral abnormality, with or without anatomic evidence of a neuronal lesion, is one of the products of DA D1 receptor supersensitization — it self an index of neurotoxicity.

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  1. Department of Pharmacology, Quillen College of Medicine, East Tennessee State University, 37614-1708, Johnson City, TN, USA

    Richard M. Kostrzewa & John P. Kostrzewa

  2. Department of Pharmacology, Medical University of Silesia, 41-808, Zabrze, Poland

    Ryszard Brus

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Kostrzewa, R.M., Kostrzewa, J.P. & Brus, R. Dopamine receptor supersensitivity: An outcome and index of neurotoxicity. neurotox res 5, 111–117 (2003). https://doi.org/10.1007/BF03033376

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