Effects of Dopaminergic Transmission Interruption on the D 2 Receptor Isoforms in Various Cerebral Tissues

Effects of Dopaminergic Transmission Interruption on the D 2 Receptor Isoforms in Various... Abstract: We examined the effects of an interruption of dopamine neurotransmission, by either dopamine receptor blockade or degeneration of dopamine neurons by 6‐hydroxydopamine, on the levels of D2 receptor mRNAs. In addition, we evaluated by the polymerase chain reaction (PCR) the relative abundance of the two D2 receptor isoform mRNAs generated by alternative splicing. Daily injections of 4 mg/kg of haloperidol to rats elicited in striatum a rapid and progressive increase in D2 receptor mRNA levels, which reached 70% after a 15‐day treatment. By contrast, there was no apparent change in D2 receptor mRNA levels in cerebral cortex and pons‐medulla, in spite of an increased density of D2 receptor in the former tissue. Using the PCR with primers flanking the alternative exon, we observed that the relative proportion of the shorter receptor isoform (D2s) mRNA was slightly but significantly enhanced in cerebral cortex (17%) and pons‐medulla (18%) after a 15‐day haloperidol treatment. Unilateral degeneration of dopamine neurons induced by local injection of 6‐hydroxydopamine resulted in a marked decrease in levels of total D2 receptor mRNAs in substantia nigra (—79%) and ventral tegmental (—63%) area, two cell body areas. In the substantia nigra, the longer isoform (D2l) mRNA was significantly more decreased in content than the D2s isoform mRNA, so that there was a large enhancement in the relative abundance of the latter (81%). In contrast, the lesion did not result in any significant change in levels of total D2 receptor mRNAs in striatum, but the relative proportion of D2s receptor mRNA tended to decrease—although nonsignificantly—as a result of a tendency of the D2l receptor mRNA abundance to rise. The present study establishes that two distinct processes of D2 receptor gene expression accompany and may contribute to the hypersensitivity known to develop at D2 receptors following either their chronic blockade by neuroleptics or dopamine denervation. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Neurochemistry Wiley

Effects of Dopaminergic Transmission Interruption on the D 2 Receptor Isoforms in Various Cerebral Tissues

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Publisher
Wiley
Copyright
Copyright © 1992 Wiley Subscription Services, Inc., A Wiley Company
ISSN
0022-3042
eISSN
1471-4159
D.O.I.
10.1111/j.1471-4159.1992.tb09770.x
Publisher site
See Article on Publisher Site

Abstract

Abstract: We examined the effects of an interruption of dopamine neurotransmission, by either dopamine receptor blockade or degeneration of dopamine neurons by 6‐hydroxydopamine, on the levels of D2 receptor mRNAs. In addition, we evaluated by the polymerase chain reaction (PCR) the relative abundance of the two D2 receptor isoform mRNAs generated by alternative splicing. Daily injections of 4 mg/kg of haloperidol to rats elicited in striatum a rapid and progressive increase in D2 receptor mRNA levels, which reached 70% after a 15‐day treatment. By contrast, there was no apparent change in D2 receptor mRNA levels in cerebral cortex and pons‐medulla, in spite of an increased density of D2 receptor in the former tissue. Using the PCR with primers flanking the alternative exon, we observed that the relative proportion of the shorter receptor isoform (D2s) mRNA was slightly but significantly enhanced in cerebral cortex (17%) and pons‐medulla (18%) after a 15‐day haloperidol treatment. Unilateral degeneration of dopamine neurons induced by local injection of 6‐hydroxydopamine resulted in a marked decrease in levels of total D2 receptor mRNAs in substantia nigra (—79%) and ventral tegmental (—63%) area, two cell body areas. In the substantia nigra, the longer isoform (D2l) mRNA was significantly more decreased in content than the D2s isoform mRNA, so that there was a large enhancement in the relative abundance of the latter (81%). In contrast, the lesion did not result in any significant change in levels of total D2 receptor mRNAs in striatum, but the relative proportion of D2s receptor mRNA tended to decrease—although nonsignificantly—as a result of a tendency of the D2l receptor mRNA abundance to rise. The present study establishes that two distinct processes of D2 receptor gene expression accompany and may contribute to the hypersensitivity known to develop at D2 receptors following either their chronic blockade by neuroleptics or dopamine denervation.

Journal

Journal of NeurochemistryWiley

Published: Feb 1, 1992

References

  • Receptor adaptations to centrally acting drugs
    Creese, Creese; Sibley, Sibley
  • Multiple receptors for dopamine
    Kebabian, Kebabian; Calne, Calne

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