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The sigma-1 antagonist BMY-14802 inhibits L-DOPA-induced abnormal involuntary movements by a WAY-100635-sensitive mechanism

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An Erratum to this article was published on 01 April 2009

Abstract

Rationale

Levodopa (L-DOPA), the gold standard treatment for Parkinson’s disease (PD), eventually causes L-DOPA-induced dyskinesia (LID) in up to 80% of patients. In the 6-hydroxydopamine (6-OHDA) rat model of PD, L-DOPA induces a similar phenomenon, which has been termed abnormal involuntary movement (AIM). We previously demonstrated that BMY-14802 suppresses AIM expression in this model.

Objectives

Although BMY-14802 is widely used as a sigma-1 antagonist, it is also an agonist at serotonin (5-HT) 1A and adrenergic α-1 receptors. The current study was conducted to determine which of these mechanisms underlies BMY-14802’s AIM-suppressing effect. This characterization included testing the 5-HT1A agonist buspirone and multiple sigma agents. When these studies implicated a 5-HT1A mechanism, we subsequently undertook a pharmacological reversal study, evaluating whether the 5-HT1A antagonist WAY-100635 counteracted BMY-14802’s AIM-suppressing effects.

Results

Buspirone dose-dependently suppressed AIM, supporting past findings. However, no AIM-suppressing effects were produced by drugs with effects at sigma receptors, including BD-1047, finasteride, SM-21, DTG, trans-dehydroandrosterone (DHEA), carbetapentane, and opipramol. Finally, we show for the first time that the AIM-suppressing effect of BMY-14802 was dose-dependently prevented by WAY-100635 but not by the α-1 antagonist prazosin.

Conclusions

BMY-14802 exerts its AIM-suppressing effects via a 5-HT1A agonist mechanism, similar to buspirone. Other 5-HT1A agonists have failed clinical trials, possibly due to submicromolar affinity at other receptors, including D2, which may exacerbate PD symptoms. BMY-14802 is a promising candidate for clinical trials due to its extremely low affinity for the D2 receptor and lack of extrapyramidal effects during prior clinical trials for schizophrenia.

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Authors and Affiliations

  1. Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR, 97239, USA

    Melanie A. Paquette, Charles K. Meshul & S. Paul Berger

  2. Department of Neurology, Oregon Health and Science University, Portland, OR, 97239, USA

    Melanie A. Paquette & Steven W. Johnson

  3. Department of Veterans Affairs Medical Center, 3710 SW US Veterans Hospital Road, Mail Code R&D 64, Portland, OR, 97239, USA

    Melanie A. Paquette, Katherine Foley, Elizabeth G. Brudney, Charles K. Meshul, Steven W. Johnson & S. Paul Berger

Authors
  1. Melanie A. Paquette
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  2. Katherine Foley
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  3. Elizabeth G. Brudney
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  4. Charles K. Meshul
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  5. Steven W. Johnson
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  6. S. Paul Berger
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Corresponding author

Correspondence to Melanie A. Paquette.

Additional information

Funding was provided by NIDA DA007262-16 (MAP), NINDS NS38715 (SJW), and Veterans Affairs Merit Reviews (CKM and SPB).

An erratum to this article can be found at http://dx.doi.org/10.1007/s00213-009-1522-7

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Paquette, M.A., Foley, K., Brudney, E.G. et al. The sigma-1 antagonist BMY-14802 inhibits L-DOPA-induced abnormal involuntary movements by a WAY-100635-sensitive mechanism. Psychopharmacology 204, 743–754 (2009). https://doi.org/10.1007/s00213-009-1505-8

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  • DOI: https://doi.org/10.1007/s00213-009-1505-8

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