Psychopharmacology

, Volume 204, Issue 4, pp 743–754 | Cite as

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

  • Melanie A. Paquette
  • Katherine Foley
  • Elizabeth G. Brudney
  • Charles K. Meshul
  • Steven W. Johnson
  • S. Paul Berger
Original Investigation

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.

Keywords

BMY-14802 Buspirone 5-HT1A 6-hydroxydopamine L-DOPA-induced dyskinesia Parkinson’s disease Rat Sigma 

Notes

Conflict of interest

No conflicts of interest are present.

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Copyright information

© Springer-Verlag 2009

Authors and Affiliations

  • Melanie A. Paquette
    • 1
    • 2
    • 3
  • Katherine Foley
    • 3
  • Elizabeth G. Brudney
    • 3
  • Charles K. Meshul
    • 1
    • 3
  • Steven W. Johnson
    • 2
    • 3
  • S. Paul Berger
    • 1
    • 3
  1. 1.Department of Behavioral NeuroscienceOregon Health and Science UniversityPortlandUSA
  2. 2.Department of NeurologyOregon Health and Science UniversityPortlandUSA
  3. 3.Department of Veterans Affairs Medical CenterPortlandUSA

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