Elsevier

Neuroscience Letters

Volume 382, Issues 1–2, 1–8 July 2005, Pages 134-138
Neuroscience Letters

The paradoxical effects of SKF83959, a novel dopamine D1-like receptor agonist, in the rat acoustic startle reflex paradigm

https://doi.org/10.1016/j.neulet.2005.03.001Get rights and content

Abstract

While the benzazepine SKF83959 elicits classical behavioral responses associated with dopamine D1 receptors, it also acts as a D1 receptor antagonist biochemically. The paradoxical properties of this agent remain an enigma. In the present study, we sought to determine the behavioral effects of SKF83959 in the rat acoustic startle reflex test. Systemic administration of SKF83959 produced a dose-related increase in the startle amplitude with a stimulus of 105 dB, and a significant group difference was observed between animals treated with 1 mg/kg SKF83959 and vehicle controls. SKF83959 also significantly reduced the latency to startle response to stimuli of 95 dB and 105 dB in a dose-dependent manner. However, unlike classical dopamine D1-like receptor agonists, SKF83959 failed to disrupt prepulse inhibition (PPI) of either the startle amplitude or the latency to startle response; rather, the agent dose-dependently increased the PPI latency to startle response of 105 dB stimulus. These results suggest that the behavioral effects of SKF83959 in the rat acoustic startle reflex paradigm are paradoxical, and these paradoxical effects may be associated with its distinct pharmacological properties.

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Acknowledgments

Zhang-Jin Zhang gratefully acknowledges the support of Theodore and Vada Stanley and the Stanley Medical Research Institute, Bethesda, MD, USA.

References (34)

  • D.R. Sibley et al.

    Molecular neurobiology of dopaminergic receptors

    Int. Rev. Neurobiol.

    (1993)
  • T.E. Sipes et al.

    DOI disrupts prepulse inhibition of startle in rats via 5-HT2A receptors in the ventral pallidum

    Brain Res.

    (1997)
  • F.J. Wan et al.

    Do D1/D2 interactions regulate prepulse inhibition in rats?

    Neuropsychopharmacology

    (1996)
  • A.M. Deveney et al.

    Pharmacological characterization of behavioural responses to SK&F 83959 in relation to ‘D1-like’ dopamine receptors not linked to adenylyl cyclase

    Br. J. Pharmacol.

    (1995)
  • D. Feifel et al.

    A systemically administered neurotensin agonist blocks disruption of prepulse inhibition produced by a serotonin-2A agonist

    Neuropsychopharmacology

    (2003)
  • P.L. Gendreau et al.

    D1 dopamine receptor mediation of social and nonsocial emotional reactivity in mice: effects of housing and strain difference in motor activity

    Behav. Neurosci.

    (1997)
  • M.K. Gordon et al.

    Lasting effect of repeated cocaine administration on acoustic and fear-potentiated startle in rats

    Psychopharmacology (Berl.)

    (1999)
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