Elsevier

Biological Psychiatry

Volume 57, Issue 12, 15 June 2005, Pages 1550-1558
Biological Psychiatry

Original article
Kappa Opioid Receptor Activation Disrupts Prepulse Inhibition of the Acoustic Startle in Rats

https://doi.org/10.1016/j.biopsych.2005.02.030Get rights and content

Background

Compelling evidence indicates that kappa opioid receptor (KOR) agonists produce perceptual distortions in animals and humans, yet the mechanism of action and clinical relevance of such effects remain unclear. Since abnormalities in preattentional functions and informational processing are hypothesized to underlie psychotic disorders, the present study has been designed to assess the role of KOR on sensorimotor gating.

Methods

The effects of the selective KOR agonist U50488 were evaluated on the behavioral paradigm of prepulse inhibition (PPI) of the acoustic startle reflex (ASR).

Results

U50488 (1.25, 2.5, and 5 mg/kg, subcutaneous [SC]) induced a dose-dependent reduction of PPI, which was efficiently prevented by the selective KOR antagonist norbinaltorphimine (nor-BNI, 10 mg/kg, SC), as well as by the atypical antipsychotic clozapine (5, 8 mg/kg, intraperitoneal [IP]) but not by the typical antipsychotic haloperidol (.1, .5 mg/kg, IP). Conversely, nor-BNI (10 mg/kg, SC) failed to reverse the PPI disruption mediated by both apomorphine (.25 mg/kg, SC) and dizocilpine (.1 mg/kg, SC).

Conclusions

Our results support a pivotal role of KOR in the regulation of preattentional functions and sensorimotor gating, pointing to these receptors as a possible neurobiological substrate especially relevant to the clusters of psychosis unresponsive to typical antipsychotics.

Section snippets

Animals

Two hundred seventy-eight male Sprague-Dawley albino rats (Harlan, Italy) weighing between 200 g and 300 g served as subjects in the present study. Rats were housed four per cage in the animal care quarters, maintained at a temperature of 22 ± 2°C on a reversed 12-hour light-dark cycle (lights went off at 7 am and on at 7 pm). Food and water were available ad libitum, and each rat was handled for 5 minutes on each of the 5 days prior to experiment to minimize stress effects. All experimental

Results

Throughout the study, no-stimulus trials data were found negligible in comparison with other startle values and nor were they affected by any drug treatment; therefore, they will not be presented here.

Discussion

The present study has shown that the administration of the potent KOR agonist U50488 induces a significant, dose-dependent reduction of PPI in rats. This effect was fully reversed by a pretreatment with the selective KOR antagonist nor-BNI, providing compelling evidence that stimulation of KOR disrupts sensorimotor gating. This result supports and complements the clinical evidence that KOR are involved in the pathophysiology of hallucinatory disorders (Pfeiffer et al 1986: Roth et al 2002:

References (73)

  • M. Leyton et al.

    The stimulation of central kappa opioid receptors decreases male sexual behavior and locomotor activity

    Brain Res

    (1992)
  • R.S. Mansbach et al.

    Prepulse inhibition of the acoustic startle response is disrupted by N-ethyl-3,4-methylenedioxyamphetamine (MDEA) in the rat

    Eur J Pharmacol

    (1989)
  • G.F. Marchesi et al.

    The therapeutic role of naltrexone in negative symptom schizophrenia

    Prog Neuropsychopharmacol Biol Psychiatry

    (1995)
  • M. Minami et al.

    Molecular biology of the opioid receptorsStructures, functions and distributions

    Neurosci Res

    (1995)
  • B. Nicol et al.

    Mu- and kappa-opioids inhibit K+ evoked glutamate release from rat cerebrocortical slices

    Neurosci Lett

    (1996)
  • W. Perry et al.

    Sensorimotor gating deficits in bipolar disorder patients with acute psychotic mania

    Biol Psychiatry

    (2001)
  • D.J. Sheffler et al.

    Salvinorin AThe “magic mint” hallucinogen finds a molecular target in the kappa opioid receptor

    Trends Pharmacol Sci

    (2003)
  • T.A. Sipes et al.

    Multiple serotonin receptor subtypes modulate prepulse inhibition of the startle response in rats

    Neuropharmacology

    (1994)
  • N.R. Swerdlow et al.

    A preliminary assessment of sensorimotor gating in patients with obsessive compulsive disorder

    Biol Psychiatry

    (1993)
  • N.R. Swerdlow et al.

    Opiate-dopamine interactions in the neural substrates of acoustic startle gating in the rat

    Prog Neuropsychopharmacol Biol Psychiatry

    (1991)
  • M. Ukai et al.

    Endomorphin-1, an endogenous mu-opioid receptor agonist, improves apomorphine-induced impairment of prepulse inhibition in mice

    Peptides

    (2003)
  • M. Akil et al.

    Lamina-specific alterations in the dopamine innervation of the prefrontal cortex in schizophrenic subjects

    Am J Psychiatry

    (1999)
  • V.P. Bakshi et al.

    Phencyclidine-induced deficits in prepulse inhibition of startle are blocked by prazosin, an alpha-1 noradrenergic antagonist

    J Pharmacol Exp Ther

    (1997)
  • V.P. Bakshi et al.

    Clozapine antagonizes phencyclidine-induced deficits in sensorimotor gating of the startle response

    J Pharmacol Exp Ther

    (1994)
  • F. Bloom et al.

    EndorphinsProfound behavioral effects on rats suggest new etiological factors in mental illness

    Science

    (1976)
  • U. Bonuccelli et al.

    Clozapine in Huntington’s chorea

    Neurology

    (1994)
  • M. Bortolato et al.

    Kappa receptors activation impairs sensorimotor gating in ratsEvidence on a new putative model of schizophrenia

    Program N. 780.12 2004 Abstract Viewer and Itinerary Planner

    (2004)
  • D.L. Braff

    Connecting the “dots” of brain dysfunction in schizophreniaWhat does the picture look like?

    Arch Gen Psychiatry

    (1999)
  • D.L. Braff et al.

    Human studies of prepulse inhibition of startleNormal subjects, patient groups, and pharmacological studies

    Psychopharmacology (Berl)

    (2001)
  • D.L. Braff et al.

    Preattentional and attentional cognitive deficits as targets for treating schizophrenia

    Psychopharmacology (Berl)

    (2004)
  • D.L. Braff et al.

    Prestimulus effects on human startle reflex in normals and schizophrenics

    Psychophysiology

    (1978)
  • F. Brambilla et al.

    Vasopressin (DDAVP) therapy in chronic schizophreniaEffects on negative symptoms and memory

    Neuropsychobiology

    (1989)
  • G. Di Chiara et al.

    Opposite effects of mu and kappa opiate agonists on dopamine release in the nucleus accumbens and in the dorsal caudate of freely moving rats

    J Pharmacol Exp Ther

    (1988)
  • L.A. Dykstra et al.

    Kappa opioids in rhesus monkeys. I. Diuresis, sedation, analgesia and discriminative stimulus effects

    J Pharmacol Exp Ther

    (1987)
  • T. Endoh et al.

    Nor-binaltorphimineA potent and selective kappa-opioid receptor antagonist with long-lasting activity in vivo

    Arch Int Pharmacodyn Ther

    (1992)
  • N.B. Farber

    The NMDA receptor hypofunction model of psychosis

    Ann N Y Acad Sci

    (2003)
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