Phencyclidine and auditory sensory gating in the hippocampus of the rat

doi:10.1016/0028-3908(92)90106-Y

Neuropharmacology

Volume 31, Issue 10, October 1992, Pages 1041-1048

https://doi.org/10.1016/0028-3908(92)90106-Y Get rights and content

Abstract

The psychotomimetic drug 1-(1-phenylcyclohexyl) piperidine (PCP, phencyclidine) was found to cause a deficit in the gating of the response of the hippocampal neuron to repeated auditory stimuli, which is similar to a particular physiological feature observed in human psychosis. Other drugs, with sigma agonist and/or $N- methyl - D - aspartate$ (NMDA) antagonist effects, were administered and their ability to cause a loss of auditory gating was compared to that of PCP. The rank order of effectiveness was levoxodrol > PCP and (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine maleate (MK-801) > N-allylnormetazocine (SKF 10047) > dexoxodrol > 3-(±)2-carboxypiperazine-4-yl) propyl-1-phosphonate (CPP). Further studies of two of the drugs, PCP and MK-801, showed that selective lesioning of the noradrenergic input with the neurotoxin DSP4, as well as less selective depletion of monoamines with reserpine, blocked the loss of gating. Phencyclidine, and other drugs with the same spectrum of action, most likely disrupt gating by increasing noradrenergic activity through a sigma mechanism.

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Citation Excerpt :
We have shown that low doses (3–6 mg/kg s.c.) of ketamine induced a deficit in prepulse inhibition (PPI) and locomotor hyperactivity, and these psychosis-relevant behaviors were accompanied by a robust increase in gamma-frequency (30–100 Hz) local field potentials (LFPs) in the hippocampus [14,15]. In addition, ketamine and similar drugs also induced a decrease in sensory gating, measured by paired-pulse auditory evoked potentials in the hippocampus [16–18]. Medial septal inactivation, or selective lesion of septal GABAergic neurons, normalized both the electrophysiological and behavioral changes induced by ketamine [15,17,18].
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Modeling schizophrenia in animals represents a formidable challenge because the most characteristic symptoms of this disorder, auditory hallucinations and delusional beliefs, cannot be directly modeled in animals. Furthermore, limited current understanding of the etiology and pathophysiology underlying the clinical features of this disorder greatly hinders the ability to develop valid models based on those aspects. To circumvent these issues, investigators have attempted to recreate the leading candidate biochemical, neuroanatomical, and genetic abnormalities for this disorder in animals using pharmacological, developmental, neurotoxic, genetic engineering, and other methods. The validity of these animal preparations as animal models for schizophrenia is generally based upon the extent to which they induce measurable behavioral changes that are homologous or analogous to the core clinical features or the information processing endophenotypes (presymptom phenotypes) that are seen in schizophrenia. The utility of any animal model to serve as a screen for novel treatments is considered related to the extent to which the schizophrenia-relevant behaviors it exhibits can be ameliorated by drugs with known efficacy in schizophrenia but not by drugs known to be therapeutic for brain disorders other than schizophrenia.
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Phencyclidine and auditory sensory gating in the hippocampus of the rat

Abstract

Biol. Psychiat.

J. Psychiat. Res.

Biol. Psychiat.

Neuropharmacology

Eur. J. Pharmac.

Eur. J. Pharmac.

Trends Neurosci.

Electroenceph. clin. Neurophysiol.

Electroenceph. clin. Neurophysiol.

Biol. Psychiat.

Schizophrenia Res.

Electroenceph. clin. Neurophysiol.

Brain Res.

Eur. J. Pharmac.

Biol. Psychiat.

Neuropharmacology

Brain Res.

Electroenceph. clin. Neurophysiol.

Eur. J. Pharmac.

Alcohol

Brain Res.

Sensory physiology and catecholamines in schizophrenia and mania

Psychiat. Res.

Sensorimotor gating and schizophrenia: Human and animal model studies

Archs gen. Psychiat.

Prestimulus effects on human startle reflex in normals and schizophrenics

Psychophysiology

Sigma receptors regulate contractions of the guinea pig ileum longitudinal muscle/myenteric plexus preparation elicited by both electrical stimulation and exogenous serotonin

J. Neurosci.

The current status of the dopamine hypothesis of schizophrenia

Neuropsychopharmacology

Rate of stimulus repetition changes evoked potential amplitude

Expl Brain Res.

Central symphathomimetic activity of (+)-5-methyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine (MK-801), a substance with potent anticovulsant, central sympathomimetic, and apparent anxiolytic properties

Drug. Dev. Res.