Abstract
Prepulse inhibition (PPI) is a form of plasticity of the startle response in which presentation of a weak stimulus immediately before an intense startling stimulus reduces the resultant startle response. Deficits in PPI, an operational measure of sensorimotor gating, are observed in schizophrenia patients and can be modeled in rats by the psychotogen phencyclidine (PCP). PCP-induced deficits in PPI in rats are resistant to dopamine and serotonin antagonists but can be antagonized by antipsychotics such as clozapine, olanzapine and Seroquel. These latter antipsychotics have antagonistic actions at several receptors, including alpha-1 and alpha-2 adrenergic, M1 muscarinic and γ-aminobutyric acid (GABA)-A receptors. Although the direct actions of PCP are thought to be mediated by noncompetitive antagonism of N-methyl-D-aspartate sites, PCP thereby indirectly activates multiple neurotransmitter systems, including those affected by the aforementioned antipsychotics. The present studies examined the possibility that an antagonist action at a particular receptor subtype might be responsible for the interaction between PCP and the clozapine-like antipsychotics by testing whether a selective antagonist at alpha-1, alpha-2, M1 or GABA-A receptors would prevent the PCP-induced deficit in PPI in rats. Animals were pretreated with either the alpha-1 antagonist prazosin (0, 0.5, 1.0 or 2.5 mg/kg), the alpha-2 antagonist RX821002 (0, 0.2 or 0.4 mg/kg), the M1 muscarinic antagonist pirenzepine (0, 10 or 30 mg/kg) or the GABA-A antagonist pitrazepin (0, 1.0 or 3.0 mg/kg) and then treated with either saline or PCP (1.5 mg/kg). Because prazosin was effective in blocking the effects of PCP, an additional experiment tested the possibility that prazosin (0, 1.0 or 2.5 mg/kg) would block the PPI deficits produced by the dopamine agonist apomorphine (0 or 0.5 mg/kg). After drug administration, animals were tested in startle chambers. PCP was found repeatedly to decrease PPI. Prazosin (1.0 and 2.5 mg/kg) blocked this deficit in two separate experiments but did not increase base-line PPI levels. The effects on PPI were dissociable from changes in startle reactivity. Furthermore, prazosin did not antagonize apomorphine-induced disruptions of PPI, which suggests that the antagonism of the PCP effect was not simply due to a generalized improvement of deficient PPI. The antagonists foralpha-2, for M1 and for GABA-A receptors had no effect on base-line PPI or on PCP-induced disruptions in PPI. These findings indicate that the PPI-disruptive effect of PCP may be mediated in part by alpha-1 adrenergic receptors and that antagonism ofalpha-1 receptors may play a major role in mediating the blockade of PCP-induced deficits in PPI by certain antipsychotics.
Footnotes
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Send reprint requests to: Mark A. Geyer, Department of Psychiatry, 0804, University of California at San Diego, La Jolla, CA 92093-0804.
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↵1 This work was supported in part by Grant MH42228 from the National Institute of Mental Health and Grant DA02925 from the National Institute on Drug Abuse.
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↵2 Supported by Grant F31-MH11636 from the National Institute of Mental Health.
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↵3 Supported by a Research Scientist Award (K05-MH01223) from the National Institute of Mental Health.
- Abbreviations:
- PCP
- phencyclidine
- PPI
- prepulse inhibition
- NMDA
- N-methyl-D-aspartate
- DA
- dopamine
- NE
- norepinephrine
- 5-HT
- serotonin
- GABA
- γ-aminobutyric acid
- M1
- muscarinic 1
- AAALAC
- Association for the Assessment and Accreditation of Laboratory Animal Care
- Received March 6, 1997.
- Accepted July 25, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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