This application for an ADAMHA Research Scientist Award follow,s ten years of NIMH support via the Type II Research Scientist Development Award. At the basic level, the project assesses the involvement of limbic dopaminergic, glutamatergic, and serotonergic systems in rats in the modulation of behavioral responsiveness to environmental stimuli. At the preclinical interface, the proposed experiments will further characterize deficits in sensorimotor gating and habituation observed in schizophrenic patients and extend related animal models derived from the basic studies. Schizophrenic patients exhibit deficits in prepulse inhibition of startle, gating of P3O event-related potentials, and habituation of startle. The proposed studies will: compare prepulse inhibition, P5O gating, and habituation functions in the same patients; relate these deficits to several clinical factors; and examine unmedicated schizophrenics, family members of schizophrenics, and schizotypal patients. In rats, prepulse inhibition of startle is reduced by D2 dopaminergic activation and by related manipulations of neuronal circuitry involving the hippo-campus, nucleus accumbens, ventral pallidum, and pedunculopontine nucleus. Prepulse inhibition is also disrupted by direct and indirect serotonin agonists, non-competitive antagonists at the N-methyl-d-aspartate receptor complex, and isolation rearing. The proposed studies will examine the psychopharmacology and neurobiological substrates relevant to this animal model of the schizophrenic deficit in sensorimotor gating. In rats, startle habituation is deceased by serotonin agonists and increased by serotonin antagonists. These serotonin agonist effects may provide a model of the schizophrenic deficit in habituation. Studies using a behavioral pattern monitor which provides a detailed profile of investigatory and locomotor behaviors, reveals that direct serotonin agonists similarly potentiate other measures of responsiveness to environmental stimuli. The release of presynaptic serotonin by indirect agonists reduces investigatory behavior while increasing locomotor activity. A variety of manipulations of serotonergic systems in rats are proposed to identify the receptor subtypes and, pathways involved in the serotonergic modulation of sensorimotor responsivity and behavioral activity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Scientist Award (K05)
Project #
5K05MH001223-05
Application #
2674406
Study Section
Clinical Neuroscience Review Committee (CNR)
Project Start
1994-09-30
Project End
1999-12-31
Budget Start
1998-05-01
Budget End
1999-12-31
Support Year
5
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Psychiatry
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Light, G A; Geyer, M A; Clementz, B A et al. (2000) Normal P50 suppression in schizophrenia patients treated with atypical antipsychotic medications. Am J Psychiatry 157:767-71
Perry, W; Geyer, M A; Braff, D L (1999) Sensorimotor gating and thought disturbance measured in close temporal proximity in schizophrenic patients. Arch Gen Psychiatry 56:277-81
Bakshi, V P; Geyer, M A (1999) Alpha-1-adrenergic receptors mediate sensorimotor gating deficits produced by intracerebral dizocilpine administration in rats. Neuroscience 92:113-21
Bakshi, V P; Geyer, M A (1999) Ontogeny of isolation rearing-induced deficits in sensorimotor gating in rats. Physiol Behav 67:385-92
Geyer, M A; Swerdlow, N R; Lehmann-Masten, V et al. (1999) Effects of LU-111995 in three models of disrupted prepulse inhibition in rats. J Pharmacol Exp Ther 290:716-24
Braff, D L; Swerdlow, N R; Geyer, M A (1999) Symptom correlates of prepulse inhibition deficits in male schizophrenic patients. Am J Psychiatry 156:596-602
Bakshi, V P; Swerdlow, N R; Braff, D L et al. (1998) Reversal of isolation rearing-induced deficits in prepulse inhibition by Seroquel and olanzapine. Biol Psychiatry 43:436-45
Geyer, M A (1998) Behavioral studies of hallucinogenic drugs in animals: implications for schizophrenia research. Pharmacopsychiatry 31 Suppl 2:73-9
Krebs-Thomson, K; Paulus, M P; Geyer, M A (1998) Effects of hallucinogens on locomotor and investigatory activity and patterns: influence of 5-HT2A and 5-HT2C receptors. Neuropsychopharmacology 18:339-51
Bakshi, V P; Geyer, M A (1998) Multiple limbic regions mediate the disruption of prepulse inhibition produced in rats by the noncompetitive NMDA antagonist dizocilpine. J Neurosci 18:8394-401

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