At the basic level, this renewal of a Type II ADAMHA Research Scientist Development Award assesses the involvement of limbic serotonergic and dopaminergic pathways in rats in the modulation of behavioral responsiveness to environmental stimuli. At the preclinical interface, experiments are proposed to clarify deficits in sensorimotor gating and habituation observed in schizophrenic patients and to further develop po- tentially related animal models derived from the basic studies. Schizophrenic patients, exhibit deficits in prepulse inhibition of startle, a measure of sensorimotor gating, and in the habituation of startle. Using electromyographic measures of the blink reflex, the proposed studies will: compare prepulse inhibition and habituation functions in the same patients; assess these deficits using both acoustic and tactile stimuli; examine unmedicated schizophrenics; and test the suggested involvement of dopamine in sensorimotor gating by testing normal subjects after the administration of methylphenidate. In rats, prepulse inhibition of startle is reduced by dopamine agonists, apparently by activating mesolimbic dopamine systems. These effects may provide an animal model of the schizophrenic deficit in sensorimotor gating. The dopamine influences on prepulse inhibition in rats will be clarified by examining dopamine receptor specificity and identifying the relevant anatomical pathways. In rats, startle habituation is decreased by serotonin agonists and increased by serotonin antagonists. Studies using a behavioral pattern monitor which provides a detailed profile of investigatory and locomotor behaviors, reveal that serotonin agonists similarly potentiate other measures of responsiveness to environmental stimuli. These serotonin agonist effects may provide a model of the schizophrenic deficit in habituation. To identify the receptor subtypes and specific pathways involved in this serotonergic modulation of sensorimotor responsivity, rats will be tested in startle and investigatory response paradigms after serotonin agonists, antagonists, releasing drugs, their combinations, or regionally specific serotonergic lesions. The candidate's professional growth will be fostered by participation in graduate within the Department of Psychiatry and direct involvement in research with psychiatric patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02MH000188-10
Application #
3069620
Study Section
Research Scientist Development Review Committee (MHK)
Project Start
1989-09-01
Project End
1994-08-31
Budget Start
1993-09-01
Budget End
1994-08-31
Support Year
10
Fiscal Year
1993
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Geyer, M A; Krebs, K M (1994) Serotonin receptor involvement in an animal model of the acute effects of hallucinogens. NIDA Res Monogr 146:124-56
Markou, A; Matthews, K; Overstreet, D H et al. (1994) Flinders resistant hypocholinergic rats exhibit startle sensitization and reduced startle thresholds. Biol Psychiatry 36:680-8
Sipes, T A; Geyer, M A (1994) Multiple serotonin receptor subtypes modulate prepulse inhibition of the startle response in rats. Neuropharmacology 33:441-8
Paulus, M P; Geyer, M A; Braff, D L (1994) The assessment of sequential response organization in schizophrenic and control subjects. Prog Neuropsychopharmacol Biol Psychiatry 18:1169-85
Paulus, M P; Geyer, M A (1993) Quantitative assessment of the microstructure of rat behavior: I, f(d), the extension of the scaling hypothesis. Psychopharmacology (Berl) 113:177-86
Swerdlow, N R; Benbow, C H; Zisook, S et al. (1993) A preliminary assessment of sensorimotor gating in patients with obsessive compulsive disorder. Biol Psychiatry 33:298-301
Swerdlow, N R; Geyer, M A (1993) Prepulse inhibition of acoustic startle in rats after lesions of the pedunculopontine tegmental nucleus. Behav Neurosci 107:104-17
Rempel, N L; Callaway, C W; Geyer, M A (1993) Serotonin1B receptor activation mimics behavioral effects of presynaptic serotonin release. Neuropsychopharmacology 8:201-11
Swerdlow, N R; Auerbach, P; Monroe, S M et al. (1993) Men are more inhibited than women by weak prepulses. Biol Psychiatry 34:253-60
Cadenhead, K S; Geyer, M A; Braff, D L (1993) Impaired startle prepulse inhibition and habituation in patients with schizotypal personality disorder. Am J Psychiatry 150:1862-7

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