Prepulse inhibition (PPI) of the acoustic startle response is deficient in patients with schizophrenia. In rats, PPI has been used to study the effects of drugs that alter brain dopamine (DA) and serotonin (5-HT) neurotransmission, since these systems are implicated in schizophrenia. Corticotropin-releasing factor (CRF) alters brain extracellular concentrations of DA, 5-HT, and norepinepherine (NE), and central administration of CRF has numerous behavioral effects. Preliminary data show that intracerebroventricular (IV) administration of CRF decreases PPI in both Brown Norway (BN) rats, a strain with low basal PPI, and in Wistar-Kyoto (WKY) rats, a strain with relatively high basal PPI. Experiments are designed to futher study the role of CRF in PPI in BN and WKY rats, and to examine whether the decrease in PPI caused by CRF is dependent on monoamine neurotransmission.
Specific Aim 1 is to examine the effects of a range of doses of CRF (ICV) on PPI and startle amplitude, and to examine whether peripheral administration of CRF, which activated the pituitary/adrenal axis, is sufficient to decrese PPI.
Specific Aim 2 is to examine whether administraion of a CRF antagonist (ICV) improves PPI in BN rats, and to examine whether administration of the antagonist, either prior to or following CRF administration, attenuates the effect of CRF on PPI.
Specific Aim 3 is to examine whether selective depletion of the monoamines (DA, 5-HT, or NE), or adminstration of drugs that are antagonists at DA, 5-HT or NE receptors attenuates the decrease in PPI produced by CRF.
Specific Aim 4 is to assess whether repeated CRF (ICV) results in sensitization or desensitization of the CRF-induced decrease in PPI or of the decrese in PPI caused by adminstration of the dopamine agonists, amphetamine and apomorphine. In addition to examining the effects of each treatment on PPI in both WKY and BN rats, effects of each treatment and of rat strain on startle amplitude and CRF-induced grooming willl be assessed. In the monoamine depletion studies, levels of DA, 5-HT, and NE in frontal cortex, hippocampus, nucleus accumbens and hypothalamus will be assessed by HPLC.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH065467-01A1
Application #
6573511
Study Section
Special Emphasis Panel (ZRG1-BDCN-6 (01))
Program Officer
Winsky, Lois M
Project Start
2002-12-01
Project End
2003-11-30
Budget Start
2002-12-01
Budget End
2003-11-30
Support Year
1
Fiscal Year
2003
Total Cost
$288,400
Indirect Cost
Name
University of California San Diego
Department
Pharmacology
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Conti, Lisa H (2012) Interactions between corticotropin-releasing factor and the serotonin 1A receptor system on acoustic startle amplitude and prepulse inhibition of the startle response in two rat strains. Neuropharmacology 62:256-63
Sutherland, Jane E; Conti, Lisa H (2011) Restraint stress-induced reduction in prepulse inhibition in Brown Norway rats: role of the CRF2 receptor. Neuropharmacology 60:561-71
Sutherland, Jane E; Burian, Linda C; Covault, Jonathan et al. (2010) The effect of restraint stress on prepulse inhibition and on corticotropin-releasing factor (CRF) and CRF receptor gene expression in Wistar-Kyoto and Brown Norway rats. Pharmacol Biochem Behav 97:227-38
Conti, Lisa H; Sutherland, Jane E; Muhlhauser, Carey M (2009) Interaction between the effects of corticotropin-releasing factor and prepulse parameters on prepulse inhibition in two inbred rat strains and the F1 generation of a cross between them. Behav Brain Res 200:165-72
Sutherland, Jane E; Page, Michelle E; Conti, Lisa H (2008) The effect of corticotropin-releasing factor on prepulse inhibition is independent of serotonin in Brown Norway and Wistar-Kyoto rats. Pharmacol Biochem Behav 89:324-37
Conti, Lisa H; Berridge, Craig W; Tayler, Jane E (2006) Both corticotropin-releasing factor and apomorphine reduce prepulse inhibition following repeated central infusion of corticotropin-releasing factor. Pharmacol Biochem Behav 85:261-72
Conti, Lisa H (2005) Characterization of the effects of corticotropin-releasing factor on prepulse inhibition of the acoustic startle response in Brown Norway and Wistar-Kyoto rats. Eur J Pharmacol 507:125-34
Conti, Lisa H; Costill, Jennifer E; Flynn, Sean et al. (2005) Effects of a typical and an atypical antipsychotic on the disruption of prepulse inhibition caused by corticotropin-releasing factor and by rat strain. Behav Neurosci 119:1052-60