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.
