|Budget Amount *help
¥3,400,000 (Direct Cost : ¥3,400,000)
Fiscal Year 2000 : ¥500,000 (Direct Cost : ¥500,000)
Fiscal Year 1999 : ¥900,000 (Direct Cost : ¥900,000)
Fiscal Year 1998 : ¥2,000,000 (Direct Cost : ¥2,000,000)
The disruption of prepulse inhibiton of acoustic startle (PPI) is an animal model for some aspects of schizophrenia. Phencyclidine causes psychotomimetic symptoms in human and disrupts PPI in animals, however, the mechanism underlying this disruption remains unclear.
In the first experiment, Dopamine and 3,4-dihydroxy phenylacetic acid (DOPAC) levels in discrete regions and apomorphine- or (-)-sulpiride- induced changes in electrically evoked dopamine release from nucleus accumbens slices were assessed after testing prepulse inhibition of acoustic startle (PPI) in rats. Dopamine and DOPAC levels in the nucleus accumbens, but not in the striatum, correlated well with PPI (r=-0.64 for dopamine, r=-0.48 for DOPAC). Evoked dopamine release from the nucleus accumbens did not differ between high-PPI (more than 60 %) and low-PPI (less than 40 %) group. When slices were superfused with 1 mM apomorphine, the S2/S1 ratio in rats showing high PPI was 0.77±0.02 (mean±SEM, 66% of control), significa
ntly smaller than in the low-PPI group (S2/S1 ratio=0.97±0.08, 94% of control, P<0.05). Moreover, (-)-sulpiride-induced increase in evoked dopamine release from the nucleus accumbens in the high-PPI group was inclined to be greater than in the low-PPI group. The results suggest that PPI differences between individuals may reflect the sensitivity of release-modulating dopamine autoreceptors in the nucleus accumbens.
In the second experiment, we tested the hypothesis that serotonin 2A receptor blocking property of drugs reverses the phencyclidine-induced PPI disruption. The ED50 value of spiperone, haloperidol, chlorpromazine, clozapine, risperidone, olanzapine, seroquel, pipamperone, mianserin or desipramine to reverse the phencyclidine- or apomorphine-induced PPI disruption in rat was determined. Then the correlation between the ED50 value and the affinity for the serotonin 2A, 2C, dopamine D2, or a-1 receptor of each drug was examined.
The ED50 value of the drugs to reverse the phencyclidine- induced PPI disruption was significantly correlated with the affinity for the serotonin 2A receptor, but not for the dopamine D2, serotonin 2C or a- 1 receptor of each drug. In contrast, the ED50 value of the drugs to reverse the apomorphine- induced PPI disruption was significantly correlated with the affinity for the dopamine D2 receptor, but not for the serotonin 2A receptor. These data indicate that an activation of serotonin 2A receptors would mediate the phencyclidine-induced PPI disruption.
All the data taken in the present project indicate that PCP-induced disruption would be caused by the stimulation of serotonergic system which was independent to dopaminergic system and be a suseful tool for investigating the pathophysiology of non-dopamine psychosis. Less