|Budget Amount *help
¥1,100,000 (Direct Cost: ¥1,100,000)
Fiscal Year 1994: ¥400,000 (Direct Cost: ¥400,000)
Fiscal Year 1993: ¥700,000 (Direct Cost: ¥700,000)
The regulation of intracelluar Ca^<2+> levels might be one of the most important factors in maintaining a homestasis of neuronal function and a control for the neuropsychiatric condition. For instance, the neuronal dysfunction induced by a neurotoxin is implicated in excessive amounts of cytosolic Ca^<2+> levels (Pharmacol & Toxicol, 72 ; 229-235,1993) . Furthermore, the rat, especially SHR,shows extraordinary hyperactivity in a stressful environment (novel circumstance with 85 dB noise) , and, under such 'fear' conditions, frontal cortical and hippocampal Ca^<2+> channel activities are potentiated. The treatments of Ca antagonists improve both potentiated activities and abnormal conditions (Neurosci Res, 12 ; 346-335,1991) . These results lead us to consider the implications of intracellular Ca^<2+> modulation for the development of new classes of phychiatric drugs.
In light of the above information, we synthesized new GABA-tripeptides, Piv-l-Ser-Leu-GABA and Piv-d-Ser-Leu-GABA,which c
an modulate cytosolic Ca^<2+> levels and can improve psychiatric disorders. In in vitro studies, we examind the inhibitory effects of these peptides on 50 mM KCl and 25 muM glutamate-increased cytosolic Ca^<2+> levels. As results, the newly synthesized peptides blocked these inceases in a dose-dependent manner. The IC_<50> values of them were between 0.5 nM and 3 nM,and these value were much less than those of nicardipine, nifedipine, verapamil and diltiazem. Moreover, these peptides significantly blocked dopamine release from rat brain striatal slices evoked by 50 mM KCl, but not glutamate release from cultured cerebellar granule cells. These results suggest that the inhibitory effects of the newly synthesized peptides on Ca^<2+> channel activity can be seen not only in the postsynaptic neuron but also in the restricted presynaptic neuron. In in vivo studies, the administration of these peptides into either caudate putamen or amygdala reduced the methamphetamine induced hyperactivity in a dose-dependent manner, and its dose-dependent reduction was appeared much more clearly after injection into the caudate putamen. Considering the pass through blood-brain barrier of these new peptides, these i.p.administrations (70 mg/kg) significantly prolonged onset of pentetrazole induced convulsions in mice. Additionally, these peptides have less pharmacological action on the cardiovascular system. Thus, the synthesis of such GABA-peptides may give a key for developing a novel psychiatric drugs with less side effects on cardiovascular system. Less