|Budget Amount *help
¥1,800,000 (Direct Cost : ¥1,800,000)
Fiscal Year 1995 : ¥600,000 (Direct Cost : ¥600,000)
Fiscal Year 1994 : ¥600,000 (Direct Cost : ¥600,000)
Fiscal Year 1993 : ¥600,000 (Direct Cost : ¥600,000)
I investigated the effects of chronic treatment of NMDA receptor antagonists (ketamine or MK-801), a psychostimulant (methamphetamine) and an antidepressant (clmipramine) on the muscarinic acetylcholine receptors (mAchRs) using both receptor binding assays and behavioral pharmacological technique in mice. In the case of clomipramine, the effects on the NMDA receptors were also examined using cGMP rormation in response to NMDA receptor agonists (glutamate or NMDA) in the cerebellar slices. Chronic treatment of ketamine (0,12.5,25 or 50 mg/kg, every three days for 5 times), MK-801 (0,0.1,0.5 or 1 mg/kg, 7 daily treatment) and clomipramine (0,5,10 or 20 mg/kg, 7 daily treatment) increased [^3H] quinuclidinyl bensilate ( [^3H] QNB) binding in a dose-and administration time-dependent manner only in the forebrain. MAP had no effects on the [^3H] QNB bindings. Coadministration of haloperidol prevented the MK-801-induced increases in [^3H] QNB bindings in a dose-dependent way, indicating that the dopaminergic activating actions of NMDA antagonists can cause the NMDA receptor-induced up-regulation of mAchRs. The up-regulation induced by the NMDA receptor antagonists were associated with the reduction of behavioral sensitivity to scopolamine (0.5 or 1mg/kg). On the other hand, clomipramine did not change the sensitivity to scopolamine. These results suggest that chronic treatment with NMDA antagonists can affect the Ach transmission more than with an antidepressant clomipramine.
Chronic treatment of clomipramine (0,10 or 20 mg/kg) also resulted in a decrease in cGMP formation in response to glutamate or NMDA,indicating that the clinical efficacy of antidepressants is related to the reduction of the NMDA transmission in the brain.