|Budget Amount *help
¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 1990: ¥500,000 (Direct Cost: ¥500,000)
Fiscal Year 1989: ¥1,500,000 (Direct Cost: ¥1,500,000)
Chronic exposure to neuroleptics frequently results in the development of tolerance, that is, a decrease in responsiveness to a drug or shift to the right of the dose-response curve. In contrast to tolerance, as result of chronic treatment with Dopamine (DA) Agonists, is the phenomenon of reverse tolerance, which is an increase in responsiveness or sift to the left of the dose-response curve.
When mice were given once a day of haloperidol for 18 days and challenged with beta-DMCM (benzodiazepine (BDZ) antagonist or inverse agonist), caffeine (adenosine antagonist), picrotoxin (Cl^-channel blocker) or bicuculline (GABAa antagonist) after 1 and 2 days withdrawal, only the threshold of beta-DMCM-induced tonic convulsion was lowered. The beta-DMCM convulsion on 2 days withdrawal was reversed by diazepam (BDZ agonist) and Ro15-1788 (BDZ antagonist or partially agonist). In this case, Ro15-1788 and beta-DMCM contributed to BDZ system as an agonist and an antagonist, respectively. There is a d
irect interaction between DA and BDZ systems but is not between DA and GABA neurons, in development of lowering seizure threshold following chronic haloperidol.
Chronic haloperidol produced an inhibition of haloperidol catarepsy response, which results in an activation of postsynaptic DA D-2 receptors. The inhibitory effect was reversed by N^6-cyclohexyl adenosine (adenosine agonist), diazepam, beta-DMCM and muscimol (GABAa agonist). In striking contrast to beta-DMCM convulsion, Ro15-1788 and beta-DMCM responded as an antagonist and an agonist, respectively, in haloperidol catarepsy. These results suggest that central inhibitory systems seem to function as regulator to DA neurons in development of tolerance.
Withdrawal from chronic apomorphine (DA receptor agonist) exerted different effects from control in high dose of apomorphine-induced stereotyped behaviors, i. e., increase of sniffing (reverse tolerance) and decrease of licking and biting (tolerance). BDZ-mimetic drugs exerted differential effects to respective stereotyped behaviors. Multifocal site of action may be involved in BDZ-DA neuronal interaction in development of tolerance, to DA antagonist and reverse tolerance to DA agonist. Withdrawal apomorphine exerted inhibition of apomorphineinduced yawning, which causes in an inhibition of presynsptic DA D-2 receptor, whereas haloperidol catarepsy mediated by postsynsptic D-2 receptor activity was unaffected. Withdrawal methamphtamine produced activation of presynaptic DA D-2 receptors and inhibition of postsynaptic D-2 receptors, i. e., stimulation of both apomorphine yawning and haloperidol catarepsy responses. Less