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Cerebellar cyclic GMP in p,p'-DDT myoclonus: effects of antimyoclonic agents
Abstract:
The relationship of DDT myoclonus and antimyoclonic agents to the concentration of cGMP in the cerebellum was investigated. Intragastric administration of 600 mg/kg DDT increased mouse cerebellar cGMP levels about 4 fold. Antimyoclonic agents, such as L-5HTP plus fluoxetine, clonazepam, phenoxybenzamine, prostaglandin E2 and harmaline, all counteracted the elevation of cerebellar cGMP induced by DDT. Cinnanserin, a 5-HT receptor blocker, did not counteract the reduction of cerebellar cGMP produced by L-5HTP plus fluoxetine, clonazepam, and phenoxybenzamine, although cinnanserin abolished the antimyoclonic actions of these agents. Destruction of the inferior olive-climbing fiber pathway by 3-acetylpyridine in rats did not prevent the elevation of cerebellar cGMP levels by DDT. L-5HTP, clonazepam and phenoxybenzamine still significantly counteracted DDT-induced elevation of cerebellar cGMP levels in the inferior olive lesioned rats, although these agents no longer had any antimyoclonic action in these animals. These data indicate that 1) DDT-induced elevation of cerebellar cGMP and DDT-induced myoclonus are not related, and 2) antimyoclonic agents counteract DDT-induced elevation of cerebellar cGMP levels via pathways other than the olivo-cerebellar tract.
Insights
DDT exposure increases cerebellar cGMP levels in mice. Antimyoclonic drugs counteract this increase, but not through the olivo-cerebellar pathway, suggesting separate mechanisms for myoclonus and cGMP changes.
Area of Science:
- Neuroscience
- Pharmacology
- Toxicology
Background:
- DDT (dichlorodiphenyltrichloroethane) is an insecticide known to cause neurological effects, including myoclonus.
- Cyclic guanosine monophosphate (cGMP) is a key second messenger in the central nervous system, particularly in cerebellar function.
- The precise mechanisms linking DDT-induced myoclonus, cerebellar cGMP levels, and the action of antimyoclonic agents remain unclear.
Purpose of the Study:
- To investigate the relationship between DDT-induced myoclonus and cerebellar cGMP concentrations.
- To determine if antimyoclonic agents counteract DDT-induced elevations in cerebellar cGMP.
- To elucidate the pathways involved in the antimyoclonic effects of these agents on cerebellar cGMP.
Main Methods:
- Mice were administered DDT (600 mg/kg) intragastrically to measure cerebellar cGMP levels.
- The effects of various antimyoclonic agents (L-5HTP plus fluoxetine, clonazepam, phenoxybenzamine, prostaglandin E2, harmaline) on DDT-induced cGMP elevation were assessed.
- The role of the inferior olive-climbing fiber pathway was examined in rats with lesions induced by 3-acetylpyridine.
Main Results:
- DDT administration significantly increased cerebellar cGMP levels approximately fourfold.
- Several antimyoclonic agents successfully counteracted the DDT-induced rise in cerebellar cGMP.
- Cinnanserin, a 5-HT receptor blocker, blocked the antimyoclonic actions but not the cGMP modulation by certain agents.
- Lesioning the inferior olive-climbing fiber pathway did not prevent DDT-induced cGMP elevation, and antimyoclonic agents still affected cGMP levels in these lesioned animals, despite losing their antimyoclonic effect.
Conclusions:
- DDT-induced elevation of cerebellar cGMP is dissociated from DDT-induced myoclonus.
- Antimyoclonic agents counteract DDT-induced cerebellar cGMP increases through mechanisms independent of the olivo-cerebellar tract.