Effectiveness of alpha 2-adrenergic receptor stimulation in reducing the central toxicity following cholinesterase inhibition.
Previous studies in this laboratory have demonstrated that the centrally-acting alpha 2-adrenergic agonist clonidine can offer significant protection against both the acute and chronic toxicity following irreversible cholinesterase inactivation with soman. The purpose of this study was to estimate the contribution of central mechanisms to soman toxicity in a rat model; and to determine the effectiveness of clonidine and a series of related agonists to offer protection against the acute and chronic manifestations of this toxicity. To investigate the central component of soman toxicity, animals were pretreated with the peripherally selective reversible cholinesterase inhibitor pyridostigmine, a standard protective agent. Pyridostigmine pretreatment resulted in significant improvement in survival following soman administration. However, pyridostigmine was not able to inhibit the signs of central soman toxicity, including convulsive behavior. Clonidine and several related drugs produced both a further reduction in lethality and a significant reduction in the central signs of soman toxicity. Signs of delayed toxicity to soman were apparent in rats surviving 48 h after administration as measured in open-field locomotor monitoring. Again, pyridostigmine did not offer protection against such delayed toxicity. When clonidine was included in the regimen, however, significant improvement in performance in this measure was observed. These results are consistent with our earlier findings of significant protection provided by clonidine and related drugs against acute and chronic manifestations of soman toxicity and provide further evidence that 1) central toxicity is an important contributor to soman's actions, and 2) stimulation of central alpha 2-adrenergic receptors limits the expression of this central toxicity.
Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta 30912.
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Buccafusco
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D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000378:metabolism*; D003000:Clonidine / Q000031:analogs & derivatives / Q000494:pharmacology; D003975:Diazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006143:Guanabenz / Q000494:pharmacology; D016316:Guanfacine / Q000494:pharmacology; D007928:Lethal Dose 50; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D011729:Pyridostigmine Bromide / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012999:Soman / Q000633:toxicity*
D000316:Adrenergic alpha-Agonists; D002800:Cholinesterase Inhibitors; D016316:Guanfacine; D012999:Soman; D006143:Guanabenz; D011729:Pyridostigmine Bromide; D003000:Clonidine; D003975:Diazepam; C025655:lofexidine