Adenosine receptor modulation of seizure susceptibility in rats Public Deposited

http://ir.library.oregonstate.edu/concern/graduate_thesis_or_dissertations/s7526g99n

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  • Adenosine is considered to be a neuromodulator or cotransmitter in the periphery and CNS. This neuromodulatory action of adenosine may be observed as an anticonvulsant effect. Dose-response curves for R-phenylisopropyladenosine (PIA), cyclohexyladenosine (CHA), 2-chloroadenosine (2-ClAdo), Nethylcarboxamidoadenosine (NECA) and S-PIA were generated against PTZ seizure thresholds in the rat. The rank order of potency for adenosine agonists to elevate PTZ seizure threshold was R-PIA > 2-ClAdo > NECA > CHA > S-PIA. R-PIA was approximately 80-fold more potent than S-PIA. This 80-fold difference in potency between the the diasteriomers of PIA was consistent with an A₁ adenosine receptor-mediated response. The anticonvulsant action of 2-ClAdo was reversed by pretreatment with theophylline. Theophylline alone produced a proconvulsant effect on PTZ seizure thresholds. This anticonvulsant action of 2-ClAdo and the proconvulsant effect of theophylline were observed with other chemoconvulsants such as bicuculline (BIC) and picrotoxinin (PTX). The respective ED₅₀ values for 2-ClAdo and theophylline were similar regardless of the chemoconvulsant used. The inability of theophylline to antagonize the anticonvulsant action of diazepam and pentobarbital demonstrates the selectivity of the anticonvulsant effect of 2-ClAdo. 2-ClAdo-induced elevation of BIC seizure threshold was not antagonized by the benzodiazepine antagonists RO 15-1788 and CGS 8216, establishing the specificity of 2-ClAdo as an adenosine receptor agonist. Chronic administration of theophylline significantly increased the specific binding of ³H-cyclohexyladenosine in membranes of the cerebral cortex and cerebellum of the rat. Chronic exposure to theophylline produced a significant increase in the densities of both the high- and low-affinity forms of A₁ adenosine receptors in the cerebral cortex. The high- and lowaffinity dissociation constants obtained from theophyllineexposed membranes of the cerebral cortex did not differ significantly from the corresponding values in saline-treated animals. Qualitatively and quantitatively similar results were observed in cerebellar membranes. Chronic exposure to theophylline resulted in significant increases in the doses of PTZ, BIC and PTX required to elicit a clonic convulsion. Thus, these results suggest that the reduced susceptibility to seizures induced by a chronic theophylline regimen represents a functional correlate of the upregulation of the A₁ adenosine receptor.
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  • description.provenance : Approved for entry into archive by Patricia Black(patricia.black@oregonstate.edu) on 2013-07-19T18:46:13Z (GMT) No. of bitstreams: 1 SzotPatricia1988.pdf: 798595 bytes, checksum: 9185eac18666d412f7161abc493e9599 (MD5)
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