ADENOSINE RECEPTOR MODULATION OF SEIZURE SUSCEPTIBILITY

Project: Research project

Description

Given the potent depressant effects of adenosine on spontaneous neuronal
firing, it has been proposed that endogenous adenosine may function as an
important modulator of neuronal activity involved in the etiology or
control of seizures. In accordance with this proposal, metabolically
stable adenosine analogs have been shown to elevate pentylenetetrazol (PTZ)
seizure threshold in rats. Moreover, the seizure suppressant effects of
adenosine analogs were antagonized by the adenosine receptor antagonist,
theophylline. This proposal describes the use of the PTZ seizure threshold
model in combination with other pharmacological, neuroanatomical and
biochemical approaches to further our understanding of the involvement of
adenosine in seizure mechanisms. An assignment of the adenosine receptor
subtype involved in seizure suppressant effects of adenosine analogs
remains to be elucidated. A rigorous pharmacological characterization of
the adenosine receptor involve in the regulation of PTZ seizure threshold
will be accomplished by determining the rank order potencies of several
adenosine analogs administered intracerebroventricularly (i.c.v.) in rats.
The rank order potencies of a series of xanthines, administered i.c.v., as
proconvulsants in the PTZ seizure threshold model will also be determined.
Possible correlations between the rank order potencies of adenosine analogs
as seizure suppressants and their affinities for adenosine A1 receptors as
labeled by (3H)cyclohexyladenosine will be explored. A delineation of the
neuroanatomic substrate for the anticonvulsant actions of adenosine analogs
is essential in attempts to elucidate the basic cellular and molecular
mechanisms involved. To this end, the effects of adenosine analogs
microinjected into various rat brain structures on PTZ seizure threshold
will be determined. A further understanding of the biochemical and
neuroanatomical mechanisms responsible for the effects of adenosine analogs
on seizure susceptibility may provide insight into one of the basic
mechanisms of seizure disorders in man.
StatusFinished
Effective start/end date7/1/866/30/91

Funding

  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $68,576.00
  • National Institutes of Health
  • National Institutes of Health

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Purinergic P1 Receptors
Seizures
Adenosine
Pentylenetetrazole
Xanthines
Pharmacology
Purinergic P1 Receptor Antagonists
Adenosine A1 Receptors
Theophylline
Anticonvulsants
Epilepsy