LONG-TERM TREATMENT WITH SOME METHYLXANTHINES DECREASES THE SUSCEPTIBILITY TO BICUCULLINE-INDUCED AND PENTYLENETETRAZOL-INDUCED SEIZURES INMICE - RELATIONSHIP TO C-FOS EXPRESSION AND RECEPTOR-BINDING
B. Johansson et al., LONG-TERM TREATMENT WITH SOME METHYLXANTHINES DECREASES THE SUSCEPTIBILITY TO BICUCULLINE-INDUCED AND PENTYLENETETRAZOL-INDUCED SEIZURES INMICE - RELATIONSHIP TO C-FOS EXPRESSION AND RECEPTOR-BINDING, European journal of neuroscience, 8(12), 1996, pp. 2447-2458
The effects of long-term oral administration of low doses of caffeine
(0.3 g/l) and its metabolites theophylline, theobromine and paraxanthi
ne (each at 0.5 g/l in drinking water) on bicuculline- and pentylenete
trazol (PTZ)-induced seizures and c-fos expression were studied in mic
e. In addition, adenosine and benzodiazepine receptor density was exam
ined. The plasma levels of the methylxanthines were much higher during
the active period at night than during the day. The maximal level of
caffeine was 14 mu M. Brain theophylline levels (8-13 nmol/g) tended t
o be higher and more constant than brain caffeine levels in caffeine-c
onsuming mice. Clonic seizures induced by bicuculline (4 mg/kg i.p.) w
ere significantly reduced in severity by 14 day caffeine treatment and
mortality was also reduced. Long-term treatment with caffeine metabol
ites was less effective. The seizures induced by PTZ (60 mg/kg i.p.) w
ere also significantly reduced by long-term caffeine treatment. After
bicuculline or PTZ treatment, c-fos mRNA expression was weaker in the
cerebral cortex in animals receiving caffeine, irrespective of whether
the animals had seizures or not. No significant changes in the bindin
g of adenosine receptor ligands or benzodiazepines were seen after lon
g-term caffeine treatment. These results show that long-term treatment
with caffeine in a dose that is commonly seen in humans decreases the
seizures induced by bicuculline, and to a lesser extent,those induced
by PTZ. This may be related to a decreased neuronal excitability. The
effect is due to the combined effects of theophylline, to which caffe
ine is metabolized in brain, and of caffeine itself, but could not be
ascribed to changes in A(1) and A(2A) adenosine or benzodiazepine rece
ptors.