Topiramate hyperpolarizes and modulates the slow poststimulus AHP of rat olfactory cortical neurones in vitro.
1. The effects of the novel antiepileptic drug topiramate (TPM) were investigated in rat olfactory cortex neurones in vitro using a current/voltage clamp technique. 2. In 80% of recorded cells, bath application of TPM (20 microm) reversibly hyperpolarized and inhibited neuronal repetitive firing by inducing a slow outward membrane current, accompanied by a conductance increase. The response was reproducible after washout, and was most likely carried largely by K(+) ions, although other ionic conductances may also have contributed. 3. In 90% of cells, TPM (20 microm) also enhanced and prolonged the slow (Ca(2+)-dependent) poststimulus afterhyperpolarization (sAHP) and underlying slow outward tail current (sI(AHP)). This effect was due to a selective enhancement/prolongation of an underlying L-type Ca(2+) current that was blocked by nifedipine (20 microm); the TPM response was unlikely to involve an interaction at PKA-dependent phosphorylation sites. 4. The carbonic anhydrase (CA) inhibitor acetazolamide (ACTZ, 20 microm) and the poorly membrane permeant inhibitor benzolamide (BZ, 50 microm) both mimicked the membrane effects of TPM, in generating a slow hyperpolarization (slow outward current under voltage clamp) and sAHP enhancement. ACTZ and BZ occluded the effects of TPM in generating the outward current response, but were additive in producing the sAHP modulatory effect, suggesting different underlying response mechanisms. 5. In bicarbonate/CO(2)-free, HEPES-buffered medium, all the membrane effects of TPM and ACTZ were reproducible, therefore not dependent on CA inhibition. 6. We propose that both novel effects of TPM and ACTZ exerted on cortical neurones may contribute towards their clinical effectiveness as anticonvulsants.
Russo
Emilio
E
Department of Pharmacology, The School of Pharmacy, 29/39 Brunswick Square, London WC1N 1AX.
Constanti
Andrew
A
D000086:Acetazolamide / Q000494:pharmacology; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000502:physiology; D004558:Electric Stimulation / Q000379:methods; D005260:Female; D005632:Fructose / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D012903:Smell / Q000502:physiology*; D000077236:Topiramate
D000077236:Topiramate; D005632:Fructose; D000086:Acetazolamide