Effects of neurosteroids on epileptiform activity induced by picrotoxin and 4-aminopyridine in the rat hippocampal slice.
The neurosteroids allopregnanolone (5alpha-pregnan-3alpha-ol-20-one; 5alpha,3alpha-P) and its 5beta-epimer pregnanolone (5beta,3alpha-P), and pregnenolone sulfate (PS) were examined for effects on spontaneous epileptiform discharges induced by 100 microM picrotoxin (PTX) and 55 microM 4-aminopyridine (4-AP) in the CA3 region of the rat hippocampal slice. At a concentration of 10 microM, 5alpha,3alpha-P partially reduced PTX-induced bursting and at 30 and 90 microM completely suppressed bursting. In contrast, 100 microM 5beta,3alpha-P failed to alter the discharge frequency. 5alpha,3alpha-P depressed 4-AP-induced bursting with similar potency as in the PTX model; 100 microM 5beta,3alpha-P was also partially effective. In the 4-AP model, 5alpha,3alpha-P inhibited both the more frequent predominantly positive-going potentials as well as the less frequent negative-going potentials that may be generated by synchronous GABAergic interneuron firing. PS enhanced the PTX bursting frequency and, in the 4-AP model, increased the frequency of negative potentials but did not alter the frequency of positive potentials. By itself, PS did not induce bursting. The effects of the steroids in the in vitro seizure models largely correspond with their activities on GABA(A) receptors; suppression of discharges may occur as a result of direct activation of these receptors rather than modulation of GABA-mediated synaptic responses. PTX and 4-AP-induced bursting in the hippocampal slice are useful models for directly assessing neurosteroid effects on seizure susceptibility under conditions that eliminate the factor of brain bioavailability.
Salazar
Patricia
P
Epilepsy Research Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, 49 Convent Drive Room 5A75 MSC 4457, Bethesda, MD 20892-4457, USA.
Tapia
Ricardo
R
Rogawski
Michael A
MA
D015761:4-Aminopyridine / Q000633:toxicity*; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology; D006624:Hippocampus / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D010852:Picrotoxin / Q000633:toxicity*; D011280:Pregnanolone / Q000494:pharmacology* / Q000627:therapeutic use; D011284:Pregnenolone / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats
D015761:4-Aminopyridine; D010852:Picrotoxin; D011280:Pregnanolone; D011284:Pregnenolone; C018370:pregnenolone sulfate