The effects of GABA receptor agonists and benzodiazepines on the minimal neurotoxicity and anticonvulsant activity of barbiturates in mice.

The effects of GABAa (progabide and THIP) or BABAb (baclofen) receptor agonists and benzodiazepines (diazepam and nitrazepam) on the minimal neurotoxicity and anticonvulsant activity of pentobarbital and phenobarbital in mice were investigated. When progabide, THIP, baclofen, diazepam, or nitrazepam was administered with pentobarbital the individual component (dose) of these drugs interacted additively by the individual component (dose) of these drugs interacted additively by the rotorod test. The administration of pentobarbital with progabide, diazepam or nitrazepam resulted in an additive effect by the pentylenetetrazol (PTZ) minimal threshold seizure (clonic) test. Likewise, combinations of phenobarbital with progabide, diazepam or nitrazepam produced an additive effect by the pentylenetetrazol (PTZ) test. THIP even after toxic doses did not alter the anti-PTZ activity of pentobarbital and phenobarbital. Combinations of pentobarbital with progabide, diazepam, or nitrazepam elicited an additive effect by the maximal electroshock seizure (MES) test. The administration of phenobarbital with progabide, diazepam, or nitrazepam resulted in an additive effect by the MES test THIP even after toxic doses did not alter the anti-MES activity of pentobarbital and phenobarbital. However, baclofen significantly potentiated the anti-MES activity of phenobarbital but not that of pentobarbital. These results suggest that a) in vitro interactions between barbiturates and either GABAa receptor agonists or benzodiazepines may not be the same in vivo, b) GABAa receptor may play a minor role in the minimal neurotoxicity and anticonvulsant activity of barbiturates, and c) inhibition of glutamate-induced excitation by baclofen may be an important action in potentiating the anti-MES activity of phenobarbital.

THE UNIVERSITY OF UTAH GRADUATE SCHOOL SUPERVISORY COMMITTEE APPROVAL of a thesis submitted by Rafael Antonio Ulloque This thesis has been read by each member of the following supervisory committee and by majority vote has been found to be satisfactory. Chairman: Andrew Y Donal J. Reed Chweh · THE UNIVERSITY OF UTA H GRADUATE SCHOOL FIN A L REA DIN G A P.P R 0 V A L To the Graduate Council of The University of Utah: I have read the thesis of Rafael Antonio Ulloque 10 Its final form and have found that (l) its format. citations, and bibliographic style are consistent and acceptable; (2) its illustrative materials including figures, tables, and charts are in place; and (3) the final manuscript is satisfactory to the Supervisory Committee and is ready for submission to the Graduate School. Andrew Y. Chwe Member, Supervisory Committee Approved for the Major Department Chairman! Dean Approved for the Graduate Council