Effect of cefepime on startle amplitude and prepulse inhibition of startle reflex in rats: manipulation of GABAA receptor function with midazolam.
Disruption of prepulse inhibition (PPI) of startle response is manifested in schizophrenia and Huntington's disease among other neuropsychiatric disorders characterized by sensorimotor gating deficit. Antagonism of GABAA receptor function was documented to reduce PPI response. However, whether GABAA antagonism reduces PPI response is yet to be established because of contradicting reports. Cefepime is one of the fourth-generation cephalosporins documented to antagonize GABAA receptor function. This study investigated the effect of intramuscular injection of cefepime (45 and 90 mg/kg) twice daily for three consecutive days on both PPI of acoustic startle response and acoustic startle amplitude in rats. The effect of administration of the GABAA receptor agonist midazolam (1 mg/kg, i.p.) in conjunction with cefepime on PPI response and startle amplitude was also investigated. Results showed that administration of both dose levels of cefepime caused PPI deficit. Treatment of animals with midazolam in conjunction with cefepime reversed the effect of the lower dose, but not the higher one, on PPI of startle response without affecting startle amplitude in both dose levels. Results of this study, therefore, support the view that GABAA antagonism reduces PPI response. It is also concluded that antagonism of GABAergic transmission may be involved in the effect of the lower dose of cefepime on PPI response. Other mechanisms may mediate the effect of the higher dose of cefepime on PPI response. Clinical investigations are needed to determine the consequence of using cefepime in disorders of sensorimotor gating.
Khalifa
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AE
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt. amani@ims.com.eg
D000818:Animals; D000077723:Cefepime; D002511:Cephalosporins / Q000008:administration & dosage / Q000494:pharmacology*; D004336:Drug Antagonism; D018755:GABA Agonists / Q000494:pharmacology*; D018756:GABA Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D008297:Male; D008874:Midazolam / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013216:Reflex, Startle / Q000187:drug effects*
D002511:Cephalosporins; D018755:GABA Agonists; D018756:GABA Antagonists; D058785:GABA-A Receptor Agonists; D058787:GABA-A Receptor Antagonists; D000077723:Cefepime; D008874:Midazolam