Positive and negative modulation of the GABA(A) receptor and outcome after traumatic brain injury in rats.
Glutamate-mediated excitotoxicity has been shown to contribute to cellular dysfunction following traumatic brain injury (TBI). Increasing inhibitory function through stimulation of gamma-aminobutyric acid (GABA(A)) receptors may attenuate excitotoxic effects and improve outcome. The present experiment examined the effects of diazepam, a positive modulator at the GABA(A) receptor, on survival and cognitive performance in traumatically brain-injured animals. In experiment 1, 15 min prior to central fluid percussion brain injury, rats (n=8 per group) were injected (i.p.) with saline or diazepam (5 mg/kg or 10 mg/kg). Additional rats (n=8) were surgically prepared but not injured (sham-injury). Rats pre-treated with the 5 mg/kg dose of diazepam had significantly lower mortality (0%) than injured, saline-treated rats (53%). Also, diazepam-treated (5 mg/kg) rats had significantly shorter latencies to reach the goal platform in the Morris water maze test performed 11-15 days post-injury. In experiment 2, at 15 min post-injury, rats were given either saline (n=5) or 5 mg/kg diazepam (n=6). Rats treated with diazepam did not differ in mortality from injured rats treated with vehicle. However, rats treated with diazepam at 15 min post-injury had significantly shorter latencies to reach the goal platform in the Morris water maze than injured, vehicle-treated rats. In experiment 3, the post-injury administration of bicuculline (1.5 mg/kg, n=8), a GABA(A) antagonist, increased Morris water maze goal latencies compared to injured animals treated with saline (n=8). These results suggest that enhancing inhibitory function during the acute post-injury period produces beneficial effects on both survival and outcome following experimental TBI.
O'Dell
D M
DM
Department of Psychology, Virginia Commonwealth University, P.O. Box 842018, Richmond, VA 23284-2018, USA. odelld@mail.med.upenn.edu
Gibson
C J
CJ
Wilson
M S
MS
DeFord
S M
SM
Hamm
R J
RJ
D000818:Animals; D001640:Bicuculline / Q000494:pharmacology; D001930:Brain Injuries / Q000188:drug therapy* / Q000401:mortality; D003071:Cognition / Q000187:drug effects*; D003975:Diazepam / Q000494:pharmacology* / Q000627:therapeutic use; D018756:GABA Antagonists / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000187:drug effects*
D018756:GABA Antagonists; D018757:GABA Modulators; D011963:Receptors, GABA-A; D003975:Diazepam; D001640:Bicuculline