Positive and negative modulation of the GABA(A) receptor and outcome aftertraumatic brain injury in rats

Glutamate-mediated excitotoxicity has been shown to contribute to cellular dysfunction following traumatic brain injury (TBI). Increasing inhibitory f unction through stimulation of gamma-aminobutyric acid (GABA(A)) receptors may attenuate excitotoxic effects and improve outcome. The present experime nt examined the effects of diazepam, a positive modulator at the GABA(A) re ceptor, on survival and cognitive performance in traumatically brain-injure d 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 bu t not injured (sham-injury). Rats pre-treated with the 5 mg/kg dose of diaz epam had significantly lower mortality (0%) than injured, saline-treated ra ts (53%). Also, diazepam-treated (5 mg/kg) rats had significantly shorter l atencies 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 significant ly shorter latencies to reach the goal platform in the Morris water maze th an injured, vehicle-treated rats. In experiment 3, the post-injury administ ration of bicuculline (1.5 mg/kg, n = 8), a GABA, antagonist, increased Mor ris water maze goal latencies compared to injured animals treated with sali ne (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. (C) 2000 Elsevier Science B.V. All rights reserved.