POSTINJURY ADMINISTRATION OF BIBN-99, A SELECTIVE MUSCARINIC M(2) RECEPTOR ANTAGONIST, IMPROVES COGNITIVE PERFORMANCE FOLLOWING TRAUMATIC BRAIN INJURY IN RATS

Mild to moderate traumatic brain injury (TBI) is associated with endur ing impairments of cognitive function in both humans acid animals. How ever, few experiments have investigated the role of post-injury pharma cologic strategies for attenuating the observed cognitive impairment a fter TBI. This investigation examined the effects of selective blockad e of the presynaptic muscarinic M2 autoreceptor with BIBN 99 on cognit ive recovery following rodent TBI. Experiment 1 investigated the effec ts of delayed post-injury administration of BIBN 99 on cognitive perfo rmance following moderate central fluid percussion TBI (2.1 +/- 0.05 a tm). On days 11-15 after injury-cognitive performance was assessed wit h a Morris water maze (MWM) task. One hour before MWM testing injured rats were injected (s.c.) with either vehicle (n = 9), 0.5 (n = 8), or 1.0 (n = 8) mg/kg of BIBN 99. Results indicated that injured rats rec eiving the delayed post-injury treatment with BIBN 99 performed no bet ter than injured-vehicle treated rats. In experiment 2, injured rats w ere injected (s.c.) once daily with either vehicle (n = 9), 0.5 (n = 9 ), or 1.0 (n = 9) mg/kg of BIBN 99 throughout the duration of the expe riment beginning 24 h after TBI. Sham-injured animals injected (s.c.) with vehicle (n = 9) or 1.0 (n = 8) mg/kg of BIBN 99 were included for comparison. On days 11-15 after injury, cognitive performance was ass essed with the MWM procedure. Results of the second experiment indicat ed that both doses of BIBN 99 were effective in attenuating cognitive deficits in the MWM as compared to the injured-vehicle treated animals (P < 0.05 for both comparisons). The results also revealed that sham- injured animals were unaffected by the 1.0 mg/kg dose of BIBN 99 on MW M performance. Thus, cholinergic enhancement by selective blockade of the presynaptic M(2) autoreceptor is an efficacious strategy for the p ost-injury amelioration of cognitive deficits following experimental T BI. However, time and duration of administration may be important fact ors that affect the efficacy of treatment.