ACTIVATING THE POSTTRAUMATIC CHOLINERGIC SYSTEM FOR THE TREATMENT OF COGNITIVE IMPAIRMENT FOLLOWING TRAUMATIC BRAIN INJURY

Cognitive impairment after traumatic brain injury (TBI) is correlated with decreased cholinergic markers of neuronal viability. The purpose of this experiment was to test the hypothesis that pharmacological act ivation of the muscarinic cholinergic system during the recovery perio d after TBI will improve cognitive performance. LU 25-109-T is a parti al muscarinic M-1 agonist that also acts as an antagonist at presynapt ic M-2 autoreceptors (thus, increasing ACh release). Injured rats were injected subcutaneously daily for 15 days with either 0.0, 3.6, or 15 mu mol/kg of LU 25-109-T beginning 24 h after a receiving a moderate (2.1 +/- 0.1 arm) level of central fluid percussion brain injury. Cogn itive performance was assessed on days 11-15 postinjury in a Morris wa ter maze (MWM). Injured rats treated with 15 mu mol/kg, but not those treated with 3.6 mu mol/kg, showed a significant improvement (P < 0.01 ) in MWM performance as compared with injured vehicle-treated rats. Th is result supports the hypotheses that a decrease in posttraumatic cho linergic neurotransmission contributes to TBI-induced cognitive defici ts and that increasing cholinergic tone during the recovery period fol lowing TBI will improve cognitive performance. (C) 1997 Elsevier Scien ce Inc.