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 activation of the muscarinic cholinergic system during the recovery period after TBI will improve cognitive performance. LU 25-109-T is a partial muscarinic M 1 agonist that also acts as an antagonist at presynaptic M 2 autoreceptors (thus, increasing ACh release). Injured rats were injected subcutaneously daily for 15 days with either 0.0, 3.6, or 15 μmol/kg of LU 25-109-T beginning 24 h after a receiving a moderate (2.1 ± 0.1 atm) level of central fluid percussion brain injury. Cognitive performance was assessed on days 11–15 postinjury in a Morris water maze (MWM). Injured rats treated with 15 μmol/kg, but not those treated with 3.6 μmol/kg, showed a significant improvement ( p < 0.01) in MWM performance as compared with injured vehicle-treated rats. This result supports the hypotheses that a decrease in posttraumatic cholinergic neurotransmission contributes to TBI-induced cognitive deficits and that increasing cholinergic tone during the recovery period following TBI will improve cognitive performance.