Chronic administration of a partial muscarinic M1 receptor agonist attenuates decreases in forebrain choline acetyltransferase immunoreactivity following experimental brain trauma.

Abstract

Lu 25-109-T is a partial muscarinic M1 receptor agonist with antagonistic effects at presynaptic M2 autoreceptors and has been shown to improve cognitive function following traumatic brain injury (TBI) in rats. This investigation examined the effects of TBI on basal forebrain choline acetyltransferase immunoreactivity (ChAT-IR) following daily administration of saline or 15 mumol/kg Lu 25-109-T. Rats received a moderate (2.1 +/- 0.1 atm) level of central fluid percussion TBI or were surgically prepared but not injured and were injected (sc) with saline or drug on Days 1-15 postinjury. Rats were sacrificed following the last daily injection, and sections were collected through the basal forebrain and processed for ChAT-IR. TBI caused a significant reduction in ChAT-IR neuronal density in saline- and Lu 25-109-T-treated rats with a 13% and 5% decrease in the medial septal nucleus (MSN), a 48 and 23% decrease in the vertical limb nucleus of the diagonal band (VDB), and a 51 and 28% decrease in the nucleus basalis magnocellularis (NBM), respectively. However, Lu 25-109-T significantly attenuated the injury-induced reductions in ChAT-IR. Loss in ChAT-IR neuronal density is not thought to result from cell death as parallel cresyl violet-stained sections indicated no decrease in neuronal cell density in the MSN, VDB, or NBM. These results support the hypothesis that increasing cholinergic tone during the recovery period after TBI will restore cholinergic function impaired by brain trauma.