Synergistic effects of tetrahydroaminoacridine and lithium on cholinergic function after excitotoxic basal forebrain lesions in rat

Effects of lithium and tetrahydroaminoacridine (THA), either alone or in co mbination, were tested in an animal model of excitotoxic cholinerqic deaffe rentation of the cerebral cortex. Rats received ibotenic acid lesions of ch olinergic basal forebrain nuclei resulting in a 30% to 40% depletion of bot h cortical choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) activity. Lithium as well as THA, given separately either prior or subsequ ently to the development of the lesion, had small but significant effects o n the recovery of cortical ChAT and AChE activity. Applied in combination, these drugs clearly showed synergistic effects. These potentiating actions might be due to neuroprotective/neurotrophic mechanisms as well as to effec ts on acetylcholine turnover and muscarinic receptor-coupled phosphoinositi de turnover. Similar approaches of combination therapy might prove useful f or the management of mental disorders associated with cholinergic dysfuncti on.