Pyrithiamine-induced
thiamine deficiency (PTD) was used to produce a rodent model of
Wernicke-Korsakoff syndrome that results in acute neurological disturbances, thalamic lesions, and learning and memory impairments. There is also
cholinergic septohippocampal dysfunction in the PTD model. Systemic (Experiment 1) and intrahippocampal (Experiment 2)
injections of the
acetylcholinesterase inhibitor physostigmine were administered to determine if increasing
acetylcholine levels would eliminate the behavioral impairment produced by PTD. Prior to spontaneous alternation testing, rats received
injections of either
physostigmine (systemic=0.075 mg/kg; intrahippocampal=20, 40 ng/muL) or saline. In Experiment 2, intrahippocampal
injections of
physostigmine significantly enhanced alternation rates in the PTD-treated rats. In addition, although intrahippocampal infusions of 40 ng of
physostigmine increased the available amount of ACh in both pair-fed (PF) and PTD rats, it did so to a greater extent in PF rats. The increase in ACh levels induced by the direct hippocampal application of
physostigmine in the PTD model likely increased activation of the extended limbic system, which was dysfunctional, and therefore led to recovery of function on the spontaneous alternation task. In contrast, the lack of behavioral improvement by intrahippocampal
physostigmine infusion in the PF rats, despite a greater rise in hippocampal ACh levels, supports the theory that there is an optimal range of
cholinergic tone for optimal behavioral and hippocampal function.