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Acetylcholinesterase inhibitors in combination with an anticholinergic, particularly anticholinergics with antiglutamatergic properties, can effectively protect against nerve agent-induced seizures and lethality. The objective of the present study was to examine potential behavioral side effects of the anticholinesterases physostigmine (0.1mg/kg), galantamine (3mg/kg), huperzine (0.5mg/kg), and donepezil (2.5mg/kg) alone or each drug in combination with anticholinergic procyclidine (3mg/kg). The results showed that rats injected intraperitoneally with galantamine displayed a mild cognitive deficit in terms of reduced preference for novelty that was similarly found among animals treated with procyclidine combined with either galantamine or donepezil. Locomotor activity and rearing were radically depressed in all groups treated with anticholinesterases as well as in combination with procyclidine. Reductions in activity were most prominent for rats injected with galantamine alone. Equalizing effects of cholinesterase inhibitors and anticholinergics were absent in the present context. Findings from previous studies that both systemic and local (amygdala) application of physostigmine cause increased fear-motivated freezing response in rats, may explain the marked reductions in activity among the present rats. In view of these findings, use of anticholinesterases (crossing the blood-brain barrier) as prophylactics against nerve agents must be carefully examined to avoid severe side effects., (Copyright 2010 Elsevier Inc. All rights reserved.)

Antiparkinson agents possess excellent anticonvulsant properties against nerve agent-induced seizures by exerting both cholinergic and glutamatergic antagonisms. It is important, however, that drugs used as prophylactics not by themselves cause impairment of cognitive capability. The purpose of the present study was to make a comparative assessment of potential cognitive effects of benactyzine (0.3 mg/kg), biperiden (0.11 mg/kg), caramiphen (10 mg/kg), procyclidine (3 mg/kg), and trihexyphenidyl (0.12 mg/kg) separately and each in combination with physostigmine (0.1 mg/kg). The results showed that benactyzine, caramiphen, and trihexyphenidyl reduced rats' innate preference for novelty, whereas biperiden and procyclidine did not. When benactyzine, caramiphen, and trihexyphenidyl were combined with physostigmine the cognitive impairment disappeared. This counteracting effect, however, caused changes in locomotor and rearing activities not seen by each drug alone. Acetylcholinesterase inhibitors and anticholinergics used as prophylactics can offset each other, but exceptions are observed in a previous study when a very potent anticholinergic (scopolamine) or a high dose of procyclidine still results in cognitive deficits in spite of coadministration with physostigmine. Among the present drugs tested, procyclidine appears to be a robust anticonvulsant with few cognitive side effects.

During early testing (1 week), there is a clear impairment of preference for novelty in rats with combined transections of the fiber connections between the temporal and lateral entorhinal cortices and the hippocampal perforant path (TC/LEC + PP lesions). During late testing (2-3 weeks), a complete recovery of the preference for novelty is seen. The purpose of this study was to pharmacologically examine whether cholinergic or glutamatergic systems might support the processes underlying the recovery. The cholinergic antagonist atropine sulfate caused a complete reappearance of the impaired preference for novelty in rats with TC/LEC + PP transections. The glutamatergic antagonist HA-966 only produced a moderate reactivation of the recovered lesion effect. A moderate impairment was also seen in intact rats treated with atropine or HA-966. The results suggest that blocking of cholinergic function impairs the recovered performance in this specific task without precluding the involvement of other uninvestigated neurochemical systems.

Disruption of the connections between the temporal cortex (TC) and lateral entorhinal cortex (LEC) in rats causes impaired memory accompanied by decreased levels of glutamate in these neocortical areas. Administration of glutamergic agonists to rats with TC/LEC disruptions improves retroactive memory. The purpose of this study was to test effects of glycine on proactive memory. The results show that a relatively large dose of glycine (750 mg/kg) injected just prior to training enhanced both acquisition and retention of a discrimination task in TC/LEC rats. Glycine given 1 day prior to training impaired the initial phase of acquisition but improved retention (Experiment 1). Injection of glycine immediately following training or just prior to retrieval reinstated normal mnemonic function in TC/LEC animals, whereas glycine given midway between learning and retention had no such effect (Experiment 2). A potential mnemonic model function of TC/LEC lesion is suggested, and possible beneficial effects of glycine on patients with Alzheimer's disease are discussed.