Trans-synaptic stimulation of cortical acetylcholine and enhancement of attentional functions: a rational approach for the development of cognition enhancers.

Activation and restoration of cholinergic function remain major foci in the development of pharmacological approaches toward the treatment of cognitive dysfunctions associated with aging and dementia. Our research has been guided by the hypothesis that (re)activation of cortical cholinergic inputs is achieved as a result of trans-synaptic disinhibition of basal forebrain cholinergic neurons. This approach depends on the ability of benzodiazepine receptor (BZR) inverse agonists to reduce the potency of GABA to block neuronal excitation. BZR inverse agonists were found to augment cortical ACh efflux through interaction with cognition-associated activation of this system. Cortical cholinergic inputs have been implicated in the processing of behaviorally significant stimuli, i.e., attentional functions. Using a recently developed and validated task for the measurement of sustained attention, or vigilance, administration of BZR inverse agonists were found to selectively increase the number of false alarms in intact animals. However, in animals with a 50-70%, but not > 90%, loss of the cortical cholinergic inputs, treatment with BZR inverse agonists alleviated the lesion-induced impairment in sustained attention and enhanced activated cortical ACh efflux. A rational development of cognitive enhancers will benefit from experiments in which cognitive and neuropharmacological variables are assessed simultaneously, thus allowing the analysis of interactions between cognition-associated neuronal activity and the neuronal and cognitive effects of putative cognition enhancers.