TRANSSYNAPTIC 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 i n the development of pharmacological approaches toward the treatment o f cognitive dysfunctions associated with aging and dementia. Our resea rch has been guided by the hypothesis that (re)activation of cortical cholinergic inputs is achieved as a result of trans-synaptic disinhibi tion of basal forebrain cholinergic neurons. This approach depends on the ability of benzodiazepine receptor (BZR) inverse agonists to reduc e the potency of GABA to block neuronal excitation. BZR inverse agonis ts were found to augment cortical ACh efflux through interaction with cognition-associated activation of this system. Cortical cholinergic i nputs have been implicated in the processing of behaviorally significa nt stimuli, i.e., attentional functions. Using a recently developed an d validated task for the measurement of sustained attention, or vigila nce, administration of BZR inverse agonists were found to selectively increase the number of false alarms in intact animals. However, in ani mals with a 50-70%, but not > 90%, loss of the cortical cholinergic in puts, treatment with BZR inverse agonists alleviated the lesion-induce d impairment in sustained attention and enhanced activated cortical AC h efflux. A rational development of cognitive enhancers will benefit f rom experiments in which cognitive and neuropharmacological variables are assessed simultaneously, thus allowing the analysis of interaction s between cognition-associated neuronal activity and the neuronal and cognitive effects of putative cognition enhancers.