Neuronal mechanisms mediating drug-induced cognition enhancement: cognitive activity as a necessary intervening variable.

The conceptual foundations of a research aimed at the determination of potential neuronal, neuropharmacological, and behavioral/cognitive mechanisms mediating drug-induced cognition enhancement are discussed. The available evidence justifies a focus on attentional processes as a target for drug-induced cognition enhancement. Neuropharmacological mechanisms that may mediate drug-induced enhancement of attentional functions are proposed to interact necessarily with attention-associated neuronal activity. The elements of a transsynaptic approach to increase the excitability of basal forebrain cholinergic neurons and hence, attentional functions are discussed. Experimental tests of this hypothesis require the demonstration of interactions between cognition-induced increases in the activity of cortical cholinergic afferents and the effects of putative cognition enhancers. The available data illustrate that the effects of benzodiazepine receptor (BZR) agonists and inverse agonists on cortical acetylcholine (ACh) efflux interact with the state of activity in this system. The feasibility, potential heuristic power, and the experimental and conceptual problems of studies attempting to simultaneously assess drug effects on behavioral/cognitive abilities, ACh efflux, and neuronal activity have been revealed by an experiment intended to correlate performance in a task measuring sustained attention with medial prefrontal ACh efflux and medial prefrontal single-unit activity. The rational development of a psychopharmacology of cognition enhancers requires a union among behavioral/cognitive pharmacology, neuropharmacological and electrophysiological approaches.