Bidirectional modulation of stimulated cortical acetylcholine release by benzodiazepine receptor ligands

In vivo microdialysis was used to determine the ability of benzodiazepine receptor (BZR) ligands to modulate stimulated cortical acetylcholine (ACh) efflux in awake, freely-moving Fischer-344/BNNia rats. Cortical ACh efflux was reliably enhanced during presentation of a complex stimulus (exposure to darkness coupled with presentation of a small amount of palatable food) in animals entrained with that stimulus. Administration of the BZR selective inverse agonist ZK 93,426 (5.0 mg/kg, i.p.) potentiated the ability of the darkness/food stimulus to enhance efflux, whereas administration of the BZR full agonist, chlordiazepoxide (5.0 mg/kg, i.p.) blocked the enhancement. The interaction of the BZR ligands with the entrained stimulus in affecting cortical ACh efflux was not secondary to effects on motor activity. These results, combined with results from a previous study, suggest that modulation of cortical ACh efflux by BZR ligands is bidirectional and dependent on the level of activity within cortical cholinergic neurons. This relationship enables the trans-synaptic stimulation of cortical ACh transmission by BZR inverse agonists to be most effective during behavioral activities which recruit the basal forebrain cholinergic system.