Prefrontal β2 Subunit-Containing and α7 Nicotinic Acetylcholine Receptors Differentially Control Glutamatergic and Cholinergic Signaling

One-second-long increases in prefrontal cholinergic activity (transients) were demonstrated previously to be necessary for the incorporation of cues into ongoing cognitive processes (cue detection). Nicotine and, more robustly, selective agonists at alpha 4 beta 2* nicotinic acetylcholine receptors (nAChRs) enhance cue detection and attentional performance by augmenting prefrontal cholinergic activity. The present experiments determined the role of beta 2-containing and alpha 7 nAChRs in the generation of prefrontal cholinergic and glutamatergic transients in vivo. Transients were evoked by nicotine, the alpha 4 beta 2* nAChR agonist ABT-089 [2-methyl-3-(2-(S)-pyrrolindinylmethoxy) pyridine dihydrochloride], or the alpha 7 nAChR agonist A-582941 [2-methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c] pyrrole]. Transients were recorded in mice lacking beta 2 or alpha 7 nAChRs and in rats after removal of thalamic glutamatergic or midbrain dopaminergic inputs to prefrontal cortex. The main results indicate that stimulation of alpha 4 beta 2* nAChRs evokes glutamate release and that the presence of thalamic afferents is necessary for the generation of cholinergic transients. ABT-089-evoked transients were completely abolished in mice lacking beta 2* nAChRs. The amplitude, but not the decay rate, of nicotine-evoked transients was reduced by beta 2* knock-out. Conversely, in mice lacking the alpha 7 nAChR, the decay rate, but not the amplitude, of nicotine-evoked cholinergic and glutamatergic transients was attenuated. Substantiating the role of alpha 7 nAChR in controlling the duration of release events, stimulation of alpha 7 nAChR produced cholinergic transients that lasted 10- to 15-fold longer than those evoked by nicotine. alpha 7 nAChR-evoked cholinergic transients are mediated in part by dopaminergic activity. Prefrontal alpha 4 beta 2* nAChRs play a key role in evoking and facilitating the transient glutamatergic-cholinergic interactions that are necessary for cue detection and attentional performance.