Prefrontal β2 subunit-containing and α7 nicotinic acetylcholine receptors differentially control glutamatergic and cholinergic signaling

Abstract

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 α4β2* nicotinic acetylcholine receptors (nAChRs) enhance cue detection and attentional performance by augmenting prefrontal cholinergic activity. The present experiments determined the role of β2-containing and α7 nAChRs in the generation of prefrontal cholinergic and glutamatergic transients in vivo. Transients were evoked by nicotine, the β4α2 * nAChR agonist ABT-089 [2-methyl-3-(2-(S)-pyrrolindinylmethoxy) pyridine dihydrochloride], or the α7 nAChRagonist A-582941 [2-methyl-5-(6-phenyl- pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole]. Transients were recorded in mice lacking β2or α7nAChRsand in rats after removal of thalamic glutamatergic or midbrain dopaminergic inputs to prefrontal cortex. The main results indicate that stimulation of α4β2* 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 β2* nAChRs. The amplitude, but not the decay rate, of nicotine-evoked transients was reduced by β2* knock-out. Conversely, in mice lacking the α7 nAChR, the decay rate, but not the amplitude, of nicotine-evoked cholinergic and glutamatergic transients was attenuated. Substantiating the role of α7 nAChR in controlling the duration of release events, stimulation of α7 nAChR produced cholinergic transients that lasted 10- to 15-fold longer than those evoked by nicotine. α7 nAChR-evoked cholinergic transients are mediated in part by dopaminergic activity. Prefrontal α4β2* nAChRs play a key role in evoking and facilitating the transient glutamatergic-cholinergic interactions that are necessary for cue detection and attentional performance. Copyright © 2010 the authors.