Effects of the selective alpha 7 nAChR agonist ABT-107 on prefrontal glutamatergic and cholinergic activity and attentional performance

Stimulation of alpha 7 nAChRs has been widely suggested as a new approach to treat the cognitive symptoms of a range of disorders, including schizophrenia. The present experiments focused on the effects of ABT-107 on cholinergic activity and attentional performance. Our prior research demonstrated that transient increases in prefrontal cholinergic activity mediate the detection of stimuli in attention-demanding contexts. Furthermore, evidence supports the hypothesis that these cholinergic transients are evoked by glutamatergic stimulation of cholinergic terminals. Compared with the effects of the non-selective nAChR agonist nicotine (Parikh et al. 2008), pressure ejections of ABT-107 (8-200 pmol) into the medial prefrontal cortex (mPFC) produced increases in glutamate and ACh release that were characterized by extremely slow decay rates (t50 >10 min, as opposed to <30 s for nicotine), reflecting lasting and only slowly diminishing ACh release. In alpha 7 knockout mice, these effects were almost completely abolished. Furthermore, administration of the dopamine D1 receptor antagonist, SKF 38393 (0.1 mg/kg; i.p.) or the D2 antagonist eticlopride (0.03 mg/kg; i.p.) attenuated the effects of ABT-107. Using microdialysis to measure ACh release in freely moving animals, ABT-107 (0.1, 3.0 µmol/kg; i.p.) evoked long-lasting (>2.5 hrs) increases in basal ACh release, reaching 200-300% over baseline. Furthermore, these increases in ACh release did not interact with increases in release that were evoked by a conditioned stimulus. Finally, the performance of rats in the standard sustained attention task (SAT) as well as the distractor version of this task (dSAT) was not significantly affected by ABT-107 (0.1, 1,0, 3.0 µmol/kg). Collectively, this evidence indicates that ABT-107 evokes robust and lasting increases in basal ACh release and that stimulation of D1 and D2 receptors mediate this effect. Alpha 7 nAChR agonists may benefit other cognitive functions through other mechanisms (Bitner et al. 2007) but ABT-107 does not evoke or modulate the brief increases in cholinergic activity that mediate enhancement of attentional performance. Finally, these results are consistent with the general view that increases in basal ACh release do not predict beneficial effects on attentional performance.