Positive allosteric modulation of α4β2* nicotinic acetylcholine receptors augments the amplitudes of prefrontal nicotine-evoked glutamatergic transients

α4β2* nicotinic acetylcholine receptors (nAChR) are a promising target for cognition enhancement. These receptors have been demonstrated to mediate the modulatory effects of the tonic component of cholinergic neurotransmission on fast prefrontal glutamatergic-cholinergic interactions. Specifically, α4β2* nAChR are expressed by thalamic glutamatergic afferents and amplify cue-evoked glutamatergic release events, thereby initiating a chain of neuronal events required for the detection of cues in attention tasks (Hasselmo & Sarter, 2011). In this study we investigated the effect of NS9283, a potent and selective positive allosteric modulator of low-sensitivity α4β2 nAChR (Timmermann et al., 2012), on nicotine-evoked glutamatergic release events in the mPFC of anaesthetized rats. Glutamatergic transients were recorded using amperometric measures of currents generated by the oxidation of glutamate and, subsequently, peroxide, on Platinum electrodes equipped with immobilized glutamate oxidase (see Parikh et al., 2010). Nicotine was pressure-ejected (0.040-2 nmol in 40-100 nL, respectively) into the vicinity of the recording electrode situated in the thalamic input layer of the prelimbic cortex. Systemic (i.p.) administration of NS9283 (3.0 mg/kg; administered 30 min prior to nicotine) enhanced the amplitude of glutamatergic transients evoked by the lowest dose of nicotine (40 pmol) by 72%. The modulator did not increase the efficacy of nicotine. Local pressure-ejections of NS9283 (400 pmol in 40 nL) per se were capable of evoking glutamatergic release events, presumably reflecting modulation of the effects of endogenous acetylcholine at these nAChRs. Accordingly, 192 IgG saporin-induced removal of cholinergic projections to the recording region abolished NS9283-evoked glutamatergic transients. Collectively, this evidence substantiates the identification of NS9283 as a positive modulator of nAChRs and its potency in vivo to modulate evoked glutamatergic release events. These results are consistent with the hypothesis that such compounds facilitate cue detection processes and thereby enhance attentional performance. Supported by NIH grant MH080332 and The Ministry of Science, Innovation and Higher Education, Denmark, PhD grant 10-084289.