Selective potentiation of (α4)3(β2)2 nicotinic acetylcholine receptors augments amplitudes of prefrontal acetylcholine- and nicotine-evoked glutamatergic transients in rats.
Prefrontal glutamate release evoked through activation of α4β2* nicotinic acetylcholine receptors (nAChRs) situated on thalamic glutamatergic afferents mediates cue detection processes and thus contributes to attentional performance. However, little is known about the respective contributions of the high sensitivity and low sensitivity (LS) stoichiometries of the α4β2 nAChR, (α4)2(β2)3 and (α4)3(β2)2, to these processes. In the present study we employed glutamate-sensitive microelectrodes and the (α4)3(β2)2-selective positive allosteric modulator (PAM) NS9283 to investigate the importance of the LS α4β2 nAChR for glutamate release in the rat medial prefrontal cortex (mPFC). Firstly, the signaling evoked by physiologically relevant ACh concentrations through the (α4)3(β2)2 nAChR in HEK293 cells was potentiated by NS9283, consistent with the classification of NS9283 as a PAM. In urethane-anesthetized rats, intra-prefrontal pressure ejections of NS9283 evoked glutamatergic transients. Importantly, this glutamate release was attenuated by removal of cholinergic projections to the recording area. This finding indicates that the effects of NS9283 depend on endogenous ACh, again consistent with effects of a PAM. We then conducted microdialysis to demonstrate the presence of extracellular ACh in urethane-anesthetized control rats. While detectable, those levels were significantly lower than in awake rats. Finally, the amplitudes of glutamatergic transients evoked by local pressure ejections of a low concentration of nicotine were significantly augmented following systemic administration of NS9283 (3.0mg/kg). In conclusion, our results indicate that a LS α4β2 nAChR PAM such as NS9283 may enhance the cholinergic modulation of glutamatergic neurotransmission in the cortex, thereby perhaps alleviating the attentional impairments common to a range of brain disorders.
Department of Psychology and Neuroscience Program, University of Michigan, 530 Church Street, 4030 East Hall, Ann Arbor, MI 48109-1109, USA; Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark; NeuroSearch A/S, Pederstrupvej 93, 2750 Ballerup, Denmark. Electronic address: mortengrupe@gmail.com.
Morten
M
Grupe
Giovanna
G
Paolone
Anders A
AA
Jensen
Karin
K
Sandager-Nielsen
Martin
M
Sarter
Morten
M
Grunnet
D000109:Acetylcholine / Q000494:pharmacology*; D000494:Allosteric Regulation; D000818:Animals; D018698:Glutamic Acid / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D008839:Microelectrodes; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D010069:Oxadiazoles / Q000494:pharmacology*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D011978:Receptors, Nicotinic / Q000378:metabolism*
C561896:3-(3-(pyridine-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile; D018722:Nicotinic Agonists; D010069:Oxadiazoles; D011725:Pyridines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D018698:Glutamic Acid; D009538:Nicotine; D000109:Acetylcholine
192-IgG saporin; 192-SAP; 2-hydroxypropyl-β-cyclodextrin; ACh; BSA; CNS; ChAT; ECD; GO; Glut; HBC; HEK293 cells stably expressing human α4β2 nAChR; HEK293-hα4β2; HPLC; LOD; LS; NS9283; Nicotinic acetylcholine receptor; PAM; Positive allosteric modulator; Prefrontal glutamate release; aCSF; acetylcholine; artificial cerebrospinal fluid; bovine serum albumin; central nervous system; choline acetyltransferase; electrochemical detection; glutamate; glutamate oxidase; high-performance liquid chromatography; limit of detection; low sensitivity; m-PD; mPFC; medial prefrontal cortex; meta-phenylenediamine; nAChR; nicotinic acetylcholine receptor; positive allosteric modulator; α4β2