Nicotinic modulation of glutamate receptor function at nerve terminal level: a fine-tuning of synaptic signals

Abstract

This review focuses on a specific interaction occurring between the nicotinic cholinergic receptors (nAChRs) and the glutamatergic receptors (GluRs) at the nerve endings level. We have employed synaptosomes in superfusion and supplemented and integrated our findings with data obtained using techniques from molecular biology and immuno-cytochemistry, and the assessment of receptor trafficking. In particular, we characterize the following: (1) the direct and unequivocal localization of native α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA) glutamatergic receptors on specific nerve terminals, (2) their pharmacological characterization and functional co-localization with nAChRs on the same nerve endings, and (3) the existence of synergistic or antagonistic interactions among them. Indeed, in the rat nucleus accumbens (NAc), the function of some AMPA and NMDA receptors present on the dopaminergic and glutamatergic nerve terminals can be regulated negatively or positively in response to a brief activation of nAChRs. This effect occurs rapidly and involves the trafficking of AMPA and NMDA receptors. The event takes place also at very low concentrations of nicotine and involves the activation of several nAChRs subtypes. This dynamic control by cholinergic nicotinic system of glutamatergic NMDA and AMPA receptors might therefore represent an important neuronal presynaptic adaptation associated with nicotine administration. The understanding of the role of these nicotine-induced functional changes might open new and interesting perspectives both in terms of explaining the mechanisms that underlie some of the effects of nicotine addiction and in the development of new drugs for smoking cessation.

Keywords: AMPA receptors; NMDA receptors; neurotransmitter release; nicotinic receptors; receptor–receptor interactions; synaptic plasticity; synaptosomes.

FIGURE 1

A schematic representation of the consequences of the pre-treatment with nAChR agonists on the ability of NMDAR agonists (100 μM NMDA and 1 μM glycine) to evoke release of dopamine (DA) and glutamate (GLU) from rat nerve terminals and on the GluN2A and GluN2B NMDARs trafficking. The asterisk indicates that the receptor subtype includes the presence of other different subunits in a variable manner in addition to the subunit specified.

FIGURE 2

A schematic representation of the consequences of the pre-treatment with nAChR agonists on the ability of NMDAR agonists (100 μM NMDA and 1 μM glycine) to evoke release of dopamine (DA) and noradrenaline (NA), acetylcholine (ACh) and GABA from rat nerve terminals and on the GluA2-cyclothiazide sensitive (GluA2 SENS) and GluA2-cyclothiazide insensitive (GluA2 INSENS) AMPARs trafficking. The asterisk indicates that the receptor subtype includes the presence of other different subunits in a variable manner in addition to the subunit specified.