Prolonged nicotine exposure down-regulates presynaptic NMDA receptors in dopaminergic terminals of the rat nucleus accumbens

Abstract

The presynaptic control of dopamine release in the nucleus accumbens (NAc) by glutamate and acetylcholine has a profound impact on reward signaling. Here we provide immunocytochemical and neurochemical evidence supporting the co-localization and functional interaction between nicotinic acetylcholine receptors (nAChRs) and N-methyl-D-aspartic acid (NMDA) receptors in dopaminergic terminals of the NAc. Most NAc dopaminergic terminals possessed the nAChR α4 subunit and the pre-exposure of synaptosomes to nicotine (30 μM) or to the α4β2-containing nAChR agonist 5IA85380 (10 nM) selectively inhibited the NMDA (100 μM)-evoked, but not the 4-aminopyridine (10 μM)-evoked, [(3)H] dopamine outflow; this inhibition was blunted by mecamylamine (10 μM). Nicotine and 5IA85380 pretreatment also inhibited the NMDA (100 μM)-evoked increase of calcium levels in single nerve terminals, an effect prevented by dihydro-β-erythroidine (1 μM). This supports a functional interaction between α4β2-containing nAChR and NMDA receptors within the same terminal, as supported by the immunocytochemical co-localization of α4 and GluN1 subunits in individual NAc dopaminergic terminals. The NMDA-evoked [(3)H]dopamine outflow was blocked by MK801 (1 μM) and inhibited by the selective GluN2B-selective antagonists ifenprodil (1 μM) and RO 25-6981 (1 μM), but not by the GluN2A-preferring antagonists CPP-19755 (1 μM) and ZnCl2 (1 nM). Notably, nicotine pretreatment significantly decreased the density of biotin-tagged GluN2B proteins in NAc synaptosomes. These results show that nAChRs dynamically and negatively regulate NMDA receptors in NAc dopaminergic terminals through the internalization of GluN2B receptors.

N-Methyl-d-aspartate Modulation of Nucleus Accumbens Dopamine Release by Metabotropic Glutamate Receptors: Fast Cyclic Voltammetry Studies in Rat Brain Slices in Vitro

“…Three possible indirect routes for this action were considered; via GABAergic systems, given the abundance of GABAergic medium spiny neurones and interneurons in NAc, via cholinergic mechanisms, on the basis of the evidence showing cholinergic modulation of dopamine release in the striatum 10,13,23,24,25 or through mGluR-mediated mechanisms, since mGluR group 2 and 3 receptors are widely distributed in striatal areas, have been shown to be inhibitory, and they decrease dopamine release, probably through presynaptic receptors located on dopamine terminals 29,30 .…”

“…The effects were blocked by the NMDA-R antagonist AP-5, indicating a specific, NMDA-R mediated mechanism, but not by picrotoxin, indicating that an intermediary action via GABA-A receptors is unlikely. Cholinergic systems are known to modulate of striatal dopamine release, through both nicotinic and muscarinic mechanisms 13,23,24,25 . In the present study we found that the α4β2 nicotinic antagonist, DHβE, attenuated the NNDA-R evoked suppression of stimulated dopamine release.…”

Neurobiological and Neurophysiological Mechanisms Underlying Nicotine Seeking and Smoking Relapse

“…Nicotine self-administration may result in increased NR2B NMDA subunit expression in NAc shell, although these changes did not reach significance [228]. In contrast, nicotine exposure has been shown to downregulate NR2B-containing NMDA subunits on nAChR-expressing dopaminergic terminals in NAc synaptosomes [229]. Moreover, nicotine self-administration is associated with decreased mGlu2/3 receptor expression in the NAc shell [93].…”

Modulation of excitatory neurotransmission by neuronal/glial signalling molecules: interplay between purinergic and glutamatergic systems

“…nACh receptors cooperate with coexisting presynaptic NMDA receptors in the facilitation of noradrenaline and dopamine release in hippocampal and striatal nerve terminals, respectively [145,146]. In contrast, nicotine has been reported to evoke internalization of presynaptic NMDA receptors in dopaminergic terminals of the rat nucleus accumbens resulting in decreased NMDA-induced dopamine release [147]. On the other hand, nicotine pretreatment increased the responses of the NMDA receptors, which contain the GluN2A subunits, via activation of α7-nACh receptor subtypes on the glutamatergic nerve endings of the nucleus accumbens [148].…”