Abstract
We here provide functional and immunocytochemical evidence supporting the co-localization and functional interaction between nicotinic acetylcholine receptors (nAChRs) and N-methyl-D-aspartic acid receptors (NMDARs) in glutamatergic terminals of the nucleus accumbens (NAc). Immunocytochemical studies showed that a significant percentage of NAc terminals were glutamatergic and possessed GluN1 and α7-containing nAChR. A short-term pre-exposure of synaptosomes to nicotine (30 µM) or choline (1 mM) caused a significant potentiation of the 100 µM NMDA-evoked [3H]D-aspartate ([3H]D-Asp) outflow, which was prevented by α-bungarotoxin (100 nM). The pre-exposure to nicotine (100 µM) or choline (1 mM) also enhanced the NMDA-induced cytosolic free calcium levels, as measured by FURA-2 fluorescence imaging in individual NAc terminals, an effect also prevented by α-bungarotoxin. Pre-exposure to the α4-nAChR agonists 5IA85380 (10 nM) or RJR2429 (1 µM) did not modify NMDA-evoked ([3H]D-Asp) outflow and calcium transients. The NMDA-evoked ([3H]D-Asp) overflow was partially antagonized by the NMDAR antagonists MK801, D-AP5, 5,7-DCKA and R(-)CPP and unaffected by the GluN2B-NMDAR antagonists Ro256981 and ifenprodil. Notably, pre-treatment with choline increased GluN2A biotin-tagged proteins. In conclusion, our results show that the GluN2A-NMDA receptor function can be positively regulated in NAc terminals in response to a brief incubation with α7 but not α4 nAChRs agonists. This might be a general feature in different brain areas since a similar nAChR-mediated bolstering of NMDA-induced ([3H]D-Asp) overflow was also observed in hippocampal synaptosomes.
Highlights
IntroductionAdaptive changes in the glutamatergic inputs triggering information processing in the nucleus accumbens (NAc)are increasingly recognized as key features underlying mood dysfunction and addiction (Carlezon and Thomas, 2009; Reissner and Kalivas, 2010)
Since we have previously shown that nicotinic acetylcholine receptors (nAChR) can control the responses of presynaptic ionotropic glutamate receptors through the regulation of their trafficking in and out of the plasma membrane (Grilli et al, 2012; Salamone et al, 2014), we posited that the nicotine-induced increase of the NMDA response in nucleus accumbens (NAc) glutamatergic terminals would rely on a control of the trafficking of GluN2A-containing N-methyl-D-aspartate receptor (NMDAR)
The present study shows that the activation of nAChR enhances the ability of NMDAR to trigger neurotransmitter release from glutamatergic terminals of the NAc
Summary
Adaptive changes in the glutamatergic inputs triggering information processing in the nucleus accumbens (NAc)are increasingly recognized as key features underlying mood dysfunction and addiction (Carlezon and Thomas, 2009; Reissner and Kalivas, 2010). In particular N-methyl-D-aspartic acid receptors (NMDARs) play a critical role in these adaptive changes (Ma et al, 2009), which are modulated by the cholinergic system, namely through nicotinic acetylcholine receptors (nAChRs; Giocomo and Hasselmo, 2007; Timofeeva and Levin, 2011) These two signaling systems are intertwined as heralded by the ability of nicotine to modulate both the subunit composition (Delibas et al, 2005; Levin et al, 2005; Wang et al, 2007) and several functions of NMDAR (Yamazaki et al, 2006; Liechti and Markou, 2008; Lin et al, 2010; Li et al, 2013; Ávila-Ruiz et al, 2014; Callahan et al, 2014; Salamone et al, 2014). We combined immunological, pharmacological and neurochemical approaches applied to purified nerve terminals to study NMDAR function in glutamatergic terminals in the NAc and we tested whether these presynaptic NMDARs were controlled by nAChRs
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