Putative role of presynaptic alpha7* nicotinic receptors in nicotine stimulated increases of extracellular levels of glutamate and aspartate in the ventral tegmental area.

We have previously provided evidence that the stimulatory action of systemic nicotine on dopamine release in the rat nucleus accumbens is initiated in the ventral tegmental area (VTA), and that it appears to be mediated partly through an indirect, presynaptic mechanism. Thus, it was found that blockade of N-methyl-D-aspartate (NMDA) receptors in the VTA attenuates the enhancing effect of nicotine on extracellular levels of dopamine in the nucleus accumbens. Moreover, the nicotine-induced dopamine output in the nucleus accumbens was found to be blocked by pretreatment with methyllycaconitine (MLA) in the VTA, indicating a role for alpha7* nicotinic acetylcholine receptors (nAChRs) in this mechanism. Thus, nicotine may exert its effects in the VTA through stimulation of alpha7* nAChRs localized on excitatory amino acid (EAA)ergic afferents. To test this hypothesis, we here measured extracellular concentrations of glutamate and aspartate in the VTA in response to systemic nicotine, with or without concurrent infusion of MLA in the VTA, using microdialysis in anaesthetized rats. Since the medial prefrontal cortex is an important source of EAA input to the VTA, we also assessed the density of alpha-bungarotoxin binding sites in the VTA in rats lesioned bilaterally in the prefrontal cortex with ibotenic acid and in sham-lesioned rats by means of quantitative autoradiography. Nicotine (0.5 mg/kg, s.c.) significantly increased extracellular levels of both aspartate and glutamate in the VTA. MLA (0.3 mM) infused locally in the VTA prevented the nicotine-induced increase in glutamate and aspartate levels. Ibotenic acid lesions of the prefrontal cortex decreased the density of alpha-bungarotoxin binding sites in the VTA by about 30%. These data indicate that nicotine increases the extracellular levels of excitatory amino acids in the VTA through stimulation of nAChRs in the VTA and that part of the alpha7* nAChR population in the VTA is localized on neurons originating in the prefrontal cortex.

Schilström B ，Fagerquist MV ，Zhang X ，Hertel P ，Panagis G ，Nomikos GG ，Svensson TH ... -  《SYNAPSE》

Nicotine-induced Fos expression in the nucleus accumbens and the medial prefrontal cortex of the rat: role of nicotinic and NMDA receptors in the ventral tegmental area.

We have previously shown that the nicotine-induced dopamine release in the nucleus accumbens can be attenuated by local administration into the ventral tegmental area (VTA), of antagonists at nicotinic and N-methyl-D-aspartate (NMDA), but not alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors. In the present study, we investigated the role of nicotinic and NMDA receptors in the VTA for the expression of Fos-like immunoreactivity (FLI) in the shell and core of the nucleus accumbens and in the medial prefrontal cortex (mPFC) of the rat after acute nicotine administration. Systemically administered nicotine increased FLI in both the mPFC and the nucleus accumbens when compared to saline controls, although this effect was more pronounced, and reached statistical significance in the nucleus accumbens, especially in the core region. When mecamylamine was delivered by reverse dialysis into the VTA, the systemic nicotine-induced FLI was significantly attenuated in the nucleus accumbens. Similarly, the NMDA receptor antagonist 2-amino-5-phosphonopentanoic acid (AP-5), infused locally in the VTA, also antagonized the nicotine-induced FLI in the nucleus accumbens. Neither mecamylamine nor AP-5 alone affected basal FLI levels in any of the structures studied. Local administration of nicotine in the VTA increased FLI in the nucleus accumbens but not in the mPFC. Since the nicotine-induced FLI is probably due to an increased dopamine release in both the nucleus accumbens and the mPFC, we conclude that FLI in the nucleus accumbens is mediated, to a large extent, through the activation of dopamine neurons via nicotinic and NMDA receptors in the VTA, whereas the nicotine-induced FLI in the mPFC is subjected to a differential control mechanism, tentatively involving nicotinic receptors at the terminal level of the mPFC-projecting dopamine neurons.

Schilström B ，De Villiers S ，Malmerfelt A ，Svensson TH ，Nomikos GG ... -  《SYNAPSE》

Systemic nicotine stimulates dopamine release in nucleus accumbens: re-evaluation of the role of N-methyl-D-aspartate receptors in the ventral tegmental area.

Fu Y ，Matta SG ，Gao W ，Brower VG ，Sharp BM ... -  《JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS》

Presynaptic alpha 7- and beta 2-containing nicotinic acetylcholine receptors modulate excitatory amino acid release from rat prefrontal cortex nerve terminals via distinct cellular mechanisms.

Dickinson JA ，Kew JN ，Wonnacott S 《-》

Systemic nicotine-induced dopamine release in the rat nucleus accumbens is regulated by nicotinic receptors in the ventral tegmental area.

Nisell M ，Nomikos GG ，Svensson TH 《SYNAPSE》