Putative role of presynaptic ?7* nicotinic receptors in nicotine stimulated increases of extracellular levels of glutamate and aspartate in the ventral tegmental area

Abstract

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 α7* nicotinic acetylcholine receptors (nAChRs) in this mechanism. Thus, nicotine may exert its effects in the VTA through stimulation of α7* 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 α‐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 α‐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 α7* nAChR population in the VTA is localized on neurons originating in the prefrontal cortex. Synapse 38:375–383, 2000. © 2000 Wiley‐Liss, Inc.

Functional brain imaging of tobacco use and dependence

“…For example, in response to nicotine, glutamate release has been demonstrated in the prelimbic prefrontal cortex (Gioanni et al, 1999), and glutamate and aspartate release have been demonstrated in the VTA (Schilstrom et al, 2000). The finding of nAChR-induced glutamate release in the prefrontal cortex has also been demonstrated by measuring spontaneous excitatory postsynaptic currents (Lambe et al, 2003).…”

Pro-Cognitive and Antipsychotic Efficacy of the α7 Nicotinic Partial Agonist SSR180711 in Pharmacological and Neurodevelopmental Latent Inhibition Models of Schizophrenia

“…Although little is known on the effects of SSR180711 on mesolimbic DA dynamics (Hansen et al, 2007), it seems unlikely that this agent would directly block NAC DA increase, given the well known action of nicotine to increase DA release in the NAC (Wonnacott et al, 2005), an effect blocked by a7 antagonists (Schilstrom et al, 1998(Schilstrom et al, , 2000. The capacity of SSR180711 to increase glutamate neurotransmission in the hippocampus as well as increase dopamine levels in the PFC (Biton et al, 2007;Pichat et al, 2007) could underlie reversal of amphetamine-induced disruption and potentiation of LI, since both would be expected to reduce mesolimbic DA function and block behavioral effects of amphetamine Grace, 2005, 2007;Grace, 1991;Jackson and Moghaddam, 2001).…”

Galantamine Enhances Dopaminergic Neurotransmission In Vivo Via Allosteric Potentiation of Nicotinic Acetylcholine Receptors

“…Previous data demonstrate that presynaptic a7-containing nAChR in the VTA can enhance glutamate release and activate NMDA receptors on dopamine cells (Mansvelder and McGehee, 2000;Schilström et al, 1998aSchilström et al, , b, 2000. Therefore, in order to test the involvement of putative a7 nAChRs and NMDA receptors, the effect of galantamine was tested in animals pretreated with the a7 nAChR antagonist methyllycaconitine (MLA, 6.0 mg/kg i.p.)…”

“…Specifically, burst firing induced by nicotine is in all probability due to presynaptic enhancement of afferent glutamate release. Nicotine has been shown to activate presynaptic a7-subunit containing nAChRs in the VTA and enhance glutamate release that leads to stimulation of Nmethyl-D-aspartate (NMDA) receptors on dopamine cells (Schilström et al, 1998a(Schilström et al, , b, 2000Mansvelder and McGehee, 2000;Schilström et al, 2003). Moreover, heteromeric b2-containing nAChRs on dopamine cell bodies and g-aminobyturic acid (GABA)-ergic interneurons also influence the activity of dopaminergic neurons (Calabresi et al, 1989;Picciotto et al, 1998;Mansvelder et al, 2002;Schilström et al, 2003).…”