Vta Da Neurons Of The Nicotine-mediated Glutamatergic Synaptic Plasticity

Part 1 Mechanisms involved in systemic nicotine-induced glutamatergic synaptic plasticity on dopamine neurons in the ventral tegmental areaSystemic exposure to nicotine, acting through nicotinic acetylcholine receptors (nAChRs), induces glutamatergic synaptic plasticity on dopamine (DA) neurons in the ventral tegmental area (VTA), but mechanisms are largely unknown. Here, we report that a single, systemic exposure to nicotine (0.5 mg/kg, i.p.) increases the ratio of VTA DA neuronal currents mediated by AMPA receptors relative to NMDA receptors (AMPA/NMDA) assessed 24 hr later based on slice patch recording. Nicotine-induced increase in AMPA/NMDA occurred after 1 hr exposure and lasted for at least 72 hr (and up to 8 days after repeated nicotine administration). This effect cannot be prevented by systemic injection of eitherα7-nAChR-selective (methyllycaconitine, MLA) orβ2-nAChR (mecamylamine, MEC) antagonist alone but is prevented by co-injection of MLA and MEC. In either nAChRα7 orβ2 subunit knock-out mice, systemic exposure to nicotine increases AMPA/NMDA. Pre-injection of an NMDA receptor antagonist (MK801) or anα1-adrenergic receptor antagonist (prazosin), but not of DA receptor antagonists (SCH23390 plus haloperidol) or a calcineurin inhibitor (cyclosporine), prevents the nicotine-induced increases in AMPA/NMDA. After systemic exposure to nicotine, glutamatergic but not GABAergic transmission is enhanced in VTA DA neurons. Correspondingly, DA neuronal firing monitored using in vivo extracellular single unit recordings is significantly faster in nicotine-treated than in saline-treated rats after 24 hr exposure. Collectively, these findings demonstrate that nicotine exposure at concentrations like those achieved in human cigarette smokers acting via eitherα7- orβ2-nAChRs increases VTA glutamatergic transmission, and consequently initiates glutamatergic synaptic plasticity, which may be an important early neuronal adaptation in developing nicotine reward and dependence.Part 2 Mechanisms involved in nicotine-induced glutamatergic synaptic plasticity on dopamine neurons in the ventral tegmental area slicesSystemic exposure to nicotine induces a variety of adaptive responses in the brain, which are thought to be important to underlie nicotine reward and reinforcement. It has been reported that low concentrations of nicotine promoted the induction of glutamatergic synaptic long-term potentiation (LTP) in dopamine (DA) neurons of midbrain slices contained ventral tegmental area (VTA), but it is unclear whether or not nicotine alone with a smoking-relevant concentration increases synaptic strength. In vivo study induces a plastic alteration in glutamatergic synapses on DA neurons of the VTA after systemic nicotine administration, but the nicotinic acetylcholine receptor (nAChR) subtype that mediates this adaptation within the VTA is unknown. To address these questions, we tested nicotinic effects on glutamatergic synaptic plasticity in VTA DA neurons using patch-clamp recordings in VTA slice preparation. We measured the ratio of AMPA and NMDA receptor-mediated current (AMPA/NMDA) after incubation of VTA slices in a nicotine-contained solution for 1 hr. The results demonstrated that compared to control (normal incubation solution), the incubation of VTA slice with 500 nM nicotine for 1 hr, but not 10 min, significantly increased AMPA/NMDA ratio. Pre-incubation with 10 nMα7-nAChR antagonist, methyllycaconitine (MLA) but not 1μMα4β2-nAChR antagonist, dihydro-β-erythroidine (DHβE) prevented nicotinic effect, suggesting thatα7-nAChRs are mainly mediated nicotinic effect under our experimental conditions. This finding was further supported by the disappearance of this nicotinic effect in nAChRα7 knockout (KO) mice. Furthermore, the nicotine-induced reduction of pair-pulse ratio of evoked excitatory postsynaptic potential in the VTA slices prepared from wild-type mice was absent in that prepared from nAChRα7 KO mice.We conclude that nicotine acting on nAChRs in the VTA is sufficient to increase glutamatergic synaptic strength on DA neurons and theα7-nAChRs likely mediate this nicotinic effect.