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. 2009 Oct 7;29(40):12428-39.
doi: 10.1523/JNEUROSCI.2939-09.2009.

Chronic nicotine selectively enhances alpha4beta2* nicotinic acetylcholine receptors in the nigrostriatal dopamine pathway

Cheng Xiao  1 , Raad Nashmi, Sheri McKinney, Haijiang Cai, J Michael McIntosh, Henry A Lester
Affiliations

Chronic nicotine selectively enhances alpha4beta2* nicotinic acetylcholine receptors in the nigrostriatal dopamine pathway

Cheng Xiao et al. J Neurosci. .

Abstract

These electrophysiological experiments, in slices and intact animals, study the effects of in vivo chronic exposure to nicotine on functional alpha4beta2* nAChRs in the nigrostriatal dopaminergic (DA) pathway. Recordings were made in wild-type and alpha4 nicotinic acetylcholine receptor (nAChR) subunit knock-out mice. Chronic nicotine enhanced methyllycaconitine citrate hydrate-resistant, dihydro-beta-erythroidine hydrobromide-sensitive nicotinic currents elicited by 3-1000 mum ACh in GABAergic neurons of the substantia nigra pars reticulata (SNr), but not in DA neurons of the substantia nigra pars compacta (SNc). This enhancement leads to higher firing rates of SNr GABAergic neurons and consequently to increased GABAergic inhibition of the SNc DA neurons. In the dorsal striatum, functional alpha4* nAChRs were not found on the neuronal somata; however, nicotine acts via alpha4beta2* nAChRs in the DA terminals to modulate glutamate release onto the medium spiny neurons. Chronic nicotine also increased the number and/or function of these alpha4beta2* nAChRs. These data suggest that in nigrostriatal DA pathway, chronic nicotine enhancement of alpha4beta2* nAChRs displays selectivity in cell type and in nAChR subtype as well as in cellular compartment. These selective events augment inhibition of SNc DA neurons by SNr GABAergic neurons and also temper the release of glutamate in the dorsal striatum. The effects may reduce the risk of excitotoxicity in SNc DA neurons and may also counteract the increased effectiveness of corticostriatal glutamatergic inputs during degeneration of the DA system. These processes may contribute to the inverse correlation between tobacco use and Parkinson's disease.

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Figures

Figure 1.
Figure 1.
Chronic nicotine modifies nicotinic currents in substantia nigra neurons. Nicotinic currents in response to puff application of 1 mm ACh were recorded from voltage-clamped substantia nigra neurons (VH = −60 mV) in midbrain slices of WT mice (A1, B1, B2, D1, E1, and E2 in the presence of 10 nm MLA) and α4-KO mice (A2 and D2). A1, DHβE (0.3 μm) blocked MLA-resistant nicotinic currents in SNr GABAergic neurons of WT mice. A2, Nicotinic currents in SNr GABAergic neurons of α4-KO mice were blocked by MLA (10 nm). B1, B2, Typical nicotinic responses, elicited by 10 μm and 1 mm ACh, recorded from SNr GABAergic neurons in chronic vehicle-treated (B1) and nicotine-treated (B2) mice. C1, Dose–response relations of MLA-resistant nicotinic currents in SNr GABAergic neurons of chronic nicotine (solid circle)- and vehicle (open circle)-treated WT mice. C2, MLA-resistant currents elicited by lower ACh concentrations as a percentage of 1 mm ACh responses. D1, DHβE (0.3 μm) blocked MLA-resistant nicotinic currents in SNc DA neurons of WT mice. D2, In seven of nine SNc DA neurons of α4-KO mice, MLA-resistant nicotinic currents were blocked by either DHβE (0.3 μm) or α-conotoxin MII (Ctx MII, 0.1 μm). The data in the two panels were recorded from the same neuron. E1, E2, Typical nicotinic responses, elicited by 30 μm and 1 mm ACh, recorded from SNc DA neurons in chronic vehicle-treated (E1) and nicotine-treated (E2) mice. F, Dose–response relations of MLA-resistant nicotinic currents in SNc DA neurons of chronic nicotine (solid circle)- and vehicle (open circle)-treated WT mice. Arrows indicate the application of ACh. Data in summary are shown as mean ± SEM. *p < 0.05, **p < 0.01, chronic nicotine- versus vehicle-treated mice.
Figure 2.
Figure 2.
Chronic nicotine modifies firing rates in substantia nigra neurons: the role of α4* nAChRs. The spikes were recorded, using whole-cell patch-clamp technique, from substantia nigra neurons in midbrain slices of WT (A1, D1, and F) and α4-KO (B and D2) mice, and also with SNr GABAergic neurons in vivo by using single-unit extracellular recording (A2). A1, A2, B, Chronic nicotine increases the firing rate of SNr GABAergic neurons in midbrain slices (A1) and in vivo (A2), but not in midbrain slices of α4-KO mice (B). C, Summary of data. D1, D2, E, In contrast, chronic nicotine decreases the activity of SNc DA neurons in WT mice (D1, pooled data; E, summary), but not in α4-KO mice (D2, pooled data; E, summary). F, Summarized time course showing that GABAzine (10 μm, a GABAA receptor blocker) eliminated the difference in the baseline firing rate of SNc DA neurons between chronic nicotine- and vehicle-treated WT mice. Data in summary are shown as mean ± SEM. ns, Not significant, chronic nicotine- versus vehicle-treated mice.
Figure 3.
Figure 3.
Chronic nicotine augments GABAergic inhibition to SNc DA neurons via presynaptic mechanisms. The sIPSCs (A1, A3), eIPSCs (B), and mIPSCs (A2, A3) were recorded from SNc DA neurons. A1–A3, Representative traces of sIPSCs (A1), mIPSCs (A2), and summary of IPSC frequency (A3) in chronic vehicle- and nicotine-treated mice. B, Averaged traces of maximal eIPSCs in all recorded neurons in chronic vehicle- or nicotine-treated mice. C, Representative traces of sIPSCs, showing that chronic nicotine enhanced the inhibition of sIPSC frequency by DHβE (0.3 μm). Summarized data are shown as mean ± SEM. ns, Not significant, chronic nicotine- versus vehicle-treated mice.
Figure 4.
Figure 4.
Current–voltage relations and nicotinic currents in striatal neurons. A–D, Top, Representative records from an MSN (A1), an FS interneuron (B1), a cholinergic interneuron (C1), and an LTS interneuron (D1), identified as described in Materials and Methods by their distinct responses to 2 s current injections (for MSN and FS: initiated from −160 pA with an increment of 40 pA; for cholinergic and LTS: initiated from −80 pA with an increment of 20 pA). Middle, Nicotinic currents recorded from voltage-clamped neurons (VH = −70 mV) in response to a puff of ACh (100–300 μm) with 0.5 μm atropine and 20 μm CNQX. The nicotinic currents in MSN (A2), FS (B2), and cholinergic neurons (C2) were blocked by 10 nm MLA. The nicotinic current in one LTS was blocked by 5 μm MEC. E, In a typical MSN, nicotinic current was recorded at 5 min intervals before (Control), during (1 μm nicotine), and after (Wash) the perfusion of 1 μm nicotine, and also in the presence of 10 nm MLA. Upper bars show each condition; negative minutes denote the time before the application of nicotine. Arrows in A2–D2 and E indicate ACh puff (100 ms, 20 PSI).
Figure 5.
Figure 5.
α4β2* nAChRs modulate MSN neuronal excitability. A, B, In MSN, the EPSP–spike coupling ratio was increased by 1 μm nicotine (A1, A2, typical traces, A3, pooled data), and 0.3 μm DHβE (B1, B2, typical traces, B3, pooled data). Insets of A1, A2 are expanded traces as indicated. CNQX (20 μm) blocked EPSPs. C, Nicotine (1 μm) did not change the EPSP–spike coupling ratio in MSNs of α4-KO mice (C1, C2, typical traces; C3, pooled data).
Figure 6.
Figure 6.
nAChRs and DA D2/D3 receptors modulate sEPSCs in MSNs. A, Typical traces (5 s, A1, A2) and time course (A3) of nicotine enhancement of sEPSCs in the absence (A1) or presence (A2) of sulpiride (10 μm). B, DHβE (0.3 μm) increases sEPSC frequency (B1, 5 s typical traces; B3, time course). The effect was also blocked by sulpiride (10 μm, B2, typical traces; B3, time course). C, MEC enhances sEPSC frequency in WT but not in α4-KO mice (C1, representative traces; C2, time course). D, Immunohistochemistry of TH (red), α4-YFP* nAChRs (green), and their colocalization (arrow) in the dorsal striatum. Data in time course and summary are shown as mean ± SEM.
Figure 7.
Figure 7.
Chronic nicotine augments nicotinic modulation of spontaneous EPSCs in MSNs. A, chronic nicotine augments nicotine (1 μm) enhancement of spontaneous EPSC frequency (A1, 5 s typical traces; A2, summarized time course). B, Chronic nicotine strengthens DHβE (0.3 μm) enhancement of spontaneous EPSC frequency (B1, 5 s typical traces; B2, summarized time course). C, Chronic nicotine reduces baseline sEPSC frequency (C1, 5 s typical traces; C2, pooled data for sEPSC frequency). Data in summarized time courses are shown as mean ± SEM.
Figure 8.
Figure 8.
Diagram of chronic nicotine modulation of nigrostriatal pathway. A, In untreated substantia nigra, ACh activates nAChRs on both SNr GABAergic neurons and SNc DA neurons. B, After chronic nicotine treatment, the nAChRs in the SNr GABAergic neuron somata, but not those in the SNc DA neuron somata, are upregulated. The activation of nAChRs by endogenous ACh causes hyperactivity of SNr GABAergic neurons, which inhibits SNc DA neurons. C, In untreated striatum, ACh activates nAChRs on DA terminals and facilitates DA release. DA activates D2/D3 receptors (D2R) on glutamatergic terminals and inhibits glutamate (Glu) release. D, Chronic nicotine upregulates nAChRs on DA terminals, enhances DA release, and causes a further inhibition of Glu release.
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