Abstract
Smoking is the leading cause of preventable death in the United States and success rates for quitting remain low. High relapse rates are attributed to pervasive nicotine-reinforced associative learning of incentive cues that is highly resistant to extinction. Why such learning is so persistent is poorly understood but may arise as a consequence of neuroadaptations in synaptic plasticity induced by chronic nicotine. We used whole-cell patch clamp recording to investigate the effect of chronic nicotine (cNIC) on synaptic plasticity in dopamine D2 receptor-expressing medium-spiny neurons in the indirect, striatopallidal pathway in dorsolateral striatum. Mice exposed to cNIC exhibited long-term potentiation in response to high-frequency stimulation instead of the expected depression. cNIC decreased baseline AMPA/NMDA ratio, arising from increased NMDA currents enriched in the NR2B subunit with a concomitant upregulation of NMDA-only, silent synapses. These data demonstrate that cNIC can increase silent synapses in MSNs, as observed with cocaine and opiates, and alter the regulation of corticostriatal plasticity. Prior work has characterized cocaine- and morphine-induced upregulation of silent synapses in the ventral striatum; we show it can occur in the dorsal striatum, a region associated with later stages of addiction, craving, and cue-induced relapse.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Abburi C, Wolfman SL, Metz RAE, Kamber R, McGehee DS, McDaid J (2016). Tolerance to Ethanol or nicotine results in increased ethanol self-administration and long-term depression in the dorsolateral striatum. eNeuro 3: ENEURO.0112–15.
Augustin SM, Beeler JA, McGehee DS, Zhuang X (2014). Cyclic AMP and afferent activity govern bidirectional synaptic plasticity in striatopallidal neurons. J Neurosci 34: 6692–6699.
Ávila-Ruiz T, Carranza V, Gustavo L-L, Limón DI, Martínez I, Flores G et al (2014). Chronic administration of nicotine enhances NMDA-activated currents in the prefrontal cortex and core part of the nucleus accumbens of rats: chronic administration of nicotine and NMDA currents. Synapse 68: 248–256.
Bagetta V, Picconi B, Marinucci S, Sgobio C, Pendolino V, Ghiglieri V et al (2011). Dopamine-dependent long-term depression is expressed in striatal spiny neurons of both direct and indirect pathways: implications for Parkinson’s disease. J Neurosci 31: 12513–12522.
Brown TE, Lee BR, Mu P, Ferguson D, Dietz D, Ohnishi YN et al (2011). A silent synapse-based mechanism for cocaine-induced locomotor sensitization. J Neurosci 31: 8163–8174.
Brunzell DH, Russell DS, Picciotto MR (2003). In vivo nicotine treatment regulates mesocorticolimbic CREB and ERK signaling in C57Bl/6J mice. J Neurochem 84: 1431–1441.
Caggiula AR, Donny EC, White AR, Chaudhri N, Booth S, Gharib MA et al (2001). Cue dependency of nicotine self-administration and smoking. Pharmacol Biochem Behav 70: 515–530.
Calabresi P, Saiardi A, Pisani A, Baik J-H, Centonze D, Mercuri NB et al (1997). Abnormal synaptic plasticity in the striatum of mice lacking dopamine D2 receptors. J Neurosci 17: 4536–4544.
Choi S, Lovinger DM (1997). Decreased probability of neurotransmitter release underlies striatal long-term depression and postnatal development of corticostriatal synapses. Proc Natl Acad Sci USA 94: 2665–2670.
Dani JA, Ji D, Zhou F-M (2001). Synaptic plasticity and nicotine addiction. Neuron 31: 349–352.
Di Chiara G (2000). Role of dopamine in the behavioural actions of nicotine related to addiction. Eur J Pharmacol 393: 295–314.
Dong Y, Nestler EJ (2014). The neural rejuvenation hypothesis of cocaine addiction. Trends Pharmacol Sci 35: 374–383.
Everitt BJ, Robbins TW (2016). Drug addiction: updating actions to habits to compulsions ten years on. Annu Rev Psychol 67: 23–50.
Exley R, Clements Ma, Hartung H, Mcintosh JM, Franklin M, Bermudez I et al (2013). Striatal dopamine transmission is reduced after chronic nicotine with a decrease in a6-nicotinic receptor control in nucleus accumbens. Eur J Neurosci 38: 3036–3043.
Gerdeman GL, Partridge JG, Lupica CR, Lovinger DM (2003). It could be habit forming: drugs of abuse and striatal synaptic plasticity. Trends Neurosci 26: 184–192.
Graziane NM, Sun S, Wright WJ, Jang D, Liu Z, Huang YH et al (2016). Opposing mechanisms mediate morphine- and cocaine-induced generation of silent synapses. Nat Neurosci 19: 915–925.
Hanse E, Seth H, Riebe I (2013). AMPA-silent synapses in brain development and pathology. Nat Rev Neurosci 14: 839–850.
Huang YH, Lin Y, Mu P, Lee BR, Brown TE, Wayman G et al (2009). In vivo cocaine experience generates silent synapses. Neuron 63: 40–47.
Huang Y-Y, Kandel ER, Levine A (2008). Chronic nicotine exposure induces a long-lasting and pathway-specific facilitation of LTP in the amygdala. Learn Mem 15: 603–610.
Hyman SE, Malenka RC, Nestler EJ (2006). Neural mechanisms of addiction: the role of reward-related learning and memory. Annu Rev Neurosci 29: 565–598.
Kim J, Alger BE (2001). Random response fluctuations lead to spurious paired-pulse facilitation. J Neurosci 21: 9608–9618.
Klanker M, Feenstra M, Denys D (2013). Dopaminergic control of cognitive flexibility in humans and animals. Front Neurosci 7: 201.
Koranda JL, Cone JJ, McGehee DS, Roitman MF, Beeler JA, Zhuang X (2014). Nicotinic receptors regulate the dynamic range of dopamine release in vivo. J Neurophysiol 111: 103–111.
Koranda JL, Krok AC, Xu J, Contractor A, McGehee DS, Beeler JA et al (2016). Chronic nicotine mitigates aberrant inhibitory motor learning induced by motor experience under dopamine deficiency. J Neurosci 36: 5228–5240.
Koya E, Cruz FC, Ator R, Golden SA, Hoffman AF, Lupica CR et al (2012). Silent synapses in selectively activated nucleus accumbens neurons following cocaine sensitization. Nat Neurosci 15: 1556–1562.
Kreitzer AC, Malenka RC (2007). Endocannabinoid-mediated rescue of striatal LTD and motor deficits in Parkinson’s disease models. Nature 445: 643–647.
Kreitzer AC, Malenka RC (2008). Striatal plasticity and basal ganglia circuit function. Neuron 60: 543–554.
Lee BR, Ma Y-Y, Huang YH, Wang X, Otaka M, Ishikawa M et al (2013). Maturation of silent synapses in amygdala-accumbens projection contributes to incubation of cocaine craving. Nat Neurosci 16: 1644–1651.
Lerner TN, Kreitzer AC (2011). Neuromodulatory control of striatal plasticity and behavior. Curr Opin Neurobiol 21: 322–327.
Lerner TN, Kreitzer AC (2012). RGS4 is required for dopaminergic control of striatal LTD and susceptibility to Parkinsonian motor deficits. Neuron 73: 347–359.
Lovinger DM (2010). Neurotransmitter roles in synaptic modulation, plasticity and learning in the dorsal striatum. Neuropharmacology 58: 951–961.
Mansvelder HD, McGehee DS (2000). Long-term potentiation of excitatory inputs to brain reward areas by nicotine. Neuron 27: 349–357.
Marie H, Morishita W, Yu X, Calakos N, Malenka RC (2005). Generation of silent synapses by acute in vivo expression of CaMKIV and CREB. Neuron 45: 741–752.
Marttila K, Raattamaa H, Ahtee L (2006). Effects of chronic nicotine administration and its withdrawal on striatal FosB/ΔFosB and c-Fos expression in rats and mice. Neuropharmacology 51: 44–51.
Matta SG, Balfour DJ, Benowitz NL, Boyd RT, Buccafusco JJ, Caggiula AR et al (2007). Guidelines on nicotine dose selection for in vivo research. Psychopharmacology 190: 269–319.
Ma Y-Y, Lee BR, Wang X, Guo C, Liu L, Cui R et al (2014). Bidirectional modulation of incubation of cocaine craving by silent synapse-based remodeling of prefrontal cortex to accumbens projections. Neuron 83: 1453–1467.
McClernon FJ, Hiott FB, Huettel SA, Rose JE (2005). Abstinence-induced changes in self-report craving correlate with event-related FMRI responses to smoking cues. Neuropsychopharmacology 30: 1940–1947.
Nakajima A, Kinugasa Y, Torii J, Hishinuma T, Tomioka Y, Yamada K et al (2012). Repeated treatment with nicotine induces phosphorylation of NMDA receptor NR2B subunit in the brain regions involved in behavioral sensitization. Neurosci Lett 524: 133–138.
Perez XA, Ly J, McIntosh JM, Quik M (2012). Long-term nicotine exposure depresses dopamine release in nonhuman primate nucleus accumbens. J Pharmacol Exp Ther 342: 335–344.
Picconi B, Centonze D, Håkansson K, Bernardi G, Greengard P, Fisone G et al (2003). Loss of bidirectional striatal synaptic plasticity in L-DOPA–induced dyskinesia. Nat Neurosci 6: 501–506.
Pierce JP, Cummins SE, White MM, Humphrey A, Messer K (2012). Quitlines and nicotine replacement for smoking cessation: do we need to change policy? Annu Rev Public Health 33: 341–356.
Pluzarev O, Pandey SC (2004). Modulation of CREB expression and phosphorylation in the rat nucleus accumbens during nicotine exposure and withdrawal. J Neurosci Res 77: 884–891.
Polesskaya OO, Smith RF, Fryxell KJ (2007). Chronic nicotine doses down-regulate PDE4 isoforms that are targets of antidepressants in adolescent female rats. Biol Psychiatry 61: 56–64.
Rose EJ, Ross TJ, Salmeron BJ, Lee M, Shakleya DM, Huestis MA et al (2013). Acute nicotine differentially impacts anticipatory valence- and magnitude-related striatal activity. Biol Psychiatry 73: 280–288.
Shen W, Flajolet M, Greengard P, Surmeier DJ (2008). Dichotomous dopaminergic control of striatal synaptic plasticity. Science 321: 848–851.
Smolka MN, Bühler M, Klein S, Zimmermann U, Mann K, Heinz A et al (2006). Severity of nicotine dependence modulates cue-induced brain activity in regions involved in motor preparation and imagery. Psychopharmacology 184: 577–588.
Surmeier DJ, Graves SM, Shen W (2014). Dopaminergic modulation of striatal networks in health and Parkinson’s disease. Curr Opin Neurobiol 29: 109–117.
Tashev R, Moura PJ, Venkitaramani DV, Prosperetti C, Centonze D, Paul S et al (2009). A substrate trapping mutant form of striatal-enriched protein tyrosine phosphatase prevents amphetamine-induced stereotypies and long-term potentiation in the striatum. Biol Psychiatry 65: 637–645.
US Department of Health and Human Services (2014). The health consequences of smoking—50 years of progress. A report of the Surgeon General. https://www.surgeongeneral.gov/library/reports/50-years-of-progress/full-report.pdf.
Whitaker LR, Carneiro de Oliveira PE, McPherson KB, Fallon RV, Planeta CS, Bonci A et al (2015). Associative learning drives the formation of silent synapses in neuronal ensembles of the nucleus accumbens. Biol Psychiatry 80: 246–256.
Yamazaki Y, Jia Y, Niu R, Sumikawa K (2006). Nicotine exposure in vivo induces long-lasting enhancement of NMDA receptor-mediated currents in the hippocampus: chronic nicotine and synaptic plasticity. Eur J Neurosci 23: 1819–1828.
Yin HH, Knowlton BJ (2006). The role of the basal ganglia in habit formation. Nat Rev Neurosci 7: 464–476.
Acknowledgements
We thank David Lovinger for his advice and feedback throughout this work. We thank Joshua Brumberg for his troubleshooting assistance.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Xia, J., Meyers, A. & Beeler, J. Chronic Nicotine Alters Corticostriatal Plasticity in the Striatopallidal Pathway Mediated By NR2B-Containing Silent Synapses. Neuropsychopharmacol 42, 2314–2324 (2017). https://doi.org/10.1038/npp.2017.87
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/npp.2017.87
This article is cited by
-
Cofilin linked to GluN2B subunits of NMDA receptors is required for behavioral sensitization by changing the dendritic spines of neurons in the caudate and putamen after repeated nicotine exposure
Behavioral and Brain Functions (2024)
-
Acute and protracted abstinence from methamphetamine bidirectionally changes intrinsic excitability of indirect pathway spiny projection neurons in the dorsomedial striatum
Scientific Reports (2022)
-
Cellular and Molecular Changes in Hippocampal Glutamate Signaling and Alterations in Learning, Attention, and Impulsivity Following Prenatal Nicotine Exposure
Molecular Neurobiology (2020)
-
Dorsolateral striatal miR-134 modulates excessive methamphetamine intake in self-administering rats
Metabolic Brain Disease (2019)
-
Dopamine and addiction: what have we learned from 40 years of research
Journal of Neural Transmission (2019)
