Chronic Nicotine Alters Corticostriatal Plasticity in the Striatopallidal Pathway Mediated By NR2B-Containing Silent Synapses

Neuropsychopharmacology (2017) 42, 2314–2324 © 2017 American College of Neuropsychopharmacology. All rights reserved 0893-133X/17 www.neuropsychopharmacology.org Chronic Nicotine Alters Corticostriatal Plasticity in the Striatopallidal Pathway Mediated By NR2B-Containing Silent Synapses Jianxun Xia1, Allison M Meyers1 and Jeff A Beeler*,1 1 Department of Psychology, Queens College and The Graduate Center, City University of New York, Flushing, NY, USA 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 receptorexpressing medium-spiny neurons in the indirect, striatopallidal pathway in dorsolateral striatum. Mice exposed to cNIC exhibited longterm 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. Neuropsychopharmacology (2017) 42, 2314–2324; doi:10.1038/npp.2017.87; published online 31 May 2017 INTRODUCTION Smoking represents a major public health problem and is the leading cause of preventable death in the United States (US Department of Health and Human Services, 2014). Despite significant reductions in smoking rates over recent decades, 42.1 million continue to smoke in the United States alone (~18% of adults), with new smokers joining daily (US Department of Health and Human Services, 2014). Rates of successful quitting remain very low, estimated at ~ 9–15% for heavy smokers (Pierce et al, 2012). Nicotine, the putative addictive agent in tobacco, is believed to mediate smoking-reinforced associative learning that underlies the cue-induced craving that makes sustained abstinence difficult (Caggiula et al, 2001; Smolka et al, 2006). It is widely believed that this learning is in some way supraphysiological and highly resistant to extinction (Di Chiara, 2000; Hyman et al, 2006), though the physiological mechanisms that underlie the persistence of nicotinereinforced learning are poorly understood (Hyman et al, 2006). *Correspondence: Dr JA Beeler, Department of Psychology, Queens College and The Graduate Center, CUNY, 65-30 Kissena Blvd, Queens, NY 11367, USA, Tel: +718 570 0517, Fax: +773 793 2588, E-mail: Received 5 November 2016; revised 22 April 2017; accepted 25 April 2017; accepted article preview online 2 May 2017 The acute effects of nicotine, including nicotine-induced dopamine release believed to underlie its addictive properties (Dani et al, 2001; Di Chiara, 2000; Mansvelder and McGehee, 2000), have been well studied. Chronic nicotine (cNIC), however, induces neuroadaptations that have been less well characterized. For example, although acute nicotine increases extracellular dopamine, cNIC substantially downregulates evoked dopamine release (Exley et al, 2013; Koranda et al, 2014; Perez et al, 2012). In humans, fMRI studies suggest that cNIC induces neuroadaptations that are independent of acute nicotine state, including reduced reward sensitivity (Rose et al, 2013) and increased cue-reactivity (McClernon et al, 2005). Whether cNIC induces alterations in the regulation of corticostriatal synaptic plasticity has not been investigated. Here we chronically administer nicotine to mice in their drinking water and assess corticostriatal plasticity in striatopallidal medium-spiny neurons of the indirect pathway (iMSNs) in the dorsolateral striatum (DLS). Although the nucleus accumbens (NAc) is widely associated with establishing and maintaining addictive behaviors, in the later stages of addiction, the DLS—a key substrate for habit learning and automaticity (Yin and Knowlton, 2006)—comes into play contributing to cue-induced cravings that promote relapse (Everitt and Robbins, 2016; Gerdeman et al, 2003). Moreover, the dopamine D2 receptor, expressed on iMSNs, plays a pivotal role in behavioral flexibility (Klanker et al, 2013), suggesting this circuit may be critical to Chronic nicotine induces silent synapses J Xia et al 2315 understanding behavioral nicotine addiction. inflexibility associated with MATERIALS AND METHODS Animals Adult mice of 11–12 weeks old were used for all experiments. To identify D2-expressing striatopallidal MSNs, mice were hemizygous for a transgene expressing enhanced green fluorescent protein under control of the Drd2 promoter (D2-EGFP, bacterial artificial chromosome) and backcrossed onto a C57BL/6 background (410 generations). All animal experiments were approved by the Queens College, CUNY, Institutional Animal Care and Use Committee in accordance with National Institutes of Health Guidelines for the responsible use of animals in research. cNIC Exposure Mice were exposed to 100 μg/ml (free base) nicotine via their drinking water for 3 weeks starting at postnatal 60 days. This dose did not alter daily water intake or body weight, as reported previously (Koranda et al, 2014, 2016). Mice were maintained on this schedule of nicotine dosing until they were removed from their homecage, anesthetized, and prepared for electrophysiological recordings. Slice Preparation Mice were anesthetized with isoflurane and decapitated. The brain was quickly removed from the cranial cavity and placed into an ice-cold (4 °C) sucrose-containing artificial cerebrospinal fluid (ACSF), in mM: 200 sucrose, 2.5 KCl, 10 MgSO4, 1.25 NaH2PO4, 26 NaHCO3, 10 glucose, 7 Naascorbate, 3 Na-pyruvate, and maintained at pH 7.4 by oxygenating with 95% O2/5% CO2. Coronal slices (300 μm) containing dorsal striatum were cut using a VT1000 S vibratome (Leica Biosystems, Buffalo Grove, IL). Slices were immediately transferred and incubated for at least 60 min in a holding chamber at 30–32 °C in oxygenated ACSF containing, in mM: 125 NaCl, 2.5 KCl, 2 CaCl2, 1 MgCl2, 1.25 NaH2PO4, 26 NaHCO3, 12.5 glucose, and 1 Naascorbate, continuously bubbled with 95% O2/5% CO2. Then the slices were incubated at room temperature (22–26 °C) during the remaining period of experiments. Electrophysiology Single hemispheric corticostriatal slices were transferred into the recording cham (...truncated)