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Selective Α4β2 Nicotinic Acetylcholine Receptor Agonists Target

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Selective Α4β2 Nicotinic Acetylcholine Receptor Agonists Target Neuropsychopharmacology (2011) 36, 1366–1374 & 2011 American College of Neuropsychopharmacology. All rights reserved 0893-133X/11 $32.00 www.neuropsychopharmacology.org Selective a4b2 Nicotinic Acetylcholine Receptor Agonists Target Epigenetic Mechanisms in Cortical GABAergic Neurons Ekrem Maloku1, Bashkim Kadriu1, Adrian Zhubi1, Erbo Dong1, Fabio Pibiri1, Rosalba Satta1 and Alessandro Guidotti*1 1 The Psychiatric Institute, Department of Psychiatry, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA Nicotine improves cognitive performance and attention in both experimental animals and in human subjects, including patients affected by neuropsychiatric disorders. However, the specific molecular mechanisms underlying nicotine-induced behavioral changes remain unclear. We have recently shown in mice that repeated injections of nicotine, which achieve plasma concentrations comparable to those reported in high cigarette smokers, result in an epigenetically induced increase of glutamic acid decarboxylase 67 (GAD67) expression. Here we explored the impact of synthetic a4b2 and a7 nAChR agonists on GABAergic epigenetic parameters. Varenicline (VAR), a high-affinity partial agonist at a4b2 and a lower affinity full agonist at a7 neuronal nAChR, injected in doses of 1–5 mg/kg/s.c. twice daily for 5 days, elicited a 30–40% decrease of cortical DNA methyltransferase (DNMT)1 mRNA and an increased expression of GAD67 mRNA and protein. This upregulation of GAD67 was abolished by the nAChR antagonist mecamylamine. Furthermore, the level of MeCP2 binding to GAD67 promoters was significantly reduced following VAR administration. This effect was abolished when VAR was administered with mecamylamine. Similar effects on cortical DNMT1 and GAD67 expression were obtained after administration of A–85380, an agonist that binds to a4b2 but has negligible affinity for a3b4 or a7 subtypes containing nAChR. In contrast, PNU–282987, an agonist of the homomeric a7 nAChR, failed to decrease cortical DNMT1 mRNA or to induce GAD67 expression. The present study suggests that the a4b2 nAChR agonists may be better suited to control the epigenetic alterations of GABAergic neurons in schizophrenia than the a7 nAChR agonists. Neuropsychopharmacology (2011) 36, 1366–1374; doi:10.1038/npp.2011.21; published online 2 March 2011 Keywords: schizophrenia; varenicline; DNA methyltransferase-1; GAD ; A–85380; PNU–282987 67 INTRODUCTION psychiatric subjects, a decrease of high- (a4b2) and low (a )-affinity nAChR subtypes is detected in the hippocam- Protracted and repeated administration of nicotine to 7 pus and cortex (Freedman et al, 1995; Olincy et al, 1997; laboratory animals, and the inhalation of large amounts of Breese et al, 2000) along with GABAergic neuropathologies nicotine from tobacco smoking in healthy human subjects in the same brain areas (Akbarian et al, 1995; Guidotti et al, and schizophrenia (SZ) patients results in an increased 2000, 2005; Lewis et al, 2005; Benes et al, 2007). These attention span and in an improvement of sensory/cognitive neuropathologies are characterized by the decreased functions (Freedman et al, 2008; Evans and Drobes, 2009; expression of glutamic acid decarboxylase 67 (GAD ) and Hasselmo and Sarter, 2011). However, the precise molecular 67 the increased expression of DNA methyltransferases correlates of the behavioral actions of nAChR stimulation (DNMTs) (Ruzicka et al, 2007; Veldic et al, 2005; Zhubi have not been extensively studied. et al, 2009; Guidotti et al, 2010). DNMTs are a family of It has now been established that when the postmortem enzymes that catalyze the methylation of the carbon 50 of brain of SZ patients is compared with that of non- cytosines embedded in cytosine phosphodiester guanine (CpG) islands of many gene promoters (Van Emburgh and Robertson, 2008). Evidence suggests that GABAergic *Correspondence: Dr A Guidotti, The Psychiatric Institute, Depart- ment of Psychiatry, College of Medicine, University of Illinois at promoter hypermethylation, mediated by the overexpres- Chicago, 1601 W Taylor Street, Chicago, IL 60612, USA. Tel: + 1 312 sion of DNMTs, may be an underlying pathophysiological 413 4594, Fax: + 1 312 413 4569, E-mail: [email protected] mechanism leading to a downregulation of GABAergic Received 21 December 2010; revised 26 January 2011; accepted 28 transmission in SZ patients (Guidotti et al, 2010). Down- January 2011 regulation of GABAergic transmission may in turn lead to Selective a4b2 nicotinic acetylcholine receptor agonists E Maloku et al 1367 an impairment of the cortical gamma oscillations related to This has provided a rationale for testing whether VAR or sensory/cognitive deficits in these patients (Lewis and the more selective a4b2 (ie, A–85380) or a7 (ie, PNU–282987) Gonzalez-Burgos, 2008). nAChR agonists with reduced nicotine-like side-effect lia- We have recently shown in mice that repeated injections bility, elicit an epigenetic-GABAergic gene upregulation in of nicotine, which achieve plasma concentrations compar- cortical or in hippocampal GABAergic neurons. able to those reported by heavy cigarette smokers, result in: (1) a downregulation of DNMT expression, (2) a decrease of GAD67 promoter methylation, and (3) an increased expres- MATERIALS AND METHODS sion of GAD67 in cortical or hippocampal but not in striatal GABAergic neurons (Satta et al, 2008). Animals and Drug Administration As these effects of nicotine are blocked by mecamylamine Male Swiss albino mice (Harlan Breeders), 60–80 days old but not by hexamethonium, the data support the notion that and weighing 20–25 g were used in this study. The following nAChR ligands active at central a4b2 and a7 nAChR may drugs were used: mecamylamine hydrochloride and 3-(2(S)- represent an effective pharmacological tool to correct the azetidinyl methoxy)pyridine dihydrochloride (A–85380), epigenetic GABAergic neuropathology present in SZ patients. from Sigma–Aldrich. N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]- Nicotine, acting on a variety of central and peripheral 4-chlorobenzamide hydrochloride (PNU–282987) and VAR nAChRs, also elicits unwanted side effects such as were a generous gift from Dr Mihaly Hajos (Department of cardiovascular toxicity, gastrointestinal toxicity, tremor, Neuroscience, Pfizer Global Research and Development, and addiction. Furthermore, if nicotine is administered by Groton, CT). All drugs were dissolved in a volume of saline smoking, serious comorbid health conditions are likely to solution corresponding to 0.05 ml/10 g body weight and develop. Hence, the potential of a4b2 and/or a7 nAChR full were injected s.c. or i.p. as indicated. or partial agonists for increasing attention and cognitive We studied the effect of VAR, A–85830, and PNU–289987 performance (Potter et al, 1999; Wilens et al, 2006; Wilens in Swiss albino mice because in a previous study (Satta et al, and Decker, 2007; Dunbar et al, 2007; Howe et al, 2010; 2008), we observed that nicotine injected into these mice in Olincy et al, 2006; Freedman et al, 2008) with minimal doses ranging from 0.75 to 3.5 mg/kg elicited a significant adverse side effects may represent an innovative and dose-related decrease of DNMT1 and an increase of GAD67 efficient way to improve cognitive deficits in patients with expression in the frontal cortex (FC) and hippocampus if neuropsychiatric disorders (Freedman et al, 2008; Smith injected protractedly and repeatedly for at least 4 days. et al, 2009; Hasselmo and Sarter, 2011). Therefore, in this study, to mimic the central effects of To test whether the epigenetic GABAergic events induced nicotine, selective nAChR agonists and antagonists were by the administration of high and repeated doses of nicotine administered for 5 days. Unless otherwise indicated, five can be replicated with specific a4b2 and/or a7 nAChR full or mice per group were used for the analyses. partial agonists endowed with a lower toxic liability than nicotine, we compared the action of varenicline (VAR) (a high-affinity partial agonist at a4b2 and a lower affinity Frontal Cortex Dissection a full agonist at 7 neuronal nAChR) with that of A–85380 To collect FC samples free of striatal tissue, brains were a b (a high-affinity full agonist at 4 2 nAChR) and PNU– sectioned coronally 2 mm anterior to the bregma. The tissue a 282987 (a high-affinity full agonist at 7 nAChR) on anterior to the section was frozen immediately and kept at GABAergic epigenetic parameters (Rollema et al, 2007; À801C until assays were carried out. Mihalak et al, 2006; Smith et al, 2007; Bodnar et al, 2005). VAR has been recently approved for smoking cessation treatment (Faessel et al, 2010). Unlike nicotine, VAR fails to Fear-Conditioning Apparatus increase sympathetic tone, such as the increase of respiratory rate, locomotor activity, and tremor, but at the same time it The fear-conditioning apparatus consisted of a transparent reduces the level of smoking addiction in patients, and blocks acrylic chamber measuring 25 cm wide, 18 cm high and 21 cm nicotine intake in rats with access to nicotine self-administra- deep (San Diego Instruments, San Diego, CA). The cage floor tion (Rollema et al, 2007; George et al, 2010). was composed of stainless steel rods connected to a shock Post-marketing reports of neuropsychiatric symptoms, generator (San Diego Instruments). The chamber was surroun- including agitation, depressed mood, and suicidal ideation in ded by a frame with 16 infrared photo beams. A computer cont- subjects attempting to quit smoking using
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