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Hilmer Et Al.Pdf Journal of Neuroscience Methods 214 (2013) 163–169 Contents lists available at SciVerse ScienceDirect Journal of Neuroscience Methods jou rnal homepage: www.elsevier.com/locate/jneumeth Basic Neuroscience The effects of lobeline on ␣4␤2* nicotinic acetylcholine receptor binding and 18 uptake of [ F]nifene in rats a,b,∗ a,b c a Ansel T. Hillmer , Dustin W. Wooten , Mohammed Farhoud , Todd E. Barnhart , d a,b,e Jogeshwar Mukherjee , Bradley T. Christian a Department of Medical Physics, University of Wisconsin-Madison, 1111 Highland Avenue, Room 1005, Madison, WI 53705, United States b Waisman Brain Imaging Laboratory, University of Wisconsin-Madison, 1500 Highland Avenue, Madison, WI 53705, United States c Comprehensive Cancer Center, University of Wisconsin-Madison, 1111 Highland Avenue, Room 7057, Madison, WI 53705, United States d Department of Radiological Sciences, University of California-Irvine, B140 Medical Sciences, Irvine, CA 92697, United States e Department of Psychiatry, University of Wisconsin-Madison, 6001 Research Park Blvd, Madison, WI 53719, United States h i g h l i g h t s Lobeline interacts with ␣4␤2* nAChRs and the BBB amine transporter. 18 PET imaging in rats assessed the interaction of lobeline with [ F]nifene in vivo. 18 Lobeline competes strongly with [ F]nifene at the ␣4␤2* site. 18 The cerebellum is not a valid reference region for [ F]nifene in the rat. 18 Small decreases in [ F]nifene BBB transport rates were observed due to lobeline. a r t i c l e i n f o a b s t r a c t Article history: Lobeline is a potential smoking cessation drug with affinity for the ␣4␤2 nicotinic acetylcholine receptor Received 28 November 2012 and may inhibit the blood–brain barrier (BBB) amine transporter. The goal of this work was to use PET Received in revised form 15 January 2013 18 imaging to evaluate the effects of lobeline on the kinetic properties of [ F]nifene in the rat brain. Methods: Accepted 18 January 2013 18 Direct ␣4␤2* competition of lobeline with [ F]nifene was evaluated using imaging experiments with 18 both displacing and blocking doses of lobeline (1 mg/kg, i.v.) given between two injections of [ F]nifene Keywords: separated by 50 min. Inhibition of the BBB amine transporter was examined using a separate imaging 18 [ F]nifene 18 protocol with three injections of [ F]nifene, first at baseline, then following (−)nicotine blocking, and Nicotinic acetylcholine receptor 18 ␣ ␤ PET finally following lobeline blocking. Results: Rapid displacement of [ F]nifene was observed in the 4 2*- ␣ ␤ lobeline rich thalamus following lobeline administration, suggesting direct competition of the drug at 4 2* sites. 18 ␣ ␤ BBB amine transporter Slight decreases in BBB transport of [ F]nifene were observed when the 4 2* system was first saturated − Smoking cessation with ( )nicotine and then given lobeline. This perturbation may be due to inhibition of the BBB amine 18 transporter by lobeline or reductions in blood flow. Significant cerebellar displacement of [ F]nifene was found following the administration of both lobeline and (−)nicotine, indicating detectable specific binding 18 in the rat cerebellum. Conclusion: The competition of lobeline with [ F]nifene is largely dominated at the ␣ ␤ 18 4 2* binding site and only small perturbations in BBB transport of [ F]nifene are seen at the 1 mg/kg dose. Similar experiments could be used to study other drugs as therapeutic agents for smoking cessation with PET. © 2013 Elsevier B.V. All rights reserved. 1. Introduction The ␣4␤2 nicotinic acetylcholine receptor (nAChR) system is Abbreviations: BBB, blood–brain barrier; B/F, bound-to-free ratio; nAChR, nico- an important target for understanding the basis of a wide variety tinic acetylcholine receptor; PET, positron emission tomography; 1TCM, one tissue of neuropathologies. NAChRs have been implicated in Alzheimer’s compartment model. ∗ Corresponding author at: Department of Medical Physics, University of disease (Court et al., 2001), Parkinson’s disease (Burghaus et al., Wisconsin-Madison, 1111 Highland Avenue, Madison, WI 53705, United States. 2003), and tobacco addiction (Poirier et al., 2002), as well Tel.: +1 608 890 2959; fax: +1 608 890 1897. as other neurodevelopemental and neurodegenerative processes E-mail addresses: [email protected] (A.T. Hillmer), [email protected] 18 (Albuquerque et al., 2009). The agonist radioligand, [ F]nifene, (D.W. Wooten), [email protected] (M. Farhoud), [email protected] was developed as a marker for ␣4␤2* nAChRs (the * denotes low (T.E. Barnhart), [email protected] (J. Mukherjee), [email protected] ␣ ␤ (B.T. Christian). levels of binding to other subtypes with 4 or 2 subunits) with 0165-0270/$ – see front matter © 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.jneumeth.2013.01.018 164 A.T. Hillmer et al. / Journal of Neuroscience Methods 214 (2013) 163–169 positron emission tomography (PET) imaging (Pichika et al., 2006). protocols were approved by the institutional animal care and use 18 Our earlier work found high uptake of [ F]nifene consistent with committee (IACUC). ␣ ␤ 4 2 nAChR distribution in the rhesus monkey brain (Hillmer et al., 18 2011). [ F]Nifene also exhibits fast kinetic properties resulting 2.2. PET procedures in accurate quantification of binding potentials in scan times of 45 min, demonstrating utility for investigating processes involving For all PET experiments, subjects were initially anesthetized ␣4␤2* nAChRs (Hillmer et al., 2012). with 5.0% isoflurane, then maintained with 2–3% isoflurane admin- 18 Recent experiments with [ F]nifene in the rat found similar istered via a nose cone for the duration of the PET experiments. binding distributions and kinetic properties, however, evaluation The subjects were placed on a heating pad, with heart and res- of the cerebellum as a suitable reference region was inconclusive piration rates monitored throughout the experiment (BioVet Suite (Kant et al., 2011). The determination of a suitable reference region with heating pad upgrade, M2M Imaging). Subjects were positioned is a critical validation step for analysis of binding levels in single with the brain at the isocenter of the PET scanner. PET data were injection PET studies. Since the cerebellum is a large structure eas- acquired with a Siemens microPET Inveon scanner, which has a field ily delineated without auxiliary MRI data and often contains low of view of 12.7 cm in the axial direction and 10 cm in the transax- receptor levels for neurotransmitters of interest (i.e. dopamine, ial direction with a reported in-plane spatial resolution of 1.5 mm serotonin), it is commonly evaluated as such a reference region. (Constantinescu and Mukherjee, 2009). After acquiring the emis- Previous in vitro studies have shown the cerebellum to contain low sion data, the bed was removed from the microPET scanner and ␣ ␤ levels of 4 2* nAChRs (Happe et al., 1994), making it a candidate transferred to the adjacent microCT Inveon scanner to acquire X-ray reference region for evaluation. transmission data for scatter and attenuation correction. Following The primary mechanism of action for the drug lobeline occurs at completion of the transmission scan the subject was returned to its the ␣4␤2* nAChR site where lobeline binds with nanomolar affinity cage and monitored until fully alert. (Brioni et al., 1996). Interestingly, lobeline has been found to antag- Two different PET scanning protocols, each described in detail onize the effects of nicotine without eliciting a neural response below, were used for the present work. A visual schematic of both from nAChRs. Therefore, lobeline has been considered as a potential protocols is illustrated in Fig. 2. Each protocol was conducted twice, treatment for smoking cessation (Damaj et al., 1997). Previous stud- once on each of two rat subjects. At least two weeks passed between ies have also demonstrated that lobeline blocks the blood–brain each experiment to prevent residual drug from interfering with barrier (BBB) basic amine transporter with a sub-millimolar inhibi- future studies. tion constant (Allen et al., 2003). In addition to nAChRs, lobeline has In the first experimental protocol, conducted with each of the affinity for ␮-opioid receptors at sub-micromolar affinities (Miller two subjects, an i.v. injection of approximately 30 MBq high spe- 18 et al., 2007), and roughly 1–100 ␮mol affinities for a wide variety cific activity [ F]nifene in 500 ␮L saline was given simultaneously of monoamine transporters, including VMAT2, DAT, SERT, and NET with the initiation of data acquisition. PET data was continuously (Miller et al., 2004; Teng et al., 1997). The chemical structures of acquired throughout the experiment for a total of 90 min. After 18 lobeline, [ F]nifene, and nicotine are shown in Fig. 1. The high 40 min of data acquisition, 1.0 mg/kg lobeline hydrochloride in affinity of lobeline for the ␣4␤2 nAChR and its inhibition of the 300 ␮L saline was administered intravenously to examine compet- 18 BBB amine transporter make it an appealing compound for use in itive binding with [ F]nifene. A second lobeline dose (1.0 mg/kg studying the in vivo kinetics of ␣4␤2* nAChR radioligands with PET in 300 ␮L saline) was administered 49 min after scan start to imaging. ensure complete ␣4␤2* saturation by lobeline. After 50 min of data The main aim of this work was to use dynamic PET imaging in the acquisition (1 min after the second lobeline dose), an injection of 18 18 rat brain to assess competition between lobeline and [ F]nifene 22–30 MBq [ F]nifene was given to examine changes in cerebellar ␣ ␤ at both the 4 2* nAChR site and the BBB amine transporter. kinetics before and after lobeline. 18 The effects of lobeline on the in vivo kinetics of [ F]nifene were A second experiment was designed to first fully saturate therefore examined in these two contexts.
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