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NEUROPHARMACOLOGY
Department of Pharmacology, Health Science Center, University of Tennessee, Memphis, Tennessee
Received for publication
December 5, 2003
Accepted
February 6, 2004.
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Abstract |
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; Santos et al., 2002). It is currently approved for the treatment of Alzheimer's disease, a common dementing disorder strongly associated with reduced expression of nAChRs in frontal and temporal cortex and hippocampus (Guan et al., 2000). Galantamine acts by binding at a site on the 
subunit of nAChRs, which is conserved across species, and is close to the acetylcholine binding site (Samochocki et al., 2003). Based on conservation of the sequence of the APL binding region present on known subunits, it has been postulated that galantamine may bind to most, if not all, nAChRs (Maelicke and Albuquerque, 2000). This allosteric action of galantamine occurs only within a specific concentration range. At lower concentrations (0.02-2.0 µM), galantamine has been shown to enhance acetylcholine-driven depolarization of human embryonic kidney-293 cells transfected with human 4
2 nAChRs. In contrast, 10 µM galantamine inhibited this response to acetylcholine, apparently by direct blockade of the ion channel (Samochocki et al., 2000).
Nicotine, the major psychoactive compound in cigarette smoke, affects myriad physiological central nervous system functions by activating nAChRs. For example, in both human and animal studies, nicotine has been reported to enhance memory (Gray et al., 1996; McGehee and Role, 1996). The hippocampus, involved in memory formation (Lee et al., 1993), is abundantly innervated by brainstem noradrenergic projections (Aston-Jones et al., 1995) that have been shown to enhance memory in experimental paradigms of inhibitory avoidance and spatial habituation (Izquierdo and Medina, 1995). The systemic administration of nicotine stimulates norepinephrine (NE) release in vivo in multiple brain regions, including hippocampus (Mitchell, 1993; Fu et al., 1998). Therefore, the memory-enhancing effects of nicotine may be related, in part, to the stimulation of noradrenergic neurotransmission. Moreover, the direct allosteric actions of galantamine may amplify the effects of nicotine on hippocampal noradrenergic neurotransmission.
These studies were designed primarily to determine whether galantamine affects the hippocampal NE response to the systemic administration of nicotine. Because DA is also released by nicotine in multiple brain regions, including the nucleus accumbens (Nisell et al., 1994), and the modulatory effects of galantamine on this interaction have not been described, studies of accumbal DA were a secondary objective of these investigations. The nucleus accumbens was selected because the release of DA in this region by systemically self-administered nicotine seems to be pivotal to the reinforcing properties of nicotine and to drugs of abuse in general (Di Chiara, 2000). The effects of galantamine on both hippocampal NE and accumbal DA release were investigated by using a model in which microdialysis was concurrently performed through two dialysis probes placed into an alert, freely moving rat. To determine whether the inhibition of AChE was involved in the effects of galantamine, rats were pretreated with donepezil instead of galantamine. A dose of donepezil was administered that results in AChE inhibition comparable with that induced by galantamine. These experiments show that galantamine enhanced nicotine-induced hippocampal NE release, but not accumbal DA secretion, independent of any effects on AChE.
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Materials and Methods |
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Animals. Adult male Holtzman rats (250-300 g; Harlan, Madison, WI) were given access to standard rat chow and water ad libitum. They were housed individually on a 12-h light cycle (lights on at 9:00 AM, off at 9:00 PM) for 14 days before the microdialysis experiments. After housing for 7 days, they were anesthetized with xylazine/ketamine (5:35 mg/kg b. wt. i.m.; Sigma-Aldrich), and chronic guide cannulae (20-gauge) were stereotaxically implanted into both the hippocampus and nucleus accumbens, according to the atlas coordinates of Paxinos and Watson (1986). The coordinates for hippocampus were AP, -3.0 mm; DV, 2.6 mm; and ML, 1.4 mm from bregma with a flat skull. For nucleus accumbens, the coordinates were AP, 1.4 mm; DV, 0.5 mm; and ML, 6.0 mm. These exact coordinates have been used to localize microdialysis probes placed into the hippocampus and nucleus accumbens in previous studies from our laboratory, which included photomicrographic evidence of microdialysis probe placement (Fu et al., 1998, 2000). Five days later, rats received jugular cannulae under xylazine/ketamine and were allowed to recover for another 2 days. All procedures were conducted in accordance with National Institutes of Health Guidelines Concerning the Care and Use of Laboratory Animals and were approved by the Animal Care and Use Committee of the University of Tennessee Health Science Center.
In Vivo Microdialysis. The microdialysis method has been described previously (Fu et al., 1998, 2000). Briefly, a 2-mm concentric probe (molecular mass cutoff, 13,000 Da; outer diameter, 235 µm) was constructed in our laboratory. The recovery rate of individual probes was determined by in vitro dialysis for 60 min at 22°C in a solution of 200 pg of NE/16 µl or 200 pg of DA/16 µl, respectively. The probes were perfused at 1 µl/min with standard perfusate (see below), and three 15-min samples were obtained; the average recovery rate was 7.1 ± 1.0 and 6.7 ± 0.8% for NE and DA, respectively (n = 10). On the day of microdialysis, rats were moved into the laboratory and placed in CMA 120 awake animal system with plastic bowl CMA/Microdialysis (Acton, MA). The probe was perfused at 1 µl/min with a solution of Krebs-Ringer buffer (147 mM NaCl, 2.7 mM KCl, 0.9 mM MgCl2, and 1.2 mM CaCl2 using 0.2-µm filter sterilized and degassed) containing 5 µM nomifensine (NE uptake blocker; Lin et al., 1997). Nomifensine was used to facilitate reliable detection of basal NE levels.
Two hours after insertion of the probes through the guide cannulae into dorsal hippocampus (CA1) and the shell of nucleus accumbens, three consecutive samples were collected to measure basal NE and DA levels before drug administration. Using an on-line microdialysis system, samples were collected through a 1.5-m length of silica tube, which ran from the probes directly to the gearbox of the two Cheminert automated injectors (one for hippocampal NE and another for accumbal DA from the same rat). Samples from each brain region were collected for 15 min before injection onto the column. Sequential injections were controlled by a digital valve controller. At the end of each experiment, the positions of probes were verified by histological examination, as demonstrated in our previous studies (Fu et al., 1998, 2000). Only data obtained from animals with probes identified in the correct location within the hippocampus and nucleus accumbens were included in the data set.
High-Pressure Liquid Chromatography-Electrochemical Analysis. Samples (15 µl) were injected immediately onto 150 x 2 mm ODS C18 columns (ESA, Chlemsford, MA) perfused by ESA model 582 solvent delivery modules at a rate of 0.25 ml/min (ESA) with a mobile phase containing 50 mM sodium dihydrogen phosphate monohydrate, 0.7 mM EDTA, 2 mM 1-decanesulfonic acid, 11% methanol, and 11% acetonitrile, pH 6.0. Samples were analyzed by an ESA Coulochem II 5200A electrochemical detector with an ESA 5041 high-sensitivity microbore analytical cell. Electrochemical detection was performed at 220 mV and 1.0 nA. The limit of detection for NE and DA was 100 fg/injection. Previous reports from our laboratory have shown representative chromatograms (Fu et al., 1998, 2000).
Experimental Protocols. The first set of experiments were performed to characterize the dose-dependent response of NE and DA to i.v. nicotine. Each animal received one dose of nicotine (0.025, 0.045, 0.065, or 0.09 mg/kg free base; all doses delivered at a rate of 0.09 mg/kg/60 s i.v.) or saline. The second set of experiments evaluated the effect of pretreatment with galantamine on nicotine-induced NE and DA release. The dose of galantamine (3.0 mg/kg s.c.) was chosen based on a preliminary study that measured rat brain galantamine concentrations over time, using five doses from 0.05 to 5.0 mg/kg b.wt. s.c. (Christopher Grantham, Janssen Pharmaceutica, Beerse, Belgium; unpublished data). This study indicated that 0.1 to 1.0 µM concentrations of brain galantamine would be expected 2 to 3 h after a subcutaneous injection of 3.0 mg/kg galantamine. Therefore, nicotine (0.045 or 0.065 mg/kg) was initially delivered 2, 3, or 4 h after galantamine. Because galantamine augmented nicotine-induced NE release only at the 3-h time interval, additional concentrations of nicotine were evaluated at this time point. The third set of experiments determined whether the enhancement of NE release by galantamine was due to inhibition of AChE. Donepezil, a more potent in vitro AChE inhibitor than galantamine (IC50 values of 15-24 nM versus 2.8-3.9 µM, respectively; Thomsen et al., 1991), has been shown to be 4-fold more potent than galantamine in the inhibition of rat brain AChE after in vivo administration (IC50 values of 0.77 mg/kg for donepezil and 2.99 mg/kg for galantamine; Barnes et al., 2000). Importantly, donepezil is devoid of APL activity (Samochocki et al., 2000). Therefore, a dose of donepezil (1.0 mg/kg s.c.) that would result in comparable, if not greater, inhibition of AChE than galantamine (3.0 mg/kg) was administered 3 h before nicotine.
Data Analysis and Statistics. Chromatographic data were collected and analyzed with the PowerChrom system (ADInstruments, Castle Hill, NSW, Australia). Data (mean ± S.E.) were expressed as a percentage of basal levels of NE or DA. Basal values were defined as the mean level detected in the three samples obtained before nicotine administration. Peak levels were measured in the samples collected 15 min after i.v. nicotine. All data were analyzed by oneway analysis of variance, followed with post hoc analyses with Fisher's protected least significant difference where appropriate (SPSS 7.5; SPSS Inc., Chicago, IL).
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Results |
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Figure 2 illustrates the effects of galantamine on nicotine-induced hippocampal NE release. Baseline NE levels (+15-45 min; see figure legend for actual values), measured in samples obtained 2.5 to 3 h after a single injection of galantamine (3.0 mg/kg), were not different from those in the control group pretreated with saline. Galantamine, administered 3 h before nicotine, significantly augmented peak NE responses (+60 min) to all but the highest dose of nicotine (0.09 mg/kg; Fig. 2B). Indeed, galantamine potentiated NE responses to 0.025 and 0.045 mg/kg nicotine (Fig. 2A), doses that were ineffective in the absence of galantamine.
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Figure 3 shows peak hippocampal NE and accumbal DA responses as a function of different galantamine pretreatment time intervals and nicotine doses. Figure 3A demonstrates that pretreatment with galantamine at 3 h, but not 2 or 4 h, consistently and significantly augmented NE responses to nicotine doses in the range of 0.025 to 0.065 mg/kg nicotine. Considering the two doses of nicotine that were not sufficient to stimulate NE release, the magnitude of potentiation by galantamine was greater for the NE response to 0.045 mg/kg nicotine than to 0.025 mg/kg. Galantamine also enhanced the response to nicotine 0.065 mg/kg, but not to 0.09 mg/kg (Fig. 2). Figure 4 shows the effects of galantamine on the dose-response relationship for nicotine-stimulated hippocampal NE release. In general, galantamine sensitized the NE response to nicotine without affecting the amount of NE released by a maximally stimulative dose of the drug (i.e., 0.09 mg/kg nicotine, a dose that would induce a maximal increase in hippocampal NE levels without affecting behavior). Higher doses of nicotine (e.g., 0.135 mg/kg), which stimulate NE release to a greater extent, were not tested because their effects on NE are potentially confounded by systemwide effects such as brief tremors, gasping, and postural imbalance (Fu et al., 1998).
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In contrast to the augmenting effect of galantamine on NE, Fig. 3B shows that galantamine pretreatment failed to alter peak DA responses to nicotine at any dose. Thus, although both NE and DA responses to nicotine were measured in samples obtained concurrently from the same rat, 2 or 3 h after galantamine, only hippocampal NE levels were augmented. In view of these findings, rats receiving galantamine 4 h before 0.045 mg/kg nicotine or 2 h before 0.065 mg/kg nicotine did not receive guide cannulae in the nucleus accumbens.
Because galantamine is also a relatively weak AChE inhibitor, donepezil was substituted for galantamine to evaluate whether the effects of galantamine depend on cholinesterase inhibition (Thomsen et al., 1991). Figure 5 illustrates the results of experiments designed to evaluate the effect of pretreatment with donepezil on NE and DA responses to 0.065 mg/kg nicotine. Pretreatment (3 h) with donepezil had no effect on baseline hippocampal NE or accumbal DA levels. As expected, nicotine significantly elevated both NE and DA levels, but donepezil did not modify these responses. The efficacy of donepezil at inhibiting rat brain AChE has been compared with galantamine at different time points after subcutaneous administration. At 3 h after injection, 1.5 and 5.0 mg/kg donepezil inhibited 27 and 33%, respectively, brain AChE activity, whereas galantamine inhibited only 1 and 9%, respectively (H. Geerts, personal communication).
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). In rats, pharmacokinetic studies indicate that subcutaneous administration of 3 mg/kg galantamine yielded peak brain tissue levels (>1 µM) in less than 1 h, and tissue concentrations between 0.1 and 1.0 µM would be expected within 2 to 3 h (C. Grantham, unpublished data). Thus, galantamine modulates nicotine-stimulated hippocampal NE release within the concentration range and time required for its APL activity in vitro. The failure of donepezil to substitute for galantamine indicates that the inhibition of acetylcholinesterase is not a substantive factor in the modulation of nicotine-stimulated NE release by galantamine. These findings, together with the effects of galantamine on the dose-response relationship between nicotine and hippocampal NE, are consistent with the known nicotinic APL effects of galantamine.
Potentiation by galantamine occurred after a pretreatment interval of 3 but not 2 h. This may be explained by the known properties of galantamine acting as an open channel blocker at brain concentrations >1 µM and an allosteric potentiator at lesser concentrations. At concentrations near 1 µM (present 2 h after galantamine 3.0 mg/kg) both properties would be evident, resulting in a balance between the two and no detectable effect at the system level. At the receptor level, one would expect that some nAChRs are potentiated by galantamine bound only to APL sites, whereas others are inhibited by drug bound to both APL sites and the channel blocking domain of the nAChR. These properties would yield an inverted U-shaped dose-response relationship, as observed previously (Samochocki et al., 2000).
nAChRs are positively modulated by physostigmine-like compounds that bind near the acetylcholine binding site on the subunit of nAChRs (Okonjo et al., 1991). These compounds, collectively known as nicotinic APLs, enhance responsiveness to acetylcholine and are insensitive to blockade by nicotinic antagonists. Galantamine has been shown to be one of these allosteric ligands (Santos et al., 2002). In addition to the enhancing effect of galantamine on nicotine-induced hippocampal NE release, electrophysiological studies using patch-clamp technique have previously shown that galantamine facilitated glutamatergic or GABAergic neurotransmission through tonically active presynaptic nAChRs in rat hippocampal and human cortical slices (Santos et al., 2002). In those experiments, the nicotinic APL activity of galantamine was implicated in the facilitation of both tonically active and acetylcholine-driven neurotransmission due to the enhanced release of glutamate and GABA.
Whole-cell patch-clamp studies of transfected human embryonic kidney-293 cells have shown galantamine-dependent enhancement of human 34, 42, and 64 nAChR activity induced by acetylcholine, indicating the breadth of the APL effect (Samochocki et al., 2003). Concentrations of 0.1 to 1.0 µM galantamine potentiated agonist-induced responses to a similar degree in all nAChRs, resulting in a shift to the left and increased slope of the concentration-response relationships; EC50 values were reduced approximately 50%. In contrast, no studies have directly determined the effects of galantamine on 632-containing nAChRs, the subunits potentially involved in the cholinergic regulation of noradrenergic neurons projecting from the locus coeruleus to the hippocampus (Lena et al., 1999). In other studies, using microinjections directly into the locus coeruleus, both conotoxins M2 and AuIB blocked nicotine-induced hippocampal NE release, without evidence of additivity (Fu et al., 1999). Those observations provide additional evidence for the expression of nAChRs containing 6, 2, and non-2 subunits by neurons in the ceruleo-hippocampal pathway. Therefore, the efficacy of galantamine in enhancing the effects of nicotine on this pathway indicates that it is likely to act as an APL on 6-containing nAChRs.
nAChRs are known to enhance NE release in multiple brain regions (Mitchell 1993; Fu et al., 1998), including the hippocampus, where noradrenergic neurotransmission is involved in cognitive function (Friedman et al., 1999). Brainstem noradrenergic input to hippocampus is involved in several memory paradigms. For example, direct hippocampal infusion of NE enhanced long-term potentiation and strengthened the memory of inhibitory avoidance and spatial habituation (Izquierdo and Medina, 1995). Furthermore, NE enhanced long-term potentiation in the CA1 region of hippocampal slice preparations through 1-adrenergic receptors (Izumi and Zorumski, 1999). On the other hand, intrahippocampal timolol, a -adrenergic receptor antagonist, induced retrograde amnesia and reduced performance in step-down inhibitory avoidance (Bevilaqua et al., 1997). In addition, lesions of the locus coeruleus, which attenuate cortical and hippocampal noradrenergic innervation, produce cognitive deficits, including a reduction in sustained attention (Carli et al., 1983) and impaired learning (Anlezark et al., 1973).
There is also evidence of cholinergic-adrenergic interactions that enhance cognitive function. For example, idazoxan, an 2 adrenoceptor antagonist, potentiates the enhanced passive avoidance learning induced by AChE inhibitors (Camacho et al., 1996). This likely reflects elevated synaptic NE levels by a reduced presynaptic inhibition of NE release. Furthermore, combined (but not separate) administration of a -adrenergic receptor antagonist and a muscarinic antagonist impaired learning on inhibitory avoidance performance and spatial learning in the Morris water maze (Decker et al., 1990). Finally, deprenyl, a monoamine oxidase inhibitor, substantially decreased the water maze escape latency in rats treated with tacrine, an AChE inhibitor (Dringenberg et al., 2000).
Treatments that augment cholinergic and adrenergic neurotransmission may improve the clinical status of patients with Alzheimer's disease (AD). Loss of neurons in the locus coeruleus seems to be a characteristic of AD that correlates with the severity of the dementia (Bondareff et al., 1982) and has not been reported in dementia caused by multiple infarcts (Mann et al., 1982). Deprenyl has been reported to briefly improve cognition in a clinical AD trial (Wilcock et al., 2002). Indeed, the combination of L-deprenyl and physostigmine, an AChE inhibitor, has been shown to be more beneficial in patients with AD than physostigmine alone (Schneider et al., 1993). Clinical studies also have shown that galantamine had broad and sustained therapeutic effects in patients with mild-to-moderate AD, improving cognition, behavior, and the ability to perform daily activities (Corey-Bloom, 2003). Although its mechanism of action has not been clarified, the inhibition of AChE may play a modest role in the efficacy of galantamine. This is suggested by the fact that galantamine is a weak AChE inhibitor compared with donepezil, yet treatment with galantamine yields comparable benefit. In two studies, galantamine produced a significant improvement in cognition as measured by the Alzheimer's disease assessment scale (Raskind et al., 2000; Wilcock et al., 2000); and in a separate study, donepezil resulted in a similar degree of clinical improvement (Rogers et al., 1998). Based on the experiments reported herein, the APL effect of galantamine specifically on endogenous nicotinic cholinergic regulation of hippocampal NE secretion may be one mode whereby galantamine ameliorates some of the cognitive deficits in AD.
In contrast to the effect on hippocampal NE, galantamine did not alter the response of nucleus accumbens DA to nicotine at any dose or time interval. This may reflect two factors. First, in vivo microdialysis can only resolve neurochemical effects that occur on the time scale of minutes. Thus, galantamine may have very brief effects on dopamine secretion, possibly at the DA terminal, (J. Dani, unpublished observation) that may not yield sufficient DA for synaptic spill-over into the extracellular space, a requirement for detection by microdialysis. Second, galantamine may interact with multiple nAChRs containing a variety of subunits expressed by neurochemically distinct neurons that regulate the activity of DA neurons intrinsic to the ventral tegmental area (some of these DA neurons project to nucleus accumbens). The relative impact of these phenotypically distinct neurons (i.e., glutamatergic and GABAergic) on the activity of DA neurons in response to nicotine (Schilstrom et al., 1998; Fu et al., 2000; Mansvelder et al., 2002) may be modified by galantamine, which may retard the desensitization of nAChRs (Maelicke et al., 2001). Under these circumstances, there may be no detectable net effect of galantamine, especially when the effect of nicotine is integrated across 15-min sampling intervals.
This study provides the first in vivo evidence that galantamine augments adrenergic neurotransmission within the hippocampus. Using in vivo microdialysis, the secretion of hippocampal NE, but not accumbal DA, was enhanced by galantamine. Thus, we postulate that galantamine may up-regulate noradrenergic neurotransmission in AD patients by augmenting the stimulative effects of endogenous nicotinic cholinergic circuits. This is supported by the fact that galantamine potentiated hippocampal NE secretion to subthreshold doses of nicotine (i.e., 0.025-0.045 mg/kg). Because the loss of central noradrenergic function has been implicated in the progress of AD and noradrenergic agents may be beneficial in treatment, augmenting NE secretion may be one of multiple mechanisms underlying the therapeutic benefit of galantamine.
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Footnotes |
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ABBREVIATIONS: APL, allosteric potentiating ligand; nAChR, nicotinic cholinergic receptor; AChE, acetylcholinesterase; NE, norepinephrine; DA, dopamine; AD, Alzheimer's disease.
Address correspondence to: Dr. Burt M. Sharp, Department of Pharmacology, Health Science Center, University of Tennessee, 874 Union Ave., Memphis, TN 38163. E-mail: bsharp{at}utmem.edu
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