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NEUROPHARMACOLOGY
Laboratory of Neurochemistry, Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, Massachusetts
Received June 3, 2004; accepted August 26, 2004.
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Abstract |
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; Gibb et al., 1987; Ricaurte and McCann, 1992), decreases in tyrosine hydroxylase activity (Gibb and Kogan, 1979), and loss of dopamine and serotonin transporters (Wagner et al., 1980). Despite these observed changes, the mechanisms underlying the toxic effects of METH remain to be elucidated.
METH also affects the vesicular monoamine transporter 2 (VMAT-2), the protein that regulates the sequestration of monoamines into vesicles for subsequent release. Repeated administrations of high doses of METH cause a loss of VMAT protein on the vesicular membrane 1 h after a repeated high-dose regimen of METH (Riddle et al., 2002) and a decrease in VMAT-2 function 1 and 24 h after the last METH administration (Brown et al., 2000). Although the transient effects of METH on VMAT-2 function have been examined, it is unknown if the distribution of VMAT-2 protein is altered 24 h after METH and how this relates to the long-term effects on dopamine content.
It has been hypothesized that METH disrupts the vesicular sequestration of dopamine, leading to the accumulation of dopamine and, consequently, the production of dopamine-derived reactive oxygen species and quinones within the cytosol of the dopamine terminal (Giovanni et al., 1995; LaVoie and Hastings, 1999; Fleckenstein and Hanson, 2003). This hypothesis is further supported by the findings that VMAT-2 heterozygous knockout mice have an increased susceptibility to the striatal monoamine depleting effects of METH (Fumagalli et al., 1999). Conversely, methylphenidate, which increases vesicular VMAT-2 function, is protective against long-term striatal neurotoxicity produced by METH (Sandoval et al., 2003). Although methylphenidate and many other pharmacological agents, as well as the attenuation of METH-induced hyperthermia, protect against METH neurotoxicity, the identification of a drug that blocks both the long-term neurotoxic and acute behavioral effects of METH may be an effective therapeutic agent and useful tool to study the neuropharmacological profile of this psychostimulant. One such drug may be L-lobeline.
L-Lobeline is an alkaloidal constituent of Lobelina inflata, commonly known as Indian tobacco. Lobeline is a nicotinic receptor ligand with affinity for the neuronal 
7 and 4
2 nicotinic receptors (Musachio et al., 1997; Briggs and McKenna, 1998). Based on in vitro studies, it has been hypothesized that lobeline alters dopamine uptake into vesicles and release through changes in VMAT-2 function (Teng et al., 1997, 1998; Dwoskin and Crooks, 2002). Consequently, recent studies have focused on the use of lobeline as a pharmacotherapeutic for methamphetamine abuse. For example, preadministration of lobeline inhibits the locomotor hyperactivity produced by METH, blocks METH-induced drug discrimination (Miller et al., 2001), and decreases the self-administration of METH (Harrod et al., 2001).
Although the effects of lobeline on the behavioral pharmacology and the in vitro effects of METH on dopamine release from striatal slices and VMAT-2 function have been studied, no studies have examined the action of lobeline on the acute in vivo neurochemical and long-term neurotoxic effects of METH. Therefore, the purpose of this study was to examine the interactions between lobeline and METH on in vivo dopamine release, VMAT-2 protein distribution at 1 and 24 h after METH, METH-induced hyperthermia, and the consequent changes in striatal tissue monoamine content. It is hypothesized that lobeline will attenuate the METH-induced changes in dopamine release, hyperthermia, VMAT-2 distribution, and the long-term depletion of striatal dopamine and 5-HT content.
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Materials and Methods |
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Drugs and Drug Administration. D-Methamphetamine hydrochloride, Dulbecco's powdered medium, and lobeline hydrochloride were purchased from Sigma-Aldrich (St. Louis, MO). Ketamine (Ketaset) was purchased from Fort Dodge Laboratories (Fort Dodge, IA). Xylazine was purchased from The Butler Company (Columbus, OH). Saline (0.9%) was administered at a dose of 1 ml/kg. In studies where lobeline was administered before METH, lobeline (10 mg/kg) or saline vehicle (1 ml/kg) was administered 15 min prior to saline (1 ml/kg) or METH (10 mg/kg). This dosing paradigm was repeated four times at 2-h intervals. For the administration of lobeline after the last (i.e., fourth) injection of METH or saline, lobeline (10 mg/kg) was injected once at 5 h after the fourth saline (1 ml/kg) or METH (10 mg/kg) or once at 5 and once at 7 h after the fourth injection of saline or METH.
Intracranial Surgery. Rats were anesthetized with ketamine/xylazine (70 mg/kg, 6 mg/kg i.p.) and placed in a stereotaxic apparatus for intracranial surgery. The skull was exposed, and a 1-mm hole was drilled over the left or right striatum (anteroposterior, +1.2 mm and mediolateral, ±3.2 mm relative to bregma) (Paxinos and Watson, 1982). Dura was removed, and a 21-gauge stainless steel guide cannula was stereotaxically placed into the hole and onto the surface of the cortex overlying the striatum. The guide cannula along with a stylet obturator was secured to the skull with cranioplastic cement and three set screws. Rats were allowed to recover for 3 days prior to microdialysis. After surgery, all rats were housed individually for the duration of the experiments.
Microdialysis Experiments. Concentric flow dialysis probes were constructed as described previously with 4 mm of exposed dialysis membrane (Yamamoto and Pehek, 1990). Rats that were awake had probes inserted through the guide cannula 12 to 15 h prior to the start of the experiment. A 26-gauge stainless steel needle with a beveled tip that extends 
0.5 mm beyond the end of the guide cannula was used to puncture the dura before insertion of dialysis probes. Probes were perfused with modified Dulbecco's phosphate-buffered saline (138 mM NaCl, 2.1 mM KCl, 0.5 mM MgCl2, 1.5 mM KH2PO4, 8.1 mm NaHPO4, 1.2 mm CaCl2, and 0.5 mM D-glucose, pH 7.4) and pumped at a flow rate of 2.0 µl/min (PHD 2000 infusion pump; Harvard Apparatus Inc., Holliston, MA). Dialysis perfusion began with a 1.5-h prebaseline period, followed by a 2-h baseline period. The experimental period consisted of an additional 8 h of perfusion. Dialysis samples were collected every 0.5 h. METH or saline was injected at the end of the baseline period and were repeated at 2-h intervals for the next 6 h. Lobeline or its saline vehicle was injected 15 min prior to each METH or saline dose. Seven days after the microdialysis experiments, rats were killed by rapid decapitation, and the brain was frozen immediately on dry ice. Brains were sectioned using a cryostat microtome and probe tract in the striatum was verified. Only those rats with probe placements in the lateral striatum were included in the data analysis.
Biochemical Measurements of Extracellular Dopamine. Striatal concentrations of dopamine were measured by high-performance liquid chromatography with electrochemical detection. Samples (20 µl) were injected onto a 3-µm C18 reverse-phase column (100 x 2.0 mm; Phenomenex, Torrance, CA). Dopamine was eluted with a mobile phase consisting of 32 mM citric acid, 54.3 mM sodium acetate, 0.074 mM EDTA, 0.215 mM octyl sodium sulfate, and 3% methanol (pH 3.8). Separation of dopamine and DOPAC was confirmed prior to each dialysis experiment. Compounds were detected with an LC-4B amperometric detector (BAS Bioanalytical Systems, West Lafayette, IN) with a glassy carbon working electrode maintained at a potential of + 0.670 V relative to an Ag/AgC1 reference electrode. Data were recorded using the EZ Chrom (Scientific Software, Pleasanton, CA) software package.
Tissue Dopamine and 5-HT Content. One week after the METH or saline injections, rats were killed by rapid decapitation, and the brains were quickly removed and dissected. Whole striata were removed and frozen immediately on dry ice. The tissue was stored at –80°C until analysis.
The tissue was sonicated in 1000 µl of cold 0.1 M perchloric acid and centrifuged at 14,000g for 5 min at 4°C. The supernatant was analyzed for dopamine and 5-HT using an high-performance liquid chromatography with electrochemical detection as described above. Protein concentrations were determined by the method of Bradford using Bradford protein dye (Bio-Rad, Hercules, CA). Concentrations are expressed as picograms per microgram of protein.
Temperature Measurements. Throughout all the experiments, the room temperature was maintained at 22–23°C. During the experiments where temperature of rats was modified, cooling was performed by placing the home cage on ice. Maintenance of hyperthermia was accomplished by placing the normal cage cover with filters on top of their home cages. These are normally removed during the experiments. Temperature of the rats was measured via a rectal probe digital thermometer (Thermalert TH-8; Physitemp Instruments, Inc., Clifton, NJ).
Western Blot Analysis of Striatal VMAT-2 Immunoreactivity. Synaptosomal, membrane-bound, and vesicular fractions were prepared from whole striatal tissue via differential centrifugation separation as described previously (Riddle et al., 2002). Striatal synaptosomes were prepared from rats decapitated 1 or 24 h after the fourth METH injection. Striatal tissue was homogenized in 1 ml of ice-cold 0.32 M sucrose and centrifuged at low speed (800g, 12 min, 4°C). This resulted in supernatant (S1) that was removed and centrifuged at high speed (22,000g, 17 min, 4°C). The resulting pellet (P2) was resuspended in ice-cold distilled H2O (200 mg of striatal wet tissue weight/1 ml of distilled H2O). This resuspended fraction yielded the synaptosomal preparation. An aliquot of the resuspended (P2) synaptosomal fraction was used for Western analysis and the remainder centrifuged at high speed (22,000g, 17 min, 4°C). The resulting supernatant (S3) yielded the vesicle fraction. The pellet of centrifuged synaptosomal fraction (P3) was resuspended (200 mg/1 ml) in ice-cold distilled H2O to yield the membrane-associated fraction.
Blots were run on a Nu-Page 12% bis-Tris 10- to 12-lane gels in a Novex minicell apparatus (Invitrogen, Carlsbad, CA). Each lane was loaded with 10 to 15 µg of protein from each sample depending on the subcellular fraction measured. Gels were transferred to a polyvinylidene difluoride membrane and blocked with 5% nonfat dry milk in Tris-buffered saline. Membranes were probed with primary VMAT-2 antibody, AB1767 (Chemicon International, Temecula, CA), overnight and an anti-rabbit secondary antibody, AP132A (Chemicon International), for 2 h the following day. Membranes were visualized via a chromagen solution (S380C and S381C; Promega, Madison, WI). Analysis was done using a KODAK Gel Logic 100 imaging system and accompanying software. Western blot data are presented as relative optical density units on each gel compared with a saline control standard. This approach normalizes differences in the development of the chromagen solution between blots. Each blot contained all experimental groups. Thus, there was a standardization across all blots.
Statistical Analysis. Two-way analysis of variance analyses with Tukey's post hoc were performed on all tissue content and VMAT-2 data. VMAT-2 data were analyzed as relative optical density units. Temperature and microdialysis data were analyzed by two-way repeated measures analysis of variance. Significance was set at p < 0.05.
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Results |
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A four-dose METH regimen caused a significant hyperthermic response as measured by core body temperature throughout the exposure period (Fig. 2). Lobeline injected prior to each METH dose significantly attenuated the METH-induced hyperthermic response throughout the exposure period. However, injections of lobeline prior to each of four saline doses did not produce a change in body temperature as compared with saline vehicle controls. Lobeline + METH rats kept with cage covers on to maintain hyperthermia exhibited a significant hyperthermic response that was not statistically different from the saline + METH-treated group. Normothermic saline + METH-treated rats in which hyperthermia was prevented by cooling showed no overall change in body temperature compared with saline + saline-treated control rats.
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The four-dose METH regimen produced a significant decrease in striatal dopamine (Fig. 3A) and 5-HT (Fig. 3B) tissue content when measured 7 days after the administration of METH (Fig. 3, A and B). Administration of lobeline 15 min prior to each METH injection significantly attenuated the METH-induced decreases in striatal dopamine and serotonin. Administration of lobeline prior to each of four doses of saline did not change either striatal dopamine or 5-HT tissue content compared with saline-treated controls when assayed 7 days after the saline injections.
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The maintenance of hyperthermia at an average temperature of 39.7°C during the administration of lobeline prior to the injections of METH reinstated the decrease in both dopamine and 5-HT content 7 days after METH (Fig. 3, A and B). Prevention of hyperthermia (mean temperature of 37.6°C) in METH-treated rats resulted in a significant but incomplete blockade of dopamine and 5HT content in the striatum 7 days after the METH injections.
Lobeline injections prior to METH significantly reversed the decrease in VMAT-2 immunoreactivity in the striatal vesicular fraction observed at 1 h after METH administration (Fig. 4). Similar to the tissue content measures of dopamine and 5HT, lobeline attenuated the METH-induced decrease in VMAT-2 immunoreactivity (lobeline + METH), but in the presence of hyperthermia, the decrease in VMAT-2 immunoreactivity persisted (Fig. 4). It should be noted, however, that there was not a significant difference between lobeline + METH and lobeline + METH + hyperthermic groups. Additionally, VMAT-2 immunoreactivity measured at 1 h after drug injections did not differ between saline controls and METH-treated animals maintained a normal body temperature (normothermic). The injections of lobeline prior to saline injections had no effect on vesicular VMAT-2 immunoreactivity when compared with saline-pretreated saline controls.
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Figure 5 illustrates that VMAT-2 immunoreactivity is significantly decreased in the synaptosomal (Fig. 5A), membrane-associated (Fig. 5B), and vesicular (Fig. 5C) subcellular striatal fractions 24 h following the METH administration regimen. Similar to the effects noted in Fig. 4, lobeline attenuated the METH-induced decrease in VMAT-2 immunoreactivity (lobeline + METH) in the synaptosomal fraction but in the presence of hyperthermia (lobeline + METH hyperthermic), the decrease in VMAT-2 immunoreactivity was still significant compared with the saline + saline group but not different from the lobeline + METH group (Fig. 5A). Injections of lobeline prior to each of four doses of METH significantly attenuated the decrease in vesicular VMAT-2 immunoreactivity induced by METH in a temperature-dependent manner (Fig. 5C) but had no protective effect on the membrane-associated fraction (Fig. 5B). Blockade of hyperthermia in METH-treated rats produced a significant but incomplete blockade of the decrease in VMAT-2 immunoreactivity in all three subcellular striatal fractions of METH-treated rats.
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A series of experiments was performed with lobeline (10 mg/kg) administered 5 h after the four injections of METH to avoid the disruption of METH-induced hyperthermia. This time point for lobeline administration was chosen because temperatures in METH treated rats return to control values by 5 h after the fourth dose of METH (Fig. 6).
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In an additional group of rats, lobeline was injected twice after METH, once at 5 h after the fourth injection of METH and another 2 h later at 7 h after the fourth injection of METH. The injection of lobeline at both 5 and 7 h after METH exposure significantly attenuated or blocked the METH-induced striatal dopamine (Fig. 7A) and 5-HT (Fig. 7B) tissue content depletions, respectively, 7 days after METH administration (Fig. 7, A and B). One dose of lobeline 5 h after METH exposure did not affect METH-induced depletions in striatal dopamine (Fig. 7A) or 5-HT (Fig. 7B) content. Two injections of lobeline at 5 and 7 h after four saline injections also had no effect.
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The late injections of lobeline at both 5 and 7 h after METH administration significantly attenuated the METH-induced decreases in synaptosomal (Fig. 8A), membrane-associated (Fig. 8B), and vesicular (Fig. 8C) VMAT-2. One dose of lobeline 5 h after METH exposure did not affect METH-induced decreases in synaptosomal, membrane-associated, and vesicular VMAT-2 immunoreactivity. Two doses of lobeline at 5 and 7 h after saline administration did not affect VMAT-2 immunoreactivity in any of the three subcellular fractions.
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Discussion |
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Systemic administration of lobeline did not affect basal or METH-induced increases in extracellular dopamine (Fig. 1). These results appear to be in contrast to previous findings indicating that intrastriatal infusion of lobeline increased dopamine release (Lecca et al., 2000), whereas systemic lobeline administration attenuated the locomotor hyperactivity after METH and decreased METH self-administration (Harrod et al., 2001; Miller et al., 2001). Differences in route of administration (systemic versus intracranial) in the microdialysis studies and the higher doses of METH used in the present study could account for the discrepant results.
The prevention of METH-induced hyperthermia attenuated or blocked the long-term decreases in dopamine and 5HT content, respectively (Fig. 3). These findings are consistent with studies showing that prevention of hyperthermia protects against the neurotoxic effects of METH (Bowyer et al., 1992; Ali et al., 1994; Albers and Sonsalla, 1995). Similar to cooling, lobeline attenuated METH-induced hyperthermia (Fig. 2) and the long-term depletion of striatal dopamine and 5HT content (Fig. 3). Moreover, maintenance of hyperthermia in lobeline-pretreated rats administered METH reinstated the long-term depletions of dopamine and 5HT. Collectively, the protective effects of lobeline against depletions of dopamine and 5HT content after METH are due partly to the acute alterations in METH-induced hyperthermia
The current study replicates studies showing a decrease in vesicular VMAT-2 immunoreactivity measured 1 h after the last METH injection (Riddle et al., 2002). The present study also provides new data illustrating that METH decreases VMAT-2 immunoreactivity 24 h after METH and further supports the hypothesis that decreases in VMAT-2 immunoreactivity and function (Brown et al., 2000; Riddle et al., 2002) are precursor events to the long-term neurotoxicity produced by METH. Furthermore, prevention of METH-induced hyperthermia (Figs. 4 and 5) attenuated the loss of VMAT-2 immunoreactivity in all of the subcellular fractions measured. The findings that hyperthermia induced in saline control rats did not alter striatal VMAT-2 (data not shown) and that prevention of hyperthermia attenuated but did not reverse the decreases in VMAT-2 24 h after METH suggest that decreases in VMAT-2 protein are not solely dependent upon hyperthermia but involve another, unidentified effect of METH. VMAT-2 immunoreactivity measured 1 and 24 h after the last METH injection was similarly affected by pretreatment with lobeline. The lobeline-mediated attenuation of the METH-induced decreases in vesicular VMAT-2 protein in the vesicular fraction at 1 and 24 h after METH is due partly to the blockade of hyperthermia, as maintenance of hyperthermia restored the METH-induced decreases in VMAT-2 but did not completely reinstate the decreases in VMAT-2 immunoreactivity in the synaptosomal and membrane-associated fractions (Fig. 5, A and B). Thus, the attenuation by lobeline of the METH-induced decreases in VMAT-2 is partly temperature-dependent and is restricted primarily to the vesicular fraction.
To elucidate the role of temperature on the interactions between lobeline and METH, lobeline was injected at time points when METH-induced hyperthermia was absent. Body temperatures remained elevated 1 h after the fourth METH injection but returned to control values within 5 h (Fig. 6). Lobeline administration at this late 5-h time point and again 2 h later (7 h after the last METH injection) still attenuated the METH-induced decreases in VMAT-2 immunoreactivity measured 24 h after METH (Fig. 8) and the depletions of striatal dopamine and 5HT content measured 7 days later (Fig. 7, A and B). These results indicate that dopamine and 5HT terminals can be rescued hours after repeated METH doses and further support the hypothesis that the neuroprotective effects of lobeline are partly independent of its effects on METH-induced hyperthermia. Furthermore, these data suggest a late-occurring component of METH toxicity that is independent of hyperthermia. The finding that pharmacological intervention after exposure of METH can be neuroprotective is similar to previous studies showing that dopamine uptake blockade (Marek et al., 1990), methylphenidate (Sandoval et al., 2003), or the perfusion of mitochondrial substrates (Stephans et al., 1998) also are protective when administered after METH. Such findings may be of relevance for the treatment of METH overdose.
High doses of METH produce decreases in VMAT-2 function 1 and 24 h after METH (Brown et al., 2000; Hogan et al., 2000) and decreases in vesicular VMAT-2 protein measured 1 h after the last METH injection (Riddle et al., 2002). The conclusion was that there is a redistribution of VMAT-2 protein within 1 h after METH to an unknown compartment in the nerve terminal (Riddle et al., 2002). The present study provides new data illustrating that a neurotoxic METH regimen produces a decrease in striatal VMAT-2 immunoreactivity in all fractions investigated (i.e., synaptosomal, membrane-associated, and vesicular) 24 h post-METH administration. This finding appears to be in contrast to previous VMAT-2 binding studies using mice (Hogan et al., 2000) in which binding to VMAT-2 in whole striatal homogenates was not decreased 24 h after METH exposure. However, the differences between this and our study are that we used separate and purified subcellular fractions (rather than whole homogenates) that may have been more sensitive for the detection of decreases in VMAT-2 immunoreactivity. Regardless, although VMAT-2 may redistribute within the terminal within 1 h after METH, there appears to be an overall loss of VMAT-2 protein from striatal terminals at 24 h after METH when individual subcellular fractions were analyzed. It is unknown if the loss of VMAT-2 immunoreactivity is a reflection of protein degradation or is indeed a redistribution to a fraction other than those isolated in the current study. If VMAT-2 protein is damaged, the formation of reactive nitrogen species derived from elevated glutamate concentrations after METH (Nash and Yamamoto, 1992) may be involved. The loss or redistribution of VMAT-2 protein could lead to oxidative stress produced by the decreased sequestration and increased cytosolic accumulation of dopamine and dopamine-derived reactive oxygen species (LaVoie and Hastings, 1999; Fleckenstein and Hanson, 2003). Within this context, it is surprising that lobeline protected against METH-induced decreases in VMAT-2 and long-term decreases in monoamine content. In vitro studies have shown that lobeline inhibits vesicular uptake (Teng et al., 1998). Decreased vesicular uptake of dopamine should enhance dopamine-derived reactive oxygen species-mediated damage following high-dose METH treatment. Therefore, it seems unlikely that lobeline, at the doses used in vivo, inhibits VMAT-2 function.
The mechanisms that mediate the lobeline-induced attenuation of decreases in VMAT-2 protein and the long-term depletions of dopamine and 5HT content produced by METH remain to be determined. Miller et al. (2004) suggest that lobeline may act in vitro at higher concentrations to block the dopamine transporter (DAT). DAT inhibitors are known to be neuroprotective against the effects of METH and decrease METH-induced dopamine release (Stephans and Yamamoto, 1994). In contrast, Fig. 1 shows no effect of lobeline on METH-induced dopamine release. Thus, it is unlikely that lobeline acts in vivo as a DAT inhibitor at the doses used. Other possibilities may explain the protective effect of lobeline. Lobeline is a nicotinic receptor ligand and has partial agonist properties for the neuronal 7 and 42 receptors (Musachio et al., 1997; Briggs and McKenna, 1998). Nicotine protects against the degeneration of dopamine neurons in animal models of Parkinson's disease or after high doses of METH (Maggio et al., 1998; Costa et al., 2001; Ryan et al., 2001; Parain et al., 2003) through its ability to modulate NMDA receptor function (Rao et al., 1997) and protect against NMDA-mediated excitotoxicity that may occur due to increases in striatal glutamate after METH (Nash and Yamamoto, 1992). In fact, in vitro studies suggest that 7 nicotinic receptor modulation is protective against NMDA-mediated excitotoxicity to PC12 cells and hippocampal cultures (Akaike et al., 1994; Carlson et al., 1998; Prendergast et al., 2001). Conversely, the protective effect of nicotine is absent in 7 NAchR knockout mice (Gahring et al., 2003). Therefore, lobeline may act at 7 cholinergic receptors to attenuate glutamate-induced excitotoxicity to VMAT-2 protein as well as dopamine and 5HT terminals after METH.
In conclusion, METH produces a decrease in VMAT-2 protein that is partly but not entirely mediated by hyperthermia. In addition, lobeline appears to have neuroprotective effects that are both dependent and independent of its ability to alter METH-induced hyperthermia. The novel finding that lobeline is partly neuroprotective when administered several hours after METH suggests that there are late temperature-independent and lobeline-sensitive components of the neurotoxic cascade of METH toxicity. Furthermore, the current findings support the utility of lobeline as a pharmacotherapy after neurotoxic METH exposure and contribute to its therapeutic potential for the prevention of METH abuse (Harrod et al., 2001).
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Acknowledgements |
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Footnotes |
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ABBREVIATIONS: METH, methamphetamine; 5-HT, serotonin; VMAT-2, vesicular monoamine transporter 2; DA, dopamine; DAT, dopamine transporter; NMDA, N-methyl-D-aspartate.
Address correspondence to: Dr. Bryan K. Yamamoto, Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, L-613, Boston, MA 02118. E-mail: bkyam{at}bu.edu
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