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The methamphetamine experience: a NIDA partnership
Neuropharmacology 47 (2004) 92–100 www.elsevier.com/locate/neuropharm
The methamphetamine experience: a NIDA partnership Glen R. Hanson , Kristi S. Rau, Annette E. Fleckenstein Department of Pharmacology and Toxicology, University of Utah, 30 South 2000 East, Skaggs Hall, Room 112, Salt Lake City, UT 84112, USA Received 14 April 2004; received in revised form 19 May 2004; accepted 28 May 2004
Abstract The neurotoxic properties of the amphetamines such as methamphetamine (METH) were originally described about the time of the National Institute on Drug Abuse’s organization, in the early 1970s. It required more than 20 years to confirm these neurotoxic properties in humans. Much like Parkinson’s disease, multiple high-dose administration of METH somewhat selectively damages the nigrostriatal dopamine (DA) projection of the brain. This effect appears to be related to the intracellular accumulation of cytosolic DA and its ability to oxidize into reactive oxygen species. Both the dopamine plasmalemmal transporter and the vesicular monoamine transporter-2 seem to play critical roles in this neurotoxicity. METH and related analogs such as methylenedioxymethamphetamine (MDMA) can also damage selective CNS serotonin neurons. The mechanism of the serotonergic neurotoxicity is not as well characterized, but also appears to be related to the formation of reactive oxygen species and monoamine transporters. Studies examining the pharmacological and neurotoxicological properties of the amphetamines have helped to elucidate some critical features of monoamine regulations as well as helped to improve our understanding of the processes associated with degenerative disorders such as Parkinson’s disease. # 2004 Elsevier Ltd. All rights reserved. Keywords: Methamphetamine; Dopamine transporter; Vesicular monoamine transporter; Neurotoxicity; Methylphenidate
1. Prologue The year of 2004 marks the 30th anniversary of the National Institute on Drug Abuse (NIDA) and is an appropriate time to take stock of the important contributions made by this institute, its dedicated staff, and its conscientious leadership. It is broadly recognized throughout the world that the NIDA leads the way in supporting and encouraging research intended to elucidate the cause and consequence of drug abuse and addiction. The fruits of these efforts have helped us to appreciate the biomedical basis of addiction, recognize its disease properties, and develop more effective intervention strategies to prevent and treat addiction. NIDA has supported research in a wide range of disciplines by some of the world’s most able scientists. The discoveries by these and other NIDA-supported researchers extend well beyond elucidating the process
of drug abuse and addiction, and have helped to identify and understand critical neurobiological systems, their regulation and important cellular mechanisms that contribute to many normal and pathological neurobiological functions. Our group is honored to be able to participate in this ‘‘NIDA intellectual celebration’’ by sharing some of the methamphetamine-related research highlights to which we have contributed, and that were made possible because of NIDA support and encouragement. Even though we have been asked to emphasize in this paper the research from our laboratories, it is important to recognize that the successes in the research of methamphetamine (METH) and related drugs have been due to the cumulative efforts of many laboratories and dedicated scientists, unfortunately too many to list and discuss in detail in this short article. 2. Introduction
Corresponding author. Tel.: +1-801-581-3174; fax: +1-801-5855111. E-mail address: [email protected] (G.R. Hanson). 0028-3908/$ - see front matter # 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropharm.2004.06.004
The potent psychostimulant properties of the synthetic drug, amphetamine were described in the early
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20th century by Gordon Alles, a researcher looking for a more potent substitute for the decongestant ephedrine. Alles discovered that when inhaled or taken orally, amphetamine dramatically reduced fatigue, increased alertness and caused a sense of confident euphoria. After these impressive findings, the Benzedrine (amphetamine) inhaler became available in 1932 as a non-prescription product across America. This product was marketed for nasal decongestion, but became widely abused for its stimulant properties. Due to a lack of restrictions, amphetamine products, including its analog METH were sold to treat a bevy of ailments including obesity, alcoholism, bed-wetting, depression, schizophrenia, heart block, head injuries, seasickness and persistent hiccups. Amphetamines have been used extensively by military personnel and truck drivers due to their ability to mask drowsiness and fatigue. More than any other single experience, the US epidemic use of prescription amphetamine anorexiant products by homemakers in the late 1960s made the addictive dangers of the amphetamines broadly recognized and feared (Hanson et al., 2004). Because of these episodes of widespread addiction with the amphetamine, in the early 1970s, the newly formed NIDA identified amphetamine-related research as one of its top priorities. It was at this time that Dr. James Gibb received his first NIDA grant to study the neurochemical consequences of METH exposure. Since these initial studies, a number of faculty, postdoctoral, graduate and undergraduate students have partnered with Dr. Gibb in this research and made major contributions to these efforts. Critical to the research success of this group over the years has been a sense of teamwork and open collaboration by its members.
3. The dopamine link to neurotoxicity The group’s early research established the critical role of DA in the neurotoxic effects of METH. It was discovered that multiple high-dose administrations, given to simulate what was occurring in the typical ‘‘run’’ by METH addicts, resulted in a dramatic reduction in tyrosine hydroxylase (TH) activity and levels of DA (Fig. 1). These deficits persisted for weeks and were selective to the nigrostriatal DA pathway, the same system damaged in Parkinson’s disease (Morgan and Gibb, 1980; Hurtig, 2000). It was concluded that multiple moderate to high doses of METH are selectively neurotoxic to the nigrostriatal DA pathway. About this same time, other investigators reported similar findings using somewhat different drug treatments and assessing other parameters such as the dopamine transporter (DAT; Seiden et al., 1976; Wagner et al., 1980). These observations served as the critical basis for much of the research that has followed
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Fig. 1. Persistent effects of METH on TH activity and DA content in the striatum. Rats were injected with either normal saline (1 mg/ kg, s.c.) or METH (15 mg/kg, s.c.) every 6 h for five doses and decapitated 36 h after the first dose. Brackets indicate S.E.M. p< 0:001 compared to saline control. Reproduced from Morgan and Gibb (1980).
in our and other’s laboratories and has also contributed to our understanding of the vulnerability of this critical DA system. Despite the frequent reproduction of these original findings by others in many animal species, it was not until the late 1990s that this selective METH-related toxicity to DA neurons was observed in humans. Volkow et al. (2001a,b) observed using PET imaging that the levels of DAT were consistently reduced in heavy METH users up to 11 months after the last drug exposure. Volkow et al. (2001a) correlated these deficits in the DA system to motor slowing and memory impairment, suggesting significant functional impact from these neurotoxic consequences. Wilson et al. (1996) also determined in postmortem tissue a persistent reduction in DA, DAT and TH levels in METH users, although they interestingly observed no significant decreases in striatal vesicular monoamine transporter-2 (VMAT-2), another protein thought to be a reliable marker of DA neuronal integrity. This finding underscored the preclinical observation that the METH-induced deficits are not associated with cellular death but a somewhat selective axonal degeneration (Kogan et al., 1976; Ricaurte et al., 1982).
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While attempting to elucidate the mechanism responsible for DA-related neurotoxicity of METH, it was speculated that DA itself played a critical role. To test this, METH was administered to DA-depleted animals pretreated with alpha-methyl tyrosine, an inhibitor of TH. It was observed that in the presence of DA depletion, the METH toxicity did not occur, suggesting that the DA molecule itself somehow contributed to the neurotoxic effects. It was hypothesized that this link might be related to the tendency of DA to readily oxidize into reactive quinones and semiquinones (Schmidt et al., 1985b). This possibility was tested and supported by our observation that METH treatment increases the production of extracellular reactive oxygen species (Fleckenstein and Hanson, 2000). Similar observations have been made by other groups (Yamamoto and Zhu, 1998; Obata and Yamanaka, 2000). With the establishment of a DA role in the neurotoxic effects of DA, our research focused on the mechanisms of this and related phenomena.
4. Dopamine dynamics and transporters Our findings lead us to three critical issues of investigation: did other psychostimulants have similar neurotoxic properties? why was the nigrostriatal projection particularly vulnerable? and where was the site of the DA-linked damage? 4.1. Other psychostimulants Although over the years our group has examined many psychostimulants chemically related and unrelated to METH, this discussion will, for the most part, be limited to methylenedioxymethamphetamine (MDMA) and cocaine. From our observations, the potent psychostimulants appeared to fall into two broad categories with some subgroups. The broad groups are those compounds, such as METH and MDMA, that principally increase extracellular monoamines such as DA and serotonin (5HT) by reversing the respective plasmalemmal transporters. The other category includes those drugs that increase the extracellular DA by blocking the plasmalemmal transporter preventing reuptake of DA released by vesicular mechanism, such as cocaine and methylphenidate. Our finding has been that in general the releaser agents have the potential to induce long-term damage to monoaminergic pathways, while this toxicity does not appear to be caused by drugs that block transporter uptake (for review, see Fleckenstein et al., 2000). In fact, the transporter blockers appeared to actually be neuroprotective, especially against the neurotoxicity caused by the releasing agents. For example, we (Schmidt et al., 1985b) and others (Marek et al., 1990; Pu et al., 1994)
observed that METH-induced reductions in striatal DA parameters are blocked by antagonists of the DAT. This protective action can occur even if the DAT blocker is administered as long as 8 h after the neurotoxic METH treatment (Marek et al., 1990): this suggests that the DAT plays a critical role not only in a priming event, but also contributes to a sequence of events occurring hours after METH treatment, required for the toxicity to eventually be expressed. The critical role of DAT was supported by the observation of Caron and coworkers that METH toxicity is completely blocked in DAT knockout mice (Fumagalli et al., 1998). Because of the apparent link between DAT function and the neurotoxic features of DA-releasing drugs such as the amphetamines, we have examined in detail the effects of the amphetamines, such as METH on functions and states of the DAT protein. These studies lead to dramatic, unexpected discoveries concerning how and why METH influences this plasmalemmal transporter. We initially found that multiple high doses of METH administered to rats rapidly and dramatically reduce DAT activity and DAT ligand binding in striatal synaptosomes, an effect that persisted even after the removal of the METH (Fig. 2; Fleckenstein et al., 2000). A similar effect could be elicited by direct incubation of striatal synaptosomes from naı¨ve animals in the presence of METH for approximately 30 min (Sandoval et al., 2001). These reductions were associated with declines in DAT protein and not changes in its affinity for DA (Fleckenstein et al., 1997a). A likely explanation for these findings was suggested by the in vitro observation of Saunders et al. (2000) that in a DAT-transfected cell line, exposure to amphetamines causes the DAT protein to redistribute away from the plasma membrane and no longer transport extracellular DA. According to these findings, it is likely that the effects we observed in vivo were the consequences of METH-induced internalization of the DAT protein, resulting in a loss of synaptosomal DA transport function. In contrast, treatment with the transporter blocking cocaine had an opposite effect and caused DAT proteins to move back into the cells’ surface membranes (Daws et al., 2002). Studies to determine cellular mechanisms of the psychostimulantinduced DAT trafficking revealed that at least a portion of the METH effect on DAT was mediated by a PKC-dependent phosphorylation of this transporter protein (Sandoval et al., 2001). Other relevant signal transduction cascades remain to be elucidated in this effect. 4.2. Nigrostriatal pathway vulnerability The nigrostriatal DA pathway has been shown to be particularly vulnerable to degradation during
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Fig. 2. Time–response effect of multiple METH administrations on [3H]DA uptake and [3H]WIN35428 binding to DAT in striatal synaptosomes. Rats received four injections of METH (2-h intervals; 10 mg/kg/injection, s.c.) or four injections of saline vehicle (1 ml/kg/injection, s.c.; zero time controls). Rats were decapitated 1 h, 24 h or 7 days after the final injection. Values represent means 1 S:E:M: of determinations in 6–14 rats. Values for METH-treated rats that differ significantly from controls. # Value for [3H]DA uptake that differs significantly from that obtained from rats decapitated 1 h after the final METH administration (p 0:05). Reproduced from Kokoshka et al. (1998).
Parkinson’s disease (for review, see Hurtig, 2000). We (Morgan and Gibb, 1980; Haughey et al., 1999) and others (Seiden et al., 1976; Seiden and Vosmer 1984; Ricaurte et al., 1982; Cass, 1997) observed a similar pattern of vulnerability when assessing deficits in DA systems after high-dose METH treatment; thus, the METH treatment that leads to striatal deficits in DA parameters has little long-term effect on similar DArelated measurements in the nucleus accumbens. Although the precise mechanism for this preferential vulnerability is not known, it has been suggested that it is linked to the substantially higher concentration and activity of DAT in the striatum (Eisch et al., 1992). This possibility would be consistent with the hypothesis that the DAT plays a critical role in mediating this toxicity. We have examined the possibility that another factor may contribute as a mediating mechanism for METHrelated neurotoxicity. It has been postulated that the storage vesicles linked with the VMAT-2 serve a critical role of sequestering cytosolic DA in vesicles where this monoamine is protected against oxidation and the production of reactive oxygen species (Liu and Edwards, 1997; Miller et al., 1999; Fleckenstein et al., 2000). Observations that heterozygotic VMAT-2 knockout mice are considerably more vulnerable to METH-related DA toxicity, supports this conclusion (Fumagalli et al., 1999). Consequently, we tested the hypothesis that the psychostimulants alter VMAT-2 function in some manner that would be linked to neurotoxicity. We observed that in purified preparations of striatal cytosolic vesicles, the neurotoxic regimen of METH dramatically reduced the ability of these vesi-
cles to sequester DA. This decline in vesicular sequestering function appeared to be related to a trafficking of the VMAT-2 transporter (for review, see Fleckenstein and Hanson, 2003). The decline in VMAT-2 activity in purified vesicle preparations persisted for at least a week, suggesting an association with the METH-initiated neurotoxic sequence of cellular events. The change in striatal VMAT-2 function was initiated within a matter of minutes after the METH treatment and was not due to a direct effect of METH as it was observed even after washing the drug away (Fleckenstein et al., 1997a). Compared to the METH-induced reduction of striatal VMAT-2 activity in the purified cytosolic fraction, blockers of DAT had an opposite effect. Thus, after administration of cocaine or another DAT inhibiting drug, methylphenidate, the transport of DA into purified vesicles increased. This effect was associated with an increase in VMAT-2 Vmax and ligand binding that occurred within minutes, was independent of the presence of the drugs, and reversed in a matter of hours (Sandoval et al., 2002). Because of the postulated importance of the VMAT-2 activity to cause METH neurotoxicity, we hypothesized that the DAT inhibitors were protective by virtue of their ability to provide more DA sequestration in the neuronal cytosolic fraction. To test this possibility, we administered a neurotoxic regimen of METH followed by a treatment with methylphenidate. We observed that the sequestering of DA in the cytosolic vesicular fraction was not reduced by the METH when post-treated with the methylphenidate (Fig. 3; Sandoval et al., 2003) nor did the typical
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Fig. 4. Post-treatment with methylphenidate (MPD) attenuates METH-induced long-term deficits dopaminergic deficits. Rats received METH (four injections of 7.5 mg/kg; s.c.; 2-h intervals) or saline (1 ml/kg, s.c.). Rats received one injection of MPD (5 mg/kg, s.c.), two injections of MPD, or three injections of MPD or saline (sal; 1 ml/kg, s.c.) 1, 3, and 5 h after the last METH or saline injection. Rats were decapitated seven days after the last METH, methylphenidate, or saline administration. Columns represent the mean DA concentrations and vertical lines 1 S.E.M. of determinations in 8–12 rats. Values that are significantly different from Sal/Sal-treated groups (p 0:05). Reproduced from Sandoval et al. (2003). Fig. 3. Post-treatment with methylphenidate (MPD) does not alter total striatal tissue DA content (A), but blocks the METH-induced decrease in vesicular DA content (B). Rats received METH (four injections; 7.5 mg/kg/injection, s.c.; 2-h intervals) or saline (Sal; 1 ml/kg, s.c.). Rats received three injections of MPD (5 mg/kg, s.c.) or saline (1 ml/kg, s.c.) after the last METH or saline injection. Rats were decapitated 6 h after the last METH, 1 h after the last MPD, or 1 h after the last saline administration. Columns represent the means and vertical lines 1 S.E.M. of determinations in six rats. Values that are significantly different from Sal/Sal-treated groups (p 0:05). Reproduced from Sandoval et al. (2003).
long-term DA deficits occur (Fig. 4; Sandoval et al., 2003). These findings support the hypothesis that VMAT-2 function and DA sequestration likely play critical roles both in mediating METH-related neurotoxicity and the neuroprotection of the DAT inhibitors. Although ongoing research is being conducted to elucidate specifically how the monoamine releasing and uptake blocking drugs mediate these changes in DA sequestration, one possibility suggested by our initial findings is that these drugs alter the trafficking of VMAT-2-associated vesicles. Employing western blot analysis with partial purification of cellular compartments, it appears that 1 h after administering either type of psychostimulant, the VMAT-2 protein likely shifts compartments with the associated vesicles. Although some details are lacking, the DA-releasing drugs such as the amphetamines appear to cause the vesicles to withdraw from the synaptic terminal, resulting in a reduction of VMAT-2 in the cytosol, a non-
membrane-associated pool (Sandoval et al., 2003), but not in the total tissue homogenate (Hogan et al., 2000). In contrast, the DAT blockers cause the VMAT-2 protein to shift from the heavy membrane fraction (likely associated with vesicles bound to the plasmalemma or some other heavy membrane) and move into the cytosolic fraction where it can increase the uptake of the cytosolic DA (Sandoval et al., 2002). These exciting findings concerning transporter protein trafficking have very important implications for drug targets and understanding the etiology of neurotoxicity, such as that associated with METH and even Parkinson’s disease. 4.3. Site of DA-linked damage While it is generally accepted that the oxidation of DA itself contributes to the damage of DA-related pathways, it is not clear if these neurotoxic oxidative events occur outside or inside the neuronal terminal. Several of the observations that METH treatment induces free radical production were done by determining an increase in striatal production of the oxidized product dihydroxybenzoic acid from salicylate coadministered with the METH (Kondo et al., 1994; Giovanni et al., 1995; Fleckenstein et al., 1997b; LaVoie and Hastings, 1999). Because these increases were measured in total tissue, the site of the DA oxidation is not clear. Subsequent reports that salicylate infusion by microdialysis results in an increased formation of
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dihydroxybenzoic acid in the dialysate after METH administration by our group (Fleckenstein and Hanson, 2000) and others (Yamamoto and Zhu, 1998; Obata and Yamanaka, 2000) demonstrates that METH treatment does increase the free radical production in the synaptic space; however, this has not been linked to eventual neurotoxicity. It has been reported that the DA-quinones are particularly likely to oxidize and bind to sulfhydryl groups (Graham, 1978) making cysteine-containing proteins especially vulnerable to DA-quinone oxidation (Hastings and Berman, 2000). A direct consequence of this DA-linked oxidation that is precipitated by neurotoxic METH treatments has been reported. Using western blots, we recently observed that the DAT protein forms several oligomeric complexes after multiple high doses of METH (Fig. 5; Baucum et al., 2004). The formation of these DAT complexes only occurs after an METH neurotoxic treatment; requires the presence of DA and hyperthermia; is reversed by a reducing environment; requires 24–36 h to express and is not observed with either TH or dopamine D2 receptors.
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The properties of this phenomenon suggest that the formation of these oligomeric complexes of DAT are closely linked to METH-induced DA neurotoxicity and that the damage to the DA striatal projections likely occurs due to DA-related oxidative events inside the neuronal terminals. This is supported by the observations described above that neurotoxic METH treatments cause a loss of VMAT-2 protein and likely the associated vesicles from the DA neuronal terminals. A reduction in these cytosolic vesicles diminishes the sequestration of freely floating DA and facilitates its oxidation to reactive quinones and oxidation of intracellular constituents. Since the DAT protein is highly susceptible to oxidation at its cysteine groups (Fleckenstein et al., 1997b: LaVoie and Hastings, 1999), this protein would be expected to form complexes as a consequence. This is consistent with our observation that the DAT oligomers induced by METH treatment were eliminated when placed in a reducing environment (Baucum et al., 2004).
5. The serotonin sequel
Fig. 5. Multiple administrations of METH increased higher molecule weight DAT complex formation as evidenced using antibody directed against the N terminus of the DAT. Rats received METH (four injections of 7.5 mg/kg/injection, s.c.; 2-h intervals) or saline (four injections of 1 ml/kg, s.c.; 2-h intervals) and were decapitated 6–72 h later. In this representative blot, two independent samples are shown for each treatment group. Reproduced from Baucum et al. (2004).
While METH-related neurotoxicity was initially associated with the striatal DA system, it was known that some amphetamine-related drugs such as parachloroamphetamine (PCA) possessed the ability to cause damage to some serotonergic pathways (Fuller and Snoddy, 1980; Fuller, 1980). Our group tested the possibility that like PCA, METH administrations also possesses the ability to damage 5HT neurons. We observed that like the DA-related effects, it required moderate to high doses of METH given in multiple administrations to observe long-lasting deficits in serotonergic parameters (Morgan and Gibb, 1980). These deficits occurred not only in the striatum, but in other brain regions as well, such as in the hippocampus and the frontal cortex (Bakhit et al., 1981). These METH effects have been duplicated by other investigators (Ricaurte et al., 1980; Trulson and Trulson, 1982). Similar to the DA toxicity, the METH-induced damage to 5HT systems requires the respective plasmalemmal monoamine transporter (Schmidt and Gibb, 1985a); is dependent on hyperthermia (Fleckenstein et al., 1997b; LaVoie and Hastings, 1999); is thought to be linked to free radical formation (Stone et al., 1989); and at least partially is associated with DA systems (Sonsalla et al., 1986; De Vito and Wagner 1989). While the potential role of METH-induced changes in vesicular trafficking in serotonergic neurons has not been investigated, there is evidence that oxidative damage is occurring inside the 5HT terminals. Thus, METH treatment causes a very rapid reduction in the activity of tryptophan hydroxylase, the rate-limiting synthetic enzyme for 5HT. This decrease in activity can totally be reversed
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when the enzyme is exposed to a reducing environment (Fleckenstein et al., 1997b; Stone et al., 1989), suggesting reactive oxygen species are forming inside the 5HT terminals after METH treatment, oxidizing the enzyme and perhaps causing other serious cellular damage. At present, the source of the oxidative events in the 5HT neurons after METH is not known. While METH toxicity is observed in both selective DA and 5HT neurons, it is somewhat unique in this feature when compared to other phenylethylaminerelated drugs. For example, MDMA has been reported by many investigators to be able to cause METH-like damages to 5HT neurons, but unlike METH, it does not appear to have long-term consequences on the nigrostriatal DA pathway (Stone et al., 1986; Ricaurte et al., 1985; Battaglia et al., 1987; Schmidt and Kehne, 1990). The reason for this distinction is not known, although MDMA does appear to have a relatively greater effect on 5HT release than does METH (Setola et al., 2003). Another drug that is a selective 5HT neurotoxin seems to be fenfluramine. Like MDMA, it causes long-term deficits to 5HT pathways while having little impact on DA levels (Baumann et al., 2000). Also like MDMA, fenfluramine has a much greater effect on 5HT release than on DA release (Rothman et al., 2003). This supports the theory that the preferential monoamine toxicity of these drugs somehow relates to the relative abilities of these drugs to influence CNS DA or 5HT activities. In general, compared to the DA toxicity, much less is known about the mechanisms underlying the 5HT toxicity caused by amphetaminerelated drugs. However, like the DA response, the 5HT deficits appear to be somewhat selective in that not all brain regions are equally affected by these drugs (O’Hearn et al., 1988; Haughey et al., 1999) and the deficits appear to be limited to 5HT terminals with cell bodies in the raphe region apparently left intact (Molliver et al., 1990). The functional consequences of these 5HT effects are not well studied nor are these effects well established in humans. The neurotoxic studies have been conducted almost exclusively in laboratory animals, although there is no reason to believe that similar 5HT deficits would not also be seen in humans comparably exposed to these drugs. 6. A broader perspective The vast majority of the amphetamine-related research described above was supported by NIDA programs. From this work, we have identified and elucidated the neurotoxic potential and mechanisms of these psychostimulants relative to monoaminergic systems. We have characterized the roles of DA, reactive oxygen species, DAT and VMAT-2 in this neurotoxicity. These findings suggest interesting strategies for protecting against DA-related neurotoxicity. For example, it is
possible that antioxidant therapy would be protective against damage caused by the formation of reactive oxygen species caused by the auto-oxidation of DA. In addition, these studies support the possibility that transporter protein trafficking can be pharmacologically manipulated based on the transporter releasing versus uptake blocking properties of drugs. Because of the similarity between METH actions and the degenerative process of Parkinson’s disease, it is speculated that similar shifts in VMAT-2 location and function are contributing to the development of this disease. If this is true, the DAT blockers such as methylphenidate may be helpful in lowering the degree of degradation that typically occurs with this disease. This needs to be tested clinically to determine its relevance to the neurological disorder.
Acknowledgements We greatly appreciate the many faculty, postdoctoral, graduate and undergraduate students who over the years have contributed so much to these studies. In particular, we acknowledge Dr. James W. Gibb, who took the first steps that laid the foundations of this research for us and so many others. We especially thank the National Institute on Drug Abuse and the National Institutes of Health for their generous support over the past 30 years.
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The methamphetamine experience: a NIDA partnership Glen R. Hanson , Kristi S. Rau, Annette E. Fleckenstein Department of Pharmacology and Toxicology, University of Utah, 30 South 2000 East, Skaggs Hall, Room 112, Salt Lake City, UT 84112, USA Received 14 April 2004; received in revised form 19 May 2004; accepted 28 May 2004
Abstract The neurotoxic properties of the amphetamines such as methamphetamine (METH) were originally described about the time of the National Institute on Drug Abuse’s organization, in the early 1970s. It required more than 20 years to confirm these neurotoxic properties in humans. Much like Parkinson’s disease, multiple high-dose administration of METH somewhat selectively damages the nigrostriatal dopamine (DA) projection of the brain. This effect appears to be related to the intracellular accumulation of cytosolic DA and its ability to oxidize into reactive oxygen species. Both the dopamine plasmalemmal transporter and the vesicular monoamine transporter-2 seem to play critical roles in this neurotoxicity. METH and related analogs such as methylenedioxymethamphetamine (MDMA) can also damage selective CNS serotonin neurons. The mechanism of the serotonergic neurotoxicity is not as well characterized, but also appears to be related to the formation of reactive oxygen species and monoamine transporters. Studies examining the pharmacological and neurotoxicological properties of the amphetamines have helped to elucidate some critical features of monoamine regulations as well as helped to improve our understanding of the processes associated with degenerative disorders such as Parkinson’s disease. # 2004 Elsevier Ltd. All rights reserved. Keywords: Methamphetamine; Dopamine transporter; Vesicular monoamine transporter; Neurotoxicity; Methylphenidate
1. Prologue The year of 2004 marks the 30th anniversary of the National Institute on Drug Abuse (NIDA) and is an appropriate time to take stock of the important contributions made by this institute, its dedicated staff, and its conscientious leadership. It is broadly recognized throughout the world that the NIDA leads the way in supporting and encouraging research intended to elucidate the cause and consequence of drug abuse and addiction. The fruits of these efforts have helped us to appreciate the biomedical basis of addiction, recognize its disease properties, and develop more effective intervention strategies to prevent and treat addiction. NIDA has supported research in a wide range of disciplines by some of the world’s most able scientists. The discoveries by these and other NIDA-supported researchers extend well beyond elucidating the process
of drug abuse and addiction, and have helped to identify and understand critical neurobiological systems, their regulation and important cellular mechanisms that contribute to many normal and pathological neurobiological functions. Our group is honored to be able to participate in this ‘‘NIDA intellectual celebration’’ by sharing some of the methamphetamine-related research highlights to which we have contributed, and that were made possible because of NIDA support and encouragement. Even though we have been asked to emphasize in this paper the research from our laboratories, it is important to recognize that the successes in the research of methamphetamine (METH) and related drugs have been due to the cumulative efforts of many laboratories and dedicated scientists, unfortunately too many to list and discuss in detail in this short article. 2. Introduction
Corresponding author. Tel.: +1-801-581-3174; fax: +1-801-5855111. E-mail address: [email protected] (G.R. Hanson). 0028-3908/$ - see front matter # 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.neuropharm.2004.06.004
The potent psychostimulant properties of the synthetic drug, amphetamine were described in the early
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20th century by Gordon Alles, a researcher looking for a more potent substitute for the decongestant ephedrine. Alles discovered that when inhaled or taken orally, amphetamine dramatically reduced fatigue, increased alertness and caused a sense of confident euphoria. After these impressive findings, the Benzedrine (amphetamine) inhaler became available in 1932 as a non-prescription product across America. This product was marketed for nasal decongestion, but became widely abused for its stimulant properties. Due to a lack of restrictions, amphetamine products, including its analog METH were sold to treat a bevy of ailments including obesity, alcoholism, bed-wetting, depression, schizophrenia, heart block, head injuries, seasickness and persistent hiccups. Amphetamines have been used extensively by military personnel and truck drivers due to their ability to mask drowsiness and fatigue. More than any other single experience, the US epidemic use of prescription amphetamine anorexiant products by homemakers in the late 1960s made the addictive dangers of the amphetamines broadly recognized and feared (Hanson et al., 2004). Because of these episodes of widespread addiction with the amphetamine, in the early 1970s, the newly formed NIDA identified amphetamine-related research as one of its top priorities. It was at this time that Dr. James Gibb received his first NIDA grant to study the neurochemical consequences of METH exposure. Since these initial studies, a number of faculty, postdoctoral, graduate and undergraduate students have partnered with Dr. Gibb in this research and made major contributions to these efforts. Critical to the research success of this group over the years has been a sense of teamwork and open collaboration by its members.
3. The dopamine link to neurotoxicity The group’s early research established the critical role of DA in the neurotoxic effects of METH. It was discovered that multiple high-dose administrations, given to simulate what was occurring in the typical ‘‘run’’ by METH addicts, resulted in a dramatic reduction in tyrosine hydroxylase (TH) activity and levels of DA (Fig. 1). These deficits persisted for weeks and were selective to the nigrostriatal DA pathway, the same system damaged in Parkinson’s disease (Morgan and Gibb, 1980; Hurtig, 2000). It was concluded that multiple moderate to high doses of METH are selectively neurotoxic to the nigrostriatal DA pathway. About this same time, other investigators reported similar findings using somewhat different drug treatments and assessing other parameters such as the dopamine transporter (DAT; Seiden et al., 1976; Wagner et al., 1980). These observations served as the critical basis for much of the research that has followed
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Fig. 1. Persistent effects of METH on TH activity and DA content in the striatum. Rats were injected with either normal saline (1 mg/ kg, s.c.) or METH (15 mg/kg, s.c.) every 6 h for five doses and decapitated 36 h after the first dose. Brackets indicate S.E.M. p< 0:001 compared to saline control. Reproduced from Morgan and Gibb (1980).
in our and other’s laboratories and has also contributed to our understanding of the vulnerability of this critical DA system. Despite the frequent reproduction of these original findings by others in many animal species, it was not until the late 1990s that this selective METH-related toxicity to DA neurons was observed in humans. Volkow et al. (2001a,b) observed using PET imaging that the levels of DAT were consistently reduced in heavy METH users up to 11 months after the last drug exposure. Volkow et al. (2001a) correlated these deficits in the DA system to motor slowing and memory impairment, suggesting significant functional impact from these neurotoxic consequences. Wilson et al. (1996) also determined in postmortem tissue a persistent reduction in DA, DAT and TH levels in METH users, although they interestingly observed no significant decreases in striatal vesicular monoamine transporter-2 (VMAT-2), another protein thought to be a reliable marker of DA neuronal integrity. This finding underscored the preclinical observation that the METH-induced deficits are not associated with cellular death but a somewhat selective axonal degeneration (Kogan et al., 1976; Ricaurte et al., 1982).
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While attempting to elucidate the mechanism responsible for DA-related neurotoxicity of METH, it was speculated that DA itself played a critical role. To test this, METH was administered to DA-depleted animals pretreated with alpha-methyl tyrosine, an inhibitor of TH. It was observed that in the presence of DA depletion, the METH toxicity did not occur, suggesting that the DA molecule itself somehow contributed to the neurotoxic effects. It was hypothesized that this link might be related to the tendency of DA to readily oxidize into reactive quinones and semiquinones (Schmidt et al., 1985b). This possibility was tested and supported by our observation that METH treatment increases the production of extracellular reactive oxygen species (Fleckenstein and Hanson, 2000). Similar observations have been made by other groups (Yamamoto and Zhu, 1998; Obata and Yamanaka, 2000). With the establishment of a DA role in the neurotoxic effects of DA, our research focused on the mechanisms of this and related phenomena.
4. Dopamine dynamics and transporters Our findings lead us to three critical issues of investigation: did other psychostimulants have similar neurotoxic properties? why was the nigrostriatal projection particularly vulnerable? and where was the site of the DA-linked damage? 4.1. Other psychostimulants Although over the years our group has examined many psychostimulants chemically related and unrelated to METH, this discussion will, for the most part, be limited to methylenedioxymethamphetamine (MDMA) and cocaine. From our observations, the potent psychostimulants appeared to fall into two broad categories with some subgroups. The broad groups are those compounds, such as METH and MDMA, that principally increase extracellular monoamines such as DA and serotonin (5HT) by reversing the respective plasmalemmal transporters. The other category includes those drugs that increase the extracellular DA by blocking the plasmalemmal transporter preventing reuptake of DA released by vesicular mechanism, such as cocaine and methylphenidate. Our finding has been that in general the releaser agents have the potential to induce long-term damage to monoaminergic pathways, while this toxicity does not appear to be caused by drugs that block transporter uptake (for review, see Fleckenstein et al., 2000). In fact, the transporter blockers appeared to actually be neuroprotective, especially against the neurotoxicity caused by the releasing agents. For example, we (Schmidt et al., 1985b) and others (Marek et al., 1990; Pu et al., 1994)
observed that METH-induced reductions in striatal DA parameters are blocked by antagonists of the DAT. This protective action can occur even if the DAT blocker is administered as long as 8 h after the neurotoxic METH treatment (Marek et al., 1990): this suggests that the DAT plays a critical role not only in a priming event, but also contributes to a sequence of events occurring hours after METH treatment, required for the toxicity to eventually be expressed. The critical role of DAT was supported by the observation of Caron and coworkers that METH toxicity is completely blocked in DAT knockout mice (Fumagalli et al., 1998). Because of the apparent link between DAT function and the neurotoxic features of DA-releasing drugs such as the amphetamines, we have examined in detail the effects of the amphetamines, such as METH on functions and states of the DAT protein. These studies lead to dramatic, unexpected discoveries concerning how and why METH influences this plasmalemmal transporter. We initially found that multiple high doses of METH administered to rats rapidly and dramatically reduce DAT activity and DAT ligand binding in striatal synaptosomes, an effect that persisted even after the removal of the METH (Fig. 2; Fleckenstein et al., 2000). A similar effect could be elicited by direct incubation of striatal synaptosomes from naı¨ve animals in the presence of METH for approximately 30 min (Sandoval et al., 2001). These reductions were associated with declines in DAT protein and not changes in its affinity for DA (Fleckenstein et al., 1997a). A likely explanation for these findings was suggested by the in vitro observation of Saunders et al. (2000) that in a DAT-transfected cell line, exposure to amphetamines causes the DAT protein to redistribute away from the plasma membrane and no longer transport extracellular DA. According to these findings, it is likely that the effects we observed in vivo were the consequences of METH-induced internalization of the DAT protein, resulting in a loss of synaptosomal DA transport function. In contrast, treatment with the transporter blocking cocaine had an opposite effect and caused DAT proteins to move back into the cells’ surface membranes (Daws et al., 2002). Studies to determine cellular mechanisms of the psychostimulantinduced DAT trafficking revealed that at least a portion of the METH effect on DAT was mediated by a PKC-dependent phosphorylation of this transporter protein (Sandoval et al., 2001). Other relevant signal transduction cascades remain to be elucidated in this effect. 4.2. Nigrostriatal pathway vulnerability The nigrostriatal DA pathway has been shown to be particularly vulnerable to degradation during
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Fig. 2. Time–response effect of multiple METH administrations on [3H]DA uptake and [3H]WIN35428 binding to DAT in striatal synaptosomes. Rats received four injections of METH (2-h intervals; 10 mg/kg/injection, s.c.) or four injections of saline vehicle (1 ml/kg/injection, s.c.; zero time controls). Rats were decapitated 1 h, 24 h or 7 days after the final injection. Values represent means 1 S:E:M: of determinations in 6–14 rats. Values for METH-treated rats that differ significantly from controls. # Value for [3H]DA uptake that differs significantly from that obtained from rats decapitated 1 h after the final METH administration (p 0:05). Reproduced from Kokoshka et al. (1998).
Parkinson’s disease (for review, see Hurtig, 2000). We (Morgan and Gibb, 1980; Haughey et al., 1999) and others (Seiden et al., 1976; Seiden and Vosmer 1984; Ricaurte et al., 1982; Cass, 1997) observed a similar pattern of vulnerability when assessing deficits in DA systems after high-dose METH treatment; thus, the METH treatment that leads to striatal deficits in DA parameters has little long-term effect on similar DArelated measurements in the nucleus accumbens. Although the precise mechanism for this preferential vulnerability is not known, it has been suggested that it is linked to the substantially higher concentration and activity of DAT in the striatum (Eisch et al., 1992). This possibility would be consistent with the hypothesis that the DAT plays a critical role in mediating this toxicity. We have examined the possibility that another factor may contribute as a mediating mechanism for METHrelated neurotoxicity. It has been postulated that the storage vesicles linked with the VMAT-2 serve a critical role of sequestering cytosolic DA in vesicles where this monoamine is protected against oxidation and the production of reactive oxygen species (Liu and Edwards, 1997; Miller et al., 1999; Fleckenstein et al., 2000). Observations that heterozygotic VMAT-2 knockout mice are considerably more vulnerable to METH-related DA toxicity, supports this conclusion (Fumagalli et al., 1999). Consequently, we tested the hypothesis that the psychostimulants alter VMAT-2 function in some manner that would be linked to neurotoxicity. We observed that in purified preparations of striatal cytosolic vesicles, the neurotoxic regimen of METH dramatically reduced the ability of these vesi-
cles to sequester DA. This decline in vesicular sequestering function appeared to be related to a trafficking of the VMAT-2 transporter (for review, see Fleckenstein and Hanson, 2003). The decline in VMAT-2 activity in purified vesicle preparations persisted for at least a week, suggesting an association with the METH-initiated neurotoxic sequence of cellular events. The change in striatal VMAT-2 function was initiated within a matter of minutes after the METH treatment and was not due to a direct effect of METH as it was observed even after washing the drug away (Fleckenstein et al., 1997a). Compared to the METH-induced reduction of striatal VMAT-2 activity in the purified cytosolic fraction, blockers of DAT had an opposite effect. Thus, after administration of cocaine or another DAT inhibiting drug, methylphenidate, the transport of DA into purified vesicles increased. This effect was associated with an increase in VMAT-2 Vmax and ligand binding that occurred within minutes, was independent of the presence of the drugs, and reversed in a matter of hours (Sandoval et al., 2002). Because of the postulated importance of the VMAT-2 activity to cause METH neurotoxicity, we hypothesized that the DAT inhibitors were protective by virtue of their ability to provide more DA sequestration in the neuronal cytosolic fraction. To test this possibility, we administered a neurotoxic regimen of METH followed by a treatment with methylphenidate. We observed that the sequestering of DA in the cytosolic vesicular fraction was not reduced by the METH when post-treated with the methylphenidate (Fig. 3; Sandoval et al., 2003) nor did the typical
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Fig. 4. Post-treatment with methylphenidate (MPD) attenuates METH-induced long-term deficits dopaminergic deficits. Rats received METH (four injections of 7.5 mg/kg; s.c.; 2-h intervals) or saline (1 ml/kg, s.c.). Rats received one injection of MPD (5 mg/kg, s.c.), two injections of MPD, or three injections of MPD or saline (sal; 1 ml/kg, s.c.) 1, 3, and 5 h after the last METH or saline injection. Rats were decapitated seven days after the last METH, methylphenidate, or saline administration. Columns represent the mean DA concentrations and vertical lines 1 S.E.M. of determinations in 8–12 rats. Values that are significantly different from Sal/Sal-treated groups (p 0:05). Reproduced from Sandoval et al. (2003). Fig. 3. Post-treatment with methylphenidate (MPD) does not alter total striatal tissue DA content (A), but blocks the METH-induced decrease in vesicular DA content (B). Rats received METH (four injections; 7.5 mg/kg/injection, s.c.; 2-h intervals) or saline (Sal; 1 ml/kg, s.c.). Rats received three injections of MPD (5 mg/kg, s.c.) or saline (1 ml/kg, s.c.) after the last METH or saline injection. Rats were decapitated 6 h after the last METH, 1 h after the last MPD, or 1 h after the last saline administration. Columns represent the means and vertical lines 1 S.E.M. of determinations in six rats. Values that are significantly different from Sal/Sal-treated groups (p 0:05). Reproduced from Sandoval et al. (2003).
long-term DA deficits occur (Fig. 4; Sandoval et al., 2003). These findings support the hypothesis that VMAT-2 function and DA sequestration likely play critical roles both in mediating METH-related neurotoxicity and the neuroprotection of the DAT inhibitors. Although ongoing research is being conducted to elucidate specifically how the monoamine releasing and uptake blocking drugs mediate these changes in DA sequestration, one possibility suggested by our initial findings is that these drugs alter the trafficking of VMAT-2-associated vesicles. Employing western blot analysis with partial purification of cellular compartments, it appears that 1 h after administering either type of psychostimulant, the VMAT-2 protein likely shifts compartments with the associated vesicles. Although some details are lacking, the DA-releasing drugs such as the amphetamines appear to cause the vesicles to withdraw from the synaptic terminal, resulting in a reduction of VMAT-2 in the cytosol, a non-
membrane-associated pool (Sandoval et al., 2003), but not in the total tissue homogenate (Hogan et al., 2000). In contrast, the DAT blockers cause the VMAT-2 protein to shift from the heavy membrane fraction (likely associated with vesicles bound to the plasmalemma or some other heavy membrane) and move into the cytosolic fraction where it can increase the uptake of the cytosolic DA (Sandoval et al., 2002). These exciting findings concerning transporter protein trafficking have very important implications for drug targets and understanding the etiology of neurotoxicity, such as that associated with METH and even Parkinson’s disease. 4.3. Site of DA-linked damage While it is generally accepted that the oxidation of DA itself contributes to the damage of DA-related pathways, it is not clear if these neurotoxic oxidative events occur outside or inside the neuronal terminal. Several of the observations that METH treatment induces free radical production were done by determining an increase in striatal production of the oxidized product dihydroxybenzoic acid from salicylate coadministered with the METH (Kondo et al., 1994; Giovanni et al., 1995; Fleckenstein et al., 1997b; LaVoie and Hastings, 1999). Because these increases were measured in total tissue, the site of the DA oxidation is not clear. Subsequent reports that salicylate infusion by microdialysis results in an increased formation of
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dihydroxybenzoic acid in the dialysate after METH administration by our group (Fleckenstein and Hanson, 2000) and others (Yamamoto and Zhu, 1998; Obata and Yamanaka, 2000) demonstrates that METH treatment does increase the free radical production in the synaptic space; however, this has not been linked to eventual neurotoxicity. It has been reported that the DA-quinones are particularly likely to oxidize and bind to sulfhydryl groups (Graham, 1978) making cysteine-containing proteins especially vulnerable to DA-quinone oxidation (Hastings and Berman, 2000). A direct consequence of this DA-linked oxidation that is precipitated by neurotoxic METH treatments has been reported. Using western blots, we recently observed that the DAT protein forms several oligomeric complexes after multiple high doses of METH (Fig. 5; Baucum et al., 2004). The formation of these DAT complexes only occurs after an METH neurotoxic treatment; requires the presence of DA and hyperthermia; is reversed by a reducing environment; requires 24–36 h to express and is not observed with either TH or dopamine D2 receptors.
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The properties of this phenomenon suggest that the formation of these oligomeric complexes of DAT are closely linked to METH-induced DA neurotoxicity and that the damage to the DA striatal projections likely occurs due to DA-related oxidative events inside the neuronal terminals. This is supported by the observations described above that neurotoxic METH treatments cause a loss of VMAT-2 protein and likely the associated vesicles from the DA neuronal terminals. A reduction in these cytosolic vesicles diminishes the sequestration of freely floating DA and facilitates its oxidation to reactive quinones and oxidation of intracellular constituents. Since the DAT protein is highly susceptible to oxidation at its cysteine groups (Fleckenstein et al., 1997b: LaVoie and Hastings, 1999), this protein would be expected to form complexes as a consequence. This is consistent with our observation that the DAT oligomers induced by METH treatment were eliminated when placed in a reducing environment (Baucum et al., 2004).
5. The serotonin sequel
Fig. 5. Multiple administrations of METH increased higher molecule weight DAT complex formation as evidenced using antibody directed against the N terminus of the DAT. Rats received METH (four injections of 7.5 mg/kg/injection, s.c.; 2-h intervals) or saline (four injections of 1 ml/kg, s.c.; 2-h intervals) and were decapitated 6–72 h later. In this representative blot, two independent samples are shown for each treatment group. Reproduced from Baucum et al. (2004).
While METH-related neurotoxicity was initially associated with the striatal DA system, it was known that some amphetamine-related drugs such as parachloroamphetamine (PCA) possessed the ability to cause damage to some serotonergic pathways (Fuller and Snoddy, 1980; Fuller, 1980). Our group tested the possibility that like PCA, METH administrations also possesses the ability to damage 5HT neurons. We observed that like the DA-related effects, it required moderate to high doses of METH given in multiple administrations to observe long-lasting deficits in serotonergic parameters (Morgan and Gibb, 1980). These deficits occurred not only in the striatum, but in other brain regions as well, such as in the hippocampus and the frontal cortex (Bakhit et al., 1981). These METH effects have been duplicated by other investigators (Ricaurte et al., 1980; Trulson and Trulson, 1982). Similar to the DA toxicity, the METH-induced damage to 5HT systems requires the respective plasmalemmal monoamine transporter (Schmidt and Gibb, 1985a); is dependent on hyperthermia (Fleckenstein et al., 1997b; LaVoie and Hastings, 1999); is thought to be linked to free radical formation (Stone et al., 1989); and at least partially is associated with DA systems (Sonsalla et al., 1986; De Vito and Wagner 1989). While the potential role of METH-induced changes in vesicular trafficking in serotonergic neurons has not been investigated, there is evidence that oxidative damage is occurring inside the 5HT terminals. Thus, METH treatment causes a very rapid reduction in the activity of tryptophan hydroxylase, the rate-limiting synthetic enzyme for 5HT. This decrease in activity can totally be reversed
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when the enzyme is exposed to a reducing environment (Fleckenstein et al., 1997b; Stone et al., 1989), suggesting reactive oxygen species are forming inside the 5HT terminals after METH treatment, oxidizing the enzyme and perhaps causing other serious cellular damage. At present, the source of the oxidative events in the 5HT neurons after METH is not known. While METH toxicity is observed in both selective DA and 5HT neurons, it is somewhat unique in this feature when compared to other phenylethylaminerelated drugs. For example, MDMA has been reported by many investigators to be able to cause METH-like damages to 5HT neurons, but unlike METH, it does not appear to have long-term consequences on the nigrostriatal DA pathway (Stone et al., 1986; Ricaurte et al., 1985; Battaglia et al., 1987; Schmidt and Kehne, 1990). The reason for this distinction is not known, although MDMA does appear to have a relatively greater effect on 5HT release than does METH (Setola et al., 2003). Another drug that is a selective 5HT neurotoxin seems to be fenfluramine. Like MDMA, it causes long-term deficits to 5HT pathways while having little impact on DA levels (Baumann et al., 2000). Also like MDMA, fenfluramine has a much greater effect on 5HT release than on DA release (Rothman et al., 2003). This supports the theory that the preferential monoamine toxicity of these drugs somehow relates to the relative abilities of these drugs to influence CNS DA or 5HT activities. In general, compared to the DA toxicity, much less is known about the mechanisms underlying the 5HT toxicity caused by amphetaminerelated drugs. However, like the DA response, the 5HT deficits appear to be somewhat selective in that not all brain regions are equally affected by these drugs (O’Hearn et al., 1988; Haughey et al., 1999) and the deficits appear to be limited to 5HT terminals with cell bodies in the raphe region apparently left intact (Molliver et al., 1990). The functional consequences of these 5HT effects are not well studied nor are these effects well established in humans. The neurotoxic studies have been conducted almost exclusively in laboratory animals, although there is no reason to believe that similar 5HT deficits would not also be seen in humans comparably exposed to these drugs. 6. A broader perspective The vast majority of the amphetamine-related research described above was supported by NIDA programs. From this work, we have identified and elucidated the neurotoxic potential and mechanisms of these psychostimulants relative to monoaminergic systems. We have characterized the roles of DA, reactive oxygen species, DAT and VMAT-2 in this neurotoxicity. These findings suggest interesting strategies for protecting against DA-related neurotoxicity. For example, it is
possible that antioxidant therapy would be protective against damage caused by the formation of reactive oxygen species caused by the auto-oxidation of DA. In addition, these studies support the possibility that transporter protein trafficking can be pharmacologically manipulated based on the transporter releasing versus uptake blocking properties of drugs. Because of the similarity between METH actions and the degenerative process of Parkinson’s disease, it is speculated that similar shifts in VMAT-2 location and function are contributing to the development of this disease. If this is true, the DAT blockers such as methylphenidate may be helpful in lowering the degree of degradation that typically occurs with this disease. This needs to be tested clinically to determine its relevance to the neurological disorder.
Acknowledgements We greatly appreciate the many faculty, postdoctoral, graduate and undergraduate students who over the years have contributed so much to these studies. In particular, we acknowledge Dr. James W. Gibb, who took the first steps that laid the foundations of this research for us and so many others. We especially thank the National Institute on Drug Abuse and the National Institutes of Health for their generous support over the past 30 years.
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