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The VMAT2 gene in mice and humans: amphetamine responses, locomotion, cardiac arrhythmias, aging, and vulnerability to dopaminergic toxins

Molecular Neurobiology Branch, NIDA-IRP, National Institutes of Health, Baltimore, Maryland 21224, USA

¹Correspondence: Molecular Neurobiology, Rm. 302, 5500 Nathan Shock Dr., Baltimore, MD 21224, USA. E-mail guhl{at}intra.nida.nih.gov

	ABSTRACT

TOP ABSTRACT VMAT2 VMAT2 GENES: HUMAN AND... MURINE MODELS FOR VMAT2... Aging HUMAN VMAT GENE POLYMORPHISMS... SUMMARY REFERENCES

 
Monoamine compartmentalization in monoaminergic neurons uses serial action of the plasma membrane and vesicular monoamine (VAMT2) transporters. We can now define the sequences of the genes encoding these transporters in mice and humans, examine influences of deletions of this gene and alteration in its expression levels in transgenic mice, and identify sequence polymorphisms in the human VMAT2 gene. Examination of VMAT2 variants can provide potential insights into roles for allelic variants at these loci in variant drug responses and in diseases linked to monoaminergic systems, including substance abuse and Parkinson’s disease.—Uhl, G. R., Li, S., Takahashi, N., Itokawa, K., Lin, Z., Hazama, M., Sora, I. The VMAT2 gene in mice and humans: amphetamine responses, locomotion, cardiac arrhythmias, aging, and vulnerability to dopaminergic toxins

Key Words: VMAT2 • serotonin • histamine • dopamine • norepinephrine • synaptic vesicle • Parkinsonism • MPTP

	VMAT2

TOP ABSTRACT VMAT2 VMAT2 GENES: HUMAN AND... MURINE MODELS FOR VMAT2... Aging HUMAN VMAT GENE POLYMORPHISMS... SUMMARY REFERENCES

 
THE BRAIN vesicular monoamine transporter (VMAT2) uses energy from vesicular proton gradients to pump monoamine neurotransmitters and Parkinsonism-inducing dopamine neurotoxins such as MPP⁺ (1-methyl-4-phenyl-phenydium) from neuronal cytoplasm into synaptic vesicles (1 2 3) . The selectivity with which monoaminergic neurons package dopamine, serotonin, norepinephrine, or histamine into their synaptic vesicles derives from the specificities of their plasma membrane transporters. Less specific vesicular monoamine transporters act in series with plasma membrane transporters to determine the amount of monoamines stored in vesicles and the rate at which free cytoplasmic stores of monoamines are sequestered into vesicles. Amphetamines release monoamines from the vesicles loaded by VMAT2 (3) whereas amphetamines and cocaine also block plasma membrane transporters for dopamine, serotonin, and norepinephrine.

Monoamine transmitters and the neurons in which they are selectively expressed are implicated in a broad range of pharmacologic, neurological, and psychiatric states. Data from humans and mouse models indicate significant genetic contributions to many of the states in which the monoamine transmitters are implicated. Better understanding of the VMAT2 gene and of individual differences at this locus could contribute to improved understanding the biology of these disorders. Understanding the differences in behavioral, pharmacologic, and physiological responses found when VMAT2 expression is altered in animal models is also important. Together, these views of this gene, its allelic variants, and the different phenotypes conferred by altering VMAT2 expression in animals provide a basis for examination of the contributions that individual differences in VMAT2 structure and/or expression could make to human individual differences in several phenotypes of interest. These phenotypes include amphetamine responsiveness, vulnerabilities to addiction, attention deficit/hyperactivity disorder, sleep disorders, schizophrenia and depression, individual differences in locomotor activity and cardiac arrhythmias, as well as features of aging and vulnerability to dopaminergic toxins.

In this study, we review work on the structure of the human, rat, and murine VMAT2 genes, current evidence for human polymorphisms in this gene, the consequences of altering VMAT2 expression through knockout techniques in mice, and initial attempts to assess the individual differences in the VMAT2 gene in humans.

	VMAT2 GENES: HUMAN AND MURINE GENES, FOCAL 5' SEQUENCE CONSERVATION, SEQUENCE VARIANTS, DISTRIBUTIONS IN CAUCASIAN AND AFRICAN-AMERICAN CONTROL AND DISEASE POPULATIONS

TOP ABSTRACT VMAT2 VMAT2 GENES: HUMAN AND... MURINE MODELS FOR VMAT2... Aging HUMAN VMAT GENE POLYMORPHISMS... SUMMARY REFERENCES

 
Gene structure
Elucidation of the structure of the murine VMAT2 gene reveals that >35 kb of genomic sequence contain the 16 exons that encode the VMAT2 5' untranslated sequence, the 517 amino acid VMAT2 protein, and the proximal portion of the genes’ 3' untranslated region sequences (4) . Analyses of proximal 5' flanking sequences reveal an apparent TATA-less, CAAT-less promoter region with several candidate transcription factor binding sites clustered in regions including the ca.[-50–-80] and [-100–-120] bp regions (4) .

Data about the mouse gene can now be assembled with data from the human cDNAs and genes from Uhl and colleagues, Xu and colleagues (5 6 7) , Hasama, Uhl et al. (unpublished results); from the rat gene from Watson and co-workers (8) ; and from genomic databases to provide the human VMAT2 gene structures noted in Fig. 1 . Variants and patterns of linkage disequilibrium are also superimposed on this figure, as discussed below.

View larger version (13K): [in this window] [in a new window]   Figure 1. Human VMAT2 gene structure, variation, and linkage disequilibrium. Top line: Numbered boxes indicate exons, with the several possible transcriptional termination sites for the 3' untranslated region indicated in exon 16. Intervals between exons are introns. The regions screened by sequencing are shown by gray lines and boxes. Middle area: The polymorphic sites found in each segment indicated are marked with the variant bases and their frequencies in a Caucasian sample (M. Hazama et al., unpublished results). The loci for the single nucleotide polymorphisms (SNPs) are: SNP1 at -349; SNP2 at -308; SNP3 at +2665; SNP4 at +2684; SNP6 at +13141; SNP7 at +14047; SNP8 at +14049; SNP9 at +14066; SNP10 at -1946; SNP11 at -4763; SNP12 at -4781. Locations of simple sequence length polymorphisms (TNP and DNPs) are: TNP1 at -2355; DNP2 at -4536; DNP3 at -5445. Lower bars: D' values for linkage disequilibrium with the -5 kb 5' dinucleotide repeat polymorphism are noted. Scale bar = 1 kb.

The murine VMAT2 gene encodes most of the mRNA’s 5' untranslated region on its first exon (4) . Assignment of a similar transcriptional start site for the human gene allows comparison of the human with mouse candidate 5' flanking region sequences. Comparisons of ca. 6 kb of human and murine VMAT2 5' flanking genomic sequences (4) elucidates a >3.5 kb region that displays multifocal sequence conservation between these species (Fig. 2 ).

View larger version (21K): [in this window] [in a new window]   Figure 2. Dot plot comparisons of sequences in human (top) and murine (side) VMAT2 5' flanking sequences. Oblique lines indicate multifocal regions of sequence similarity suggestive of functional conservation.

Many of the misalignments in this area come from the presence of Alu-like repeats in the human sequence. This 5' flanking region is also rich in transcription factor recognition motifs. Approximately 2 kb portions of this region can drive reporter gene expression in rat lymphoid precursor cells that normally express VAMT2 (8) . This promoter sequence fragment is also able to support expression of a sensitive reporter gene in SHSY-5Y cells that normally express little VMAT2 (7) . Within the 5' regions most conserved between mouse and human genes, there are several islands of quite highly conserved sequence. One of these is a 154 bp region immediately 5' to the transcription initiation site. This region shows 55% sequence identity between mouse and human sequences. The human and mouse genes share many of the same candidate transcription factor binding elements in this area, including Sp1, AP1-like, AP2-like, and CRE-like motifs. Many of these features are also found in the rat gene 5' flanking sequences (8 ; GENBANK accession # AF047575). The human gene sequences reported by Xu and co-workers (7) also show sequence similarities in this region, retaining transcription factor binding sites that include CRE and Sp1 elements. None of these genomic sequences displays a TATA or CCAAT box. Although these regions are thus good candidates for providing promoter/enhancer elements important for proper cell-specific patterns of brain expression, no current mouse or human data provide unequivocal evidence to identify the sequences important for the cell specificity of expression that is a hallmark of the wild-type VMAT2 expression.

	MURINE MODELS FOR VMAT2 GENE VARIATION: INFLUENCES ON AMPHETAMINE ACTIONS, LETHALITY, MPP+ TOXICITY, CARDIAC CONDUCTION, AND AGING

TOP ABSTRACT VMAT2 VMAT2 GENES: HUMAN AND... MURINE MODELS FOR VMAT2... Aging HUMAN VMAT GENE POLYMORPHISMS... SUMMARY REFERENCES

 
To assess vesicular contributions to amphetamine-induced locomotion, amphetamine-induced reward, and sequestration and resistance to dopaminergic neurotoxins, we and others have constructed and analyzed transgenic VMAT2 knockout mice (9 10 11) . Each group has found that heterozygous VMAT2 knockouts are viable into adult life and display VMAT2 levels half of wild-type values, although most homozygous knockouts do not feed properly and fail to survive more than days after birth. We focus on data from our mice in this paper; see Table 1 for discussion of other VMAT2 knockout strains.

Heterozygous mice manifest modest differences from wild-type mice in monoaminergic markers, heart rate, and blood pressure. They display weight gain, fertility, habituation, passive avoidance, and locomotor activities similar to wild-type littermates (9) .

In VMAT2 heterozygous knockout mice, amphetamine produces diminished behavioral reward, as measured by conditioned place preference, while enhancing locomotor responses to amphetamine (9) . Administration of the MPP⁺ precursor MPTP (N-methyl-1,2,3,6-tetrahydropyridine) to heterozygotes produces more than twice the dopamine cell losses found in wild-type mice (9) . Amphetamine sensitization and lethality are also altered (N. Takayashi and G. R. Uhl, unpublished results). Cardiac conduction differences that could predispose to fatal arrhythmia are identified in these animals, manifest as prolonged QT intervals (12) . Initial data indicate that age-related alterations in locomotion might also be altered in these mice (K. Itokawa and G. R. Uhl, unpublished results).

Properties of VMAT2 knockout mice
Expression of VMAT2 protein in neonatal brains, measured by saturation analyses of [³H]dihydrotetrabenazine binding, is decreased 50% in heterozygotes compared to wild-type mice and is undetectable in homozygous mice (9) . Analyses of offspring of matings between heterozygotes revealed that whereas the expected fractions of homozygous and heterozygous mice emerged at birth, homozygous mice were poorly viable postnatally. Pathological examination of homozygous mice killed on P1 revealed only reduced milk in the stomachs. Heterozygote VMAT2 knockout mice were histologically normal, viable into adult life, gained weight at rates similar to their wild-type littermate controls, and expressed VMAT2 protein levels (as examined by binding studies) about half those of wild-type mice. Although expression of at least some VMAT2 is thus necessary for good viability past the immediate postnatal period, mice with half the wild-type levels of VMAT2 expression are able to develop and display many normal baseline behaviors that include complex reproductive behaviors. Most heterozygous knockout mice with half of wild-type levels of VMAT2 expression are viable into adult life. However, 10–15% of these animals die suddenly between 2 and 4 months of age without apparent antecedents (9 , 12) .

Cardiovascular effects
Anesthetized mice: heart rate, blood pressure, and baseline behaviors
Heterozygous mice reveal heart rates, systolic, diastolic, and mean femoral arterial blood pressures greater than those of wild-type mice when assessed under anesthesia using femoral catheters (9) . They are similar to wild-type mice in expression of a previously conditioned passive avoidance habit, stress responses emitted in a stressful novel environment, the ability to hang onto an inverted screen, and gross locomotor activity measured under bright illumination.

Freely moving mice: heart rates and conduction intervals
To further explore cardiovascular parameters in mice free from anesthesia and assess possible mechanisms for the apparent sudden death that afflicts as many as 10–15% of the heterozygotes in their second and third months of life, we telemetered EKG data from these mice (12) . Freely moving mice with normal VMAT2 expression and heterozygous knockout littermates had similar resting heart rates, PQ intervals, and QRS durations. However, heterozygous mice displayed 20% increases in QT intervals. These differences were also seen when QT intervals were corrected for heart rate. A single heterozygous mouse that later died displayed the most prolonged QT interval (12) . Variation in expression of the VMAT2 gene could contribute to interindividual differences in QT interval duration and to differences in vulnerability to lethal arrhythmias.

VMAT2 is expressed in several locations where altered expression could contribute to the prolonged QT intervals found in heterozygous VMAT2 knockout mice, including sympathetic neurons, hypothalamic, and brainstem sites. If altered VMAT2 expression in humans leads to the same prolongation of QT intervals noted in these mice, this gene could be a candidate to contribute to human cardiac sudden death syndromes. Since human individual differences in the extent of expression of VMAT2 in central neurons can be even greater than those that distinguish wild-type from heterozygous mice (15) , allelic variants of the VMAT2 gene are attractive candidates for studies seeking other gene differences that could predispose to human long QT syndromes, cardiac arrhythmia, and sudden death.

Amphetamine effects
Acute
Gross locomotion
One and 3 mg/kg amphetamine doses enhance locomotor activity in both wild-type and heterozygous mice. At 1 mg/kg, heterozygote locomotion was almost 1.5-fold that of wild-type values (9) .

Reward
In a test of amphetamine reward, wild-type and heterozygote animals also displayed conditioning for an initially nonpreferred place where they received 1 or 3 mg/kg conditioning doses of amphetamine (9) . Heterozygote mice displayed less conditioned place preference than wild-type control mice when they received either of these doses in the initially nonpreferred place. Heterozygotes also displayed less conditioned place preference when they received 1 mg/kg amphetamine at the initially preferred place, suggesting that amphetamine pairing enhances the rewarding properties associated with a specific environment rather than reducing aversive features.

Lethality
Amphetamine administration can be lethal; speed does kill. Methamphetamine also kills animals from many species, with mechanisms that are likely to include but not be limited to cardiovascular and central nervous system phenomena, including induction of cardiac arrhythmia and epileptiform processes (1) . In heterozygous VMAT2 knockout mice, amphetamine LD₅₀ values shift leftward compared to values noted in wild-type littermate control mice (N. Takayashi and G. R. Uhl, unpublished results).

To improve the understanding of mechanisms of this lethality, mice were pretreated 15 min prior to amphetamine injection with doses of the D1 antagonist SCH23390 or the D2 antagonist sulpiride (RBI, Natick, Mass.). Pretreatment with SCH23390 caused a striking dose- dependent reduction in the lethality induced by 65 mg/kg amphetamine doses in the heterozygous knockout animals. In contrast, when sulpiride pretreatments were given at 20 or 40 mg/kg, the lethality induced by 50 mg/kg amphetamine doses was substantially enhanced (N. Takayashi and G. R. Uhl, unpublished results).

These data are consistent with roles for vesicular monoamine storage in the lethality that amphetamine induces. Finding enhanced toxicity in mice with fewer vesicular transporters who are likely to have more modest intravesicular monoamine stores could suggest that enhanced quantal release from these vesicles by calcium-dependent mechanisms might not play the major role in amphetamine toxicity. The enhanced cytoplasmic neurotransmitter concentrations likely to result from reduced VMAT2 expression could also enhance neurotransmitter release through nonexocytotic, calcium-independent mechanisms. The effects of receptor antagonists also suggest that the toxicity differences are related to actions of extracellularly released dopamine, as reported in wild-type mice. Observations that D2- and D-1 family receptor blockers can enhance or reduce lethality support prominent roles for both dopaminergic receptor systems in amphetamine toxic phenomena. These data fit with observations that dopamine depletion protects against amphetamine toxicity, suggesting that amphetamine-induced elevations of dopamine in and released from cytoplasmic/extra-vesicular compartments may be key to its lethality.

Chronic amphetamine responses: sensitization
Behavioral changes induced by repeated psychostimulant administration can include tolerance, conditioned responses, and enhanced responses termed ‘sensitization’ (16 17 18) . Sensitization is most easily measured as enhanced locomotor responses to later moderate daily doses of amphetamine or cocaine (19) . The exact biochemical mechanisms underlying sensitization are not clearly understood, although interference with behavioral sensitization by blockers of protein synthesis, dopaminergic and glutaminergic receptors, G-proteins, calcium channels, and protein kinases, including protein kinase C, have suggested that different biochemical steps must be necessary for sensitization (18 , 19) . To assess possible contributions from amphetamine’s vesicular actions in sensitization, we studied methamphetamine- and cocaine-induced sensitization in transgenic heterozygous knockout mice that express half of wild-type levels of VMAT2 (N. Takayashi and G. R. Uhl, unpublished results).

Wild-type mice showed methamphetamine- and cocaine-induced sensitization. Day 1 drug-induced activities were almost doubled after the seventh of the daily methamphetamine challenges. As noted above, the initial responses to 1 mg/kg amphetamine challenges in heterozygous mice were substantially greater than the locomotor responses to its first administration in the wild-type mice. Heterozygotes, however, revealed no statistically significant sensitization to amphetamine, only a slight trend in this direction. These results contrasted with those for cocaine sensitization. Both wild-type and heterozygous mice treated with cocaine manifested significant sensitization.

The differences between the effects of the two psychostimulant types in the VMAT2 heterozygote mice suggest a substantial contribution of amphetamine’s actions at synaptic vesicles to its sensitizing properties. The modest, statistically insignificant difference between day 1 and day 7 amphetamine responses in the heterozygous VMAT2 knockout mice could be explained by the fact that half of the vesicular transporters remain in the heterozygous knockout mice. This could also reflect participation of a different site for this component of amphetamine sensitization, such as the plasma membrane transporters. Unfortunately, the postnatal lethality of homozygous VMAT2 knockout mice prevents assessments of amphetamine sensitization in mice devoid of VMAT2.

Since sensitization provides one useful experimental model for some of the long-term sequelae of psychostimulant administration, the differential effect of vesicular transporter disruption on this adaptation to long-term psychostimulant administration suggests that actions at synaptic vesicles must be kept in mind when thinking about long-term consequences of amphetamine use.

MPTP toxicity
Young VMAT2 heterozygotes appear to display ventral midbrains that are histologically indistinguishable from wild-type mice. Substantia nigra dopaminergic neuronal numbers, estimated via counting tyrosine hydroxylase-immunostained neurons in 6-wk-old heterozygote mice, were similar to those of wild-type animals (9) . However, the effects of an MPTP regimen were substantially different in VMAT2 heterozygotes. MPTP treatments that led to 13% fewer TH immunoreactive neurons in wild-type mice led to 30% reductions in heterozygotes. These data reveal the importance of normal levels of vesicular transport for full MPP⁺ resistance, even in heterozygote animals with half of wild-type levels of VMAT2 expression.

	Aging

TOP ABSTRACT VMAT2 VMAT2 GENES: HUMAN AND... MURINE MODELS FOR VMAT2... Aging HUMAN VMAT GENE POLYMORPHISMS... SUMMARY REFERENCES

 
Since VMAT2 plays significant roles in determining the intracellular compartmentalization of dopamine, a potential age-related oxidative toxin, we have assessed age-related changes in baseline- and psychostimulant-modulated locomotor activities in VMAT2 heterozygote and littermate wild-type mice animals tested at various ages. Age produced larger decreases in VMAT2 heterozygotes than in wild-type mice in locomotor activity in a novel environment and the increment in locomotor activity after test doses of 1 mg/kg amphetamine (K. Itokawa and G. R. Uhl, unpublished results). Each of these results is consistent with the idea that mice with 50% reductions in VMAT2 expression display enhanced age-related age changes. Each of these observations is in the direction of the age-related differences between young and aged wild-type mice.

	HUMAN VMAT GENE POLYMORPHISMS AND STUDIES IN HUMAN DISORDERS

TOP ABSTRACT VMAT2 VMAT2 GENES: HUMAN AND... MURINE MODELS FOR VMAT2... Aging HUMAN VMAT GENE POLYMORPHISMS... SUMMARY REFERENCES

 
Our initial studies that identified the human VMAT2 cDNA mapped the human VMAT2 gene to the long arm of chromosome 10 (5) . This work also identified a TaqI RFLP restriction fragment length coding region polymorphism in this gene. Availability of this initial VMAT2 polymorphic marker has allowed exclusion of this coding region of the VMAT2 locus in studies of schizophrenic pedigrees (20) . No differences in RFLP marker frequencies were found between drug abuser and control or in Parkinson’s disease and control populations (A. Persico and G. R. Uhl, unpublished observations). The strength of these observations was limited, however, by the likelihood that this coding sequence polymorphism could poorly reflect variation in promoter/enhancer sequences that could contribute to individual differences in levels of VMAT2 expression.

In the upstream border of the conserved 5' flanking sequence region, we have recognized imperfect dinucleotide repeat sequences located ca. 5 kb 5' from exon 1 (Fig. 1 ; M. Hazama and G. R. Uhl, unpublished results). This -5 kb simple sequence repeat consisted, in the initial individual studied, of (CA)₇ and (GA)₁₁ gapped with four nucleotides that resemble the cognate repeat GAGAAA. Since such dinucleotide repeats often reveal polymorphism, we tested whether this microsatellite could show polymorphisms.

Polymerase chain reaction products from this region showed several distinct patterns in different individuals. Three common alleles are termed A (161 bp), B (165 bp) and C (172 bp) (M. Hazama and G. R. Uhl, unpublished results). Sequencing amplification products from individuals with these genotypes revealed that they are formed by different numbers of dinucleotide repeats. The A, B, and C alleles have (CA)₇/(GA)₉, (CA)₇/(GA)₁₁, and (CA)₁₄/(GA)₁₁, respectively. These alleles generally distribute across genotypes according to Hardy-Weinberg equilibria. In addition to these common genotypes, we have tentatively identified several other genotype patterns present more rarely, most in African-Americans.

Genotype frequencies of the more common alleles differ between Caucasian and African-Americans. AA genotypes are present in more than 54% of Caucasians and only 16% of African-Americans. Conversely, BB and BC genotypes are more frequent (14 vs. 6 and 16 vs. 1%) in African-Americans than in Caucasians.

To seek possible functional correlations with these polymorphisms, we typed these markers in several control individuals dying without substantial neurological disease whose striatal [³H]dihydro-tetrabenazine B_max values had been previously determined (M. Hazama, S. Kish, and G. R. Uhl, unpublished results). The average striatal VMAT2 expression levels, determined by postmortem binding, were 10–15% different between individuals with one and those with two A genotypes. This trend suggests that further attempts to link genotype with disorders that can be modulated with VMAT2 expression level differences, including substance abuse and Parkinsonism, might be valuable.

VMAT2–5 kb simple sequence repeat genotypes were assessed in 177 and 120 Caucasians characterized as polysubstance abusers and control nonabusers of addictive substances. No significant differences were noted (M. Hazama and G. R. Uhl, unpublished results). The distributions of these gene markers in 82 individuals diagnosed with Parkinsonism again did not differ from those of these drug abusers or controls.

Failure to identify different frequencies of the simple sequence repeat polymorphism in polysubstance abusers and controls could indicate that no VMAT2 promoter sequence variant in linkage disequilibrium with these markers exists. Alternatively, the complex mix of likely polygenic and environmental factors that contribute to substance abuse vulnerabilities could simply provide too much noise for such an approach. Under these circumstances, the sorts of single gene VMAT2 expression level variant effects on drug responses that can be readily elucidated in transgenic mice with other genetic backgrounds and environment held constant might be difficult to identify. Conceivably, effects on acute drug responses noted in mice could also be identified in humans even in the absence of noticeable influences on overall vulnerability to substance abuse and dependence disorders.

	SUMMARY

TOP ABSTRACT VMAT2 VMAT2 GENES: HUMAN AND... MURINE MODELS FOR VMAT2... Aging HUMAN VMAT GENE POLYMORPHISMS... SUMMARY REFERENCES

 
Levels of expression of the VMAT2 gene can clearly contribute to variation in a variety of animal models of clinically important drug and toxin responses. Human haplotypes at the VMAT2 locus, especially those that involve the 5' region of this gene, could well contribute to human individual differences in levels of VMAT2 expression that could provide individual differences in some of these same physiological, pharmacologic and pathological parameters. VMAT2 remains an interesting gene locus for important human variation.

	ACKNOWLEDGMENTS

 
We gratefully acknowledge Donna Walther and the Charles River NIDA support staff for much technical assistance with the studies outlined here, financial support from the NIDA-IRP, National Institutes of Health, and generous support to M.H. from the Pharmacology Laboratories, Takeda Chemical Industries Ltd., Osaka, Japan.

	REFERENCES

TOP ABSTRACT VMAT2 VMAT2 GENES: HUMAN AND... MURINE MODELS FOR VMAT2... Aging HUMAN VMAT GENE POLYMORPHISMS... SUMMARY REFERENCES

 

1. Johnson, R. G. (1988) Accumulation of biological amines into chromaffin granules: a model for hormone and neurotransmitter transport. Physiol. Rev. 68,232-307[Free Full Text]
2. Henry, J.-P., Botton, D., Sagne, C., Isambert, M.-F., Desnos, C., Blanchard, V., Raisman-Vozari, R., Krejci, E., Massoulie, J., Gasnier, B. (1994) Biochemistry and molecular biology of the vesicular monoamine transporter from chromaffin granules. J. Exp. Biol. 196,251-262[Abstract/Free Full Text]
3. Kuczenski, R., Segal, D. S. (1994) Behavioral pharmacology of amphetamine. Cho, A. K. Segal, D. S. eds. Amphetamine and its Analogs ,81-113 Academic Press San Diego.
4. Takahashi, N., Uhl, G. R. (1997) Murine vesicular monoamine transporter 2: molecular cloning and genomic structure. Brain Res. Mol. Brain Res. 49,7-14[Medline]
5. Surratt, C. K., Persico, A. M., Yang, X., gar, S. R., Bird, G. S., Hawkins, A. L., Griffin, C. A., Li, X., Jabs, E. W., Uhl, G. R. (1993) A human synaptic vesicle monoamine transporter cDNA predicts posttranslational modifications, reveals chromosome 10 gene localization and identifies TaqI RFLPs. FEBS Lett 318,325-330[Medline]
6. Liu, L., Xu, W., Harrington, K. A., Emson, P. C. (1994) The molecular cloning and expression of a human synaptic vesicle amine transporter that suppresses MPP+ toxicity. Mol. Brain Res. 25,90-96[Medline]
7. Xu, W., Liu, L., Mooslerhner, K., Emson, P. C. (1997) Structural organization of the human vesicular monoamine transporter type-2 gene and promoter analysis using the jelly fish green fluorescent protein as a reporter. Mol. Brain Res. 45,41-49[Medline]
8. Watson, F., Deavall, D. G., Macro, J. A., Kiernan, R., Dimaline, R. (1999) Transcriptional activation of vesicular monoamine transporter 2 in the pre-B cell line Ea3.123. Biochem. J. 337,193-199
9. Takahashi, N., Miner, L. L., Sora, I., Ujike, H., Revay, R. S., Kostic, V., Jackson-Lewis, V., Przedborski, S., Uhl, G. R. (1997) VMAT2 knockout mice: heterozygotes display reduced amphetamine-conditioned reward, enhanced amphetamine locomotion, and enhanced MPTP toxicity. Proc. Natl. Acad. Sci. USA 94,9938-9943[Abstract/Free Full Text]
10. Wang, Y. M., Gainetdinov, R. R., Fumagalli, F., Xu, F., Jones, S. R., Bock, C. B., Miller, G. W., Wightman, R. M., Caron, M. G. (1997) Knockout of the vesicular monoamine transporter 2 gene results in neonatal death and supersensitivity to cocaine and amphetamine. Neuron 19,1285-1296
11. Fon, E. A., Pothos, E. N., Sun, B. C., Killeen, N., Sulzer, D., Edwards, R. H. (1997) Vesicular transport regulates monoamine storage and release but is not essential for amphetamine action. Neuron 19,1271-1283[Medline]
12. Itokawa, K., Sora, I., Schindler, C. W., Itokawa, M., Takahashi, N., Uhl, G. R. (1999) Heterozygous VMAT2 knockout mice display prolonged QT intervals: possible contributions to sudden death. Brain Res. Mol. Brain Res. 71,354-357[Medline]
13. Travis, E. R., Wang, Y. M., Michael, D. J., Caron, M. G., Wightman, R. M. (2000) Differential quantal release of histamine and 5-hydroxytryptamine from mast cells of vesicular monoamine transporter 2 knockout mice. Proc. Natl. Acad. Sci. USA 97,162-167[Abstract/Free Full Text]
14. Fumagalli, F., Gainetdinov, R. R., Wang, Y. M., Valenzano, K. J., Miller, G. W., Caron, M. G. (1999) Increased methamphetamine neurotoxicity in heterozygous vesicular monoamine transporter 2 knockout mice. J. Neurosci. 19,2424-2431[Abstract/Free Full Text]
15. Wilson, J. M., Levey, A. I., Bergeron, C., Kalasinsky, K., Ang, L., Peretti, F., Adams, V. I., Smialek, J., Anderson, W. R., Shannak, K., Deck, J., Niznik, H. B., Kish, S. J. (1996) Striatal dopamine, dopamine transporter, and vesicular monoamine transporter in chronic cocaine users. Ann. Neurol. 40,428-439[Medline]
16. Ellinwood, E. H., Cohen, S. (1971) Amphetamine abuse. Science 171,420-421[Free Full Text]
17. Post, R. M., Rose, H. (1976) Increasing effects of repetitive cocaine administration in the rat. Nature (London) 260,731[Medline]
18. Nestler, E. J. (1992) Molecular mechanisms of drug addiction. J. Neurosci. 12,2439-2450[Medline]
19. Robinson, T. E., Berridge, K. C. (1993) The neural basis of drug craving: an incentive-sensitization theory of addiction. Brain Res. Brain Res. Rev. 18,247-291[Medline]
20. Persico, A. M., Wang, Z. W., Black, D. W., Andreasen, N. C., Uhl, G. R., Crowe, R. R. (1995) Exclusion of close linkage between the synaptic vesicular monoamine transporter locus and schizophrenia spectrum disorders. Am. J. Med. Genet. 60,563-565[Medline]

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				A. SIDHU, C. WERSINGER, C. E-H. MOUSSA, and P. VERNIER The Role of {alpha}-Synuclein in Both Neuroprotection and Neurodegeneration Ann. N.Y. Acad. Sci., December 1, 2004; 1035(1): 250 - 270. [Abstract] [Full Text] [PDF]

				A. L. Numis, E. L. Unger, D. L. Sheridan, A. C. Chisnell, and A. M. Andrews The Role of Membrane and Vesicular Monoamine Transporters in the Neurotoxic and Hypothermic Effects of 1-Methyl-4-(2'-aminophenyl)-1,2,3,6-tetrahydropyridine (2'-NH2-MPTP) Mol. Pharmacol., September 1, 2004; 66(3): 718 - 727. [Abstract] [Full Text] [PDF]

				A. SIDHU, C. WERSINGER, and P. VERNIER Does {alpha}-synuclein modulate dopaminergic synaptic content and tone at the synapse? FASEB J, April 1, 2004; 18(6): 637 - 647. [Abstract] [Full Text] [PDF]

				L. E. EIDEN The vesicular neurotransmitter transporters: current perspectives and future prospects FASEB J, December 1, 2000; 14(15): 2396 - 2400. [Full Text]

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