- Email: [email protected]
Dopamine Transporter Changes in Neuropsychiatric Disorders
DAT Changes in Neuropsychiatric Disorders
2 19
3. Marek, K. L., Seibly, J. P., Zoghbi, er ill. (1996). ['Z31]P-CIT SPECT imaging demonstrates bilateral loss of dopamine transporters in hemi-Parkinson's disease. Neurology 46,231-237. 4. Laruelle, M., Abi-Dargham, A,, van Dyck, C. H., er al. (1995).SPECT imaging of striatal dopamine release after amphetamine challenge in humans. J. Nucl. Med. 36, 1182-1190. 5. Laruelle, M., Abi-Dargham, A,, van Dyck, C., etal. (1996).SPECT imagingof amphetamineinduced dopamine release in drug free schizophrenic subjects. Proc. Natl. Acad. Sci. U.S.A. 93, 9235-9240.
D. F. Wong," G. Ricaurte," G. Grunder, R. Rothman,t S. Naidu,* H. Singer," J. Harris,* F. Yokoi," V. Villemagne," S. Szymanski," A. Gjedde,$ and M. Kuhad *Department of Radiology Johns Hopkins University Baltimore, Maryland 2 I287 +National Institute of Drug Abuse Baltimore, Maryland 2 I224 SAarhus University 8000 Aarhus, Denmark §Neuroscience Branch Emory University Atlanta, Georgia 30322
Dopamine Transporter Changes in Neuropsychiatric Disorders The dopamine transporter (DAT) protein is a member of Na+-dependent membrane transporters with very high affinity and substrate specificity. Reuptake of dopamine (DA) into the presynaptic neuron by means of DAT is believed to be the primary mechanism for termination of dopaminergic neurotransmission. Moreover, DAT is the key target for psychostimulants like amphetamine or cocaine as well as for neurotoxins like 1-methyl-4-phenylpyridine (MPP'). The highest concentrations of DATs are found in the basal ganglia, corresponding to the amount of DA nerve terminals in this brain region. Numerous studies demonstrating parallel losses of DA levels and DAT after lesions of nigrostriatal DA neurons suggest that the density of DAT is an excellent marker of the structural integrity of the dopaminergic system. In vivo imaging of DAT has been performed mainly in patients with Parkinson's disease to demonstrate the marked loss of nigrostriatal DA nerve terminals in this disorder. However, positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging of DAT have been shown to be useful in various other neurodegenerative disorders, including Advances in Pharmacology, Volume 42 Copyright 0 1998 by Academic Press. All rights of reproduction in any form reserved 1054-3589/98 $25.00
220
D. F. Wong et al.
Lesch-Nyhan disease (LND), Rett syndrome, Tourette's syndrome, stimulant abuse, and progressive supranuclear palsy. Using PET and ["CIWIN 35 428 as the radiotracer (l),we have recently reported a marked 50-63% reduction of tracer binding to DATs in the caudate and a 64-75% reduction in the putamen of six patients with classic LND compared with 10 normal controls (2).The almost total absence of hypoxanthineguanine phosphoribosyl transferase activity leads to hyperuricemia, choreoathetosis, dystonia, and compulsive self-injury, which characterize this devastating X-linked disease of infantile onset. A postmortem study of three LND patients and the results of animal studies had suggested the link between diminished DA function and self-injurious behavior in LND. The observed difference in the caudate-cerebellum ratio between the LND patients and the controls was even greater when we performed a partial volume correction of caudate time activity curves, which was necessary because volumetric magnetic resonance imaging studies had detected a 30% reduction in caudate volume in our patient sample. These results were confirmed soon thereafter in a PET study with ['8F]fluorodopa (3).The ratio of specific-to-nonspecificbinding of this tracer as an index of dopa decarboxylase activity was lowered in various brain regions of 12 patients with LND compared with normal controls. The ratio was diminished to between 31% in the putamen and 57% in the ventral tegmental area. Rett syndrome is a severe neurodevelopmental disease of females, characterized by microcephaly with cognitive retardation and autistic behavior, abnormalities of movement and muscle tone, and seizures. Postmortem studies suggest involvement of the basal forebrain cholinergic as well as nigrostriatal dopaminergic systems, with reduced melanin content and tyrosine hydroxylase activity in the substantia nigra. We have studied 12 patients with Rett syndrome with a single injection of [llC]WIN35 428 (2).When compared with age- (n = 11)or age/gender-matched (n = 5) healthy controls, we found a significant reduction in binding potential (k3/k4)of up to 45% both in the caudate and in the putamen of the patients. Interestingly, while we found low to low-normal values for the receptor density (Bmax) of postsynaptic D2-like DA receptors in the caudate in 12 patients with Rett syndrome measured with ["CINMSP, Chiron et al. (4)have reported markedly increased specific binding of [1231]iodolisuride, a SPECT tracer for the D2like DA receptor, in 11children with Rett syndrome. These authors concluded that the dopaminergic deficiency in Rett syndrome, which could be confirmed by our aforementioned findings in vivo, consecutively leads to an upregulation of postsynaptic receptors. The divergence of these findings is presently unexplained. Tourette's syndrome is a disorder that is usually characterized by complex cognitive and behavioral features such as obsessions and compulsions, impulsivity, coprolalia, self-injurious behavior, and involuntary motor and vocal tics. An increase in numbers of DATs has been reported in Tourette's syndrome from postmortem studies (5).This finding was corroborated by SPECT studies using the ligand ['231]P-CITin a small number of patients (6).In five neurolepticfree adult patients with Tourette's syndrome, striatal [1z31]/3-CITbinding was a mean of 37% higher than in the age- and gender-matched healthy controls. However, our PET studies with ["CIWIN 35 428 showed inconsistent results; although early findings pointed to increased numbers of DATs in patients with clinical Tourette's syndrome (7), this result is yet to be confirmed consistently in a larger patient sample. Moreover, imaging of presynaptic DA metabolism
D A T Changes in Neuropsychiatric Disorders
22 I
with ['*F]fluoro-dopa revealed no abnormality in presynaptic dopaminergic function in 10 patients with this disorder, compared with normal subjects (8). Because seven of these patients were treated with neuroleptic drugs, these results must be considered cautiously. Also, striatal [ "Clraclopride and ["CINMSP binding potentials, respectively, in PET studies (8, 9), as well as striatal uptake of [LZ31]IBZM in SPECT investigations ( l o ) , were reported to be normal in patients with Tourette's syndrome, compared with normal subjects. It is unclear why some studies suggest a defect in dopaminergic (especially presynaptic) function and some do not. One explanation could be that the patient population is biologically heterogeneous. It is now well established that the psychostimulant cocaine exhibits its psychotropic action via DAT. Volkow et al. (11)have recently shown that there is a direct relationship between the subjective effects of cocaine and DAT occupancy and that commonly abused cocaine doses block between 60-80Y0 of DATs. It may be possible to develop cocaine antagonists for the treatment of cocaine addiction, that will prevent cocaine binding without blocking DAT. Preliminary baboon studies with cocaine antagonists are being carried out by our group to measure DAT occupancy as a prelude to treatment trials in humans. Papio anubis baboons underwent two ["CIWIN 3.5 428 PET scans, one baseline (with saline) and a second with GBR 12909, either 1 mg/kg or 3 mg/kg, 90 min before the second tracer injection. When occupancy of the DAT was determined as percentage change in binding potential (k3/k4),we found a marked occupancy of DAT in the range of SO-70%. A marked reduction of striatal DAT densities has been reported in methamphetamine treated animals ( 12). In baboon studies with methamphetamine treatment, we could demonstrate a dose-related reduction in DAT densities. These studies were followed by postmortem analysis of neurochemical parameters. In recent years, the synthetic amphetamine analogue methcathinone ( 2 methylamino-1-phenylpropanone,ephedrone,"Cat") has emerged as a recreational drug of abuse. In animals, methcathinone, like methamphetamine, produces toxic effects on brain DA and serotonin neurons. Moreover, our studies in human subjects with a history of methcathinone abuse suggest a DAT decline as well (13). We employed ["CIWIN 35 428 imaging in five subjects who abused Cat. Preliminary analysis revealed a -26% and a - 17% decrement in caudate and putamen DAT, respectively, compared with age-matched controls. Of the three neurodevelopmental disorders studied, there seems to be a progression from markedly low to borderline elevated in LND, Rett syndrome, and Tourette's syndrome. These observations undoubtedly relate to degrees of involvement of the dopamine neuronal loss/transporter loss, and/or transporter upregulation in these young adults. This suggests that a dopaminergic involvement is justified in all of these disorders, and the rationale for the degree and direction has yet to be elucidated. These findings are illustrated for the putamen in Figure 1. Studies involving methcathinone and methamphetamine abuse confirmed the prior studies that significant DAT loss can occur in these drug abuse paradigms. Baboon studies with a neurochemical correlate will determine the doseresponse curve. The human studies with methcathinone document the dopaminergic damage in such substance abusers. The preliminary studies in baboons demonstrating DAT occupancy are an important means of screening drugs capable of blocking cocaine's actions at the DAT and will be an important target of cocaine treatment strategies in the
222
D. F. Wong et a/.
'"1 .
7.5
2 22
5
2.5
n LN
RETT
NOR
TS
FIGURE I
Mean 2 SEM DAT binding of ["CIWIN 35 428 for six LN, three RETT, 10 normals, and six Tourette subjects. DAT is significantly reduced for the LN compared with the other groups. LN, Lesch-Nyhan disease; RETT, Rett syndrome; NOR, normals; TS, Tourette's syndrome.
future. Thus, in analogy to receptor imaging studies that have been used to screen neuroleptics for antipsychotic action, it is likely that such imaging studies will be very useful in imaging DAT occupancy for such drug development. Acknowledgments Supported by NIH grants DA09482, HD24061, DA09487, MH42821, MD24448, Tourette Syndrome Assoc.
References 1. Wong, D. F., Yung B, Dannals, R. F., Shaya, E. K., Ravert, H. T., Chen, C. A., Chan, B., Folio, T., Scheffel, U., Ricaurte, G. A., Neumeyer, J. L., Wagner, H. N. Jr., and Kuhar, M. J. (1993). In uivo imaging of baboon and human dopamine transporters by positron emission tomography using ["CIWIN 35,428. Synapse 15, 130-142. 2. Wong, D. F., Harris, J.C., Naidu, S., Yokoi, F., Marenco, S., Dannals, R. F., Ravert, H. T., Yaster, M., Evans, A., Rousset, O., Bryan, R. N., Gjedde, A., Kuhar, M. J., and Breese, G. R. (1996).Dopamine transporters are markedly reduced in Lesch-Nyhan disease in vivo. Proc. Natl. Acad. Sci. U.S.A. 93, 5539-5543. 3 . Ernst, M., Zametkin, A. J., Matochik, J. A., Pascualvaca, D., Jons, P. H., Hardy, K., Hankerson, J. G., Doudet, D. J., and Cohen, R. M. (1996). Presynaptic dopaminergic deficits in Lesch-Nyhan disease. N. Engl. I. Med. 334, 1568-1572. 4. Chiron, C., Bulteau, C., Loc'h, C., Raynaud, C., Garreau, B., Syrota, A., and Maziere, B. (1993). Dopaminergic D2 receptor SPECT imaging in Ratt syndrome: increase of specific binding in striatum. I. Nucl. Med. 34, 1717-1721. 5. Singer, H. S., Hahn, I. H., and Moran, T. H. (1991). Abnormal dopamine uptake sites in postmortem striatum from patients with Tourette's syndrome. Ann. Neurol. 30,558-562.
Molecular. Biochemical Studies of Rat VMATI
223
6. Malison, R. T., McDougle, C. I., van Dyck, C. H., Scahill, L., Baldwin, R. M., Seibyl, J. P., Price, L. H., Leckman, J. F., and Innis, R. B. (1995).[123I]beta-CIT SPECT imaging of striatal doparnine transporter binding in Tourette's disorder. Am. J. Psycbiutry 152, 1359-1361. 7. Wong, D. F., Singer, H., Marenco, S., Brown, J., Yung, B., Yokoi, F., Chan, B., Matthews, W., Musachio, J., and Dannals, R. (1994).Dopamine transporter reuptake sites measured by ["CIWIN 35,428 PET imaging are elevated in Tourette syndrome. 1. Nucl. Med. 35, 130P. (Abstract). 8. Turjanski, N., Sawle, G. V., Playford, E. D., Weeks, R., Lammertsma, A. A., Lees, A. J., and Brooks, D. J. (1994).PET studies of the presynaptic and postsynaptic dopaminergic system in Tourette's syndrome. J . Neurol. Neurosurg. Psychiatry 57, 688-692. 9. Singer, H. S., Wong, D.F., Brown, J. E., Brandt, J., Krafft, L., Shaya, E., Dannals, R. F., and Wagner, H. N. Jr. (1992). Positron emission tomography evaluation of dopamine D2 receptors in adults with Tourette syndrome. Adv. NeuPol. 58, 233-239. 10. George, M. S., Robertson, M. M., Costa, D. C., Ell, P. J., Trimble, M. R., Pilowsky, L., Verhoeff, N. P. (1994). Dopamine receptor availability in Tourette's syndrome. Psychiatry Res. 55, 193-203. 11. Volkow, N. D., Wang, G. J., Fischman, M. W., Foltin, R. W., Fowler, J. S., Abumrad, N. N., Vitkun, S., Logan, J., Gatley, S. J., Pappas, N., Hitzemann, R., and Shea, C. E. (1997). Relationship between subjective effects of cocaine and dopamine transporter occupancy. Nature 386, 827-830. 12. Seiden, L. S., Ricaurte, G. A. Neurotoxicity of methamphetamine and related drugs. In Psychopharrnacology-A Generation of Progress. (Meltzer, H. Y., ed.), pp. 359-366. Raven Press, New York, NY. 13. Ricaurte, G., Wong, D. F., Szaho, Z . , Yokoi, F., Scheffel, U., Matthews, W., Ravert, M., Dannals R., and Naidu, S. (1996).Reductions in brain dopamine and serotonintransporters detected in humans previously exposed to repeated high doses of methcathinone using PET. Soc. Neurosci. 22, 1915 (Ahstract)
Shimon Schuldiner, Sonia Steiner-Mordoch, and Rodrigo Yelin Alexander Silberman Institute of Life Sciences Hebrew University Jerusalem, 9 I904 Israel
Molecular and Biochemical Studies of Rat Vesicular Monoamine Transporter Classical neurotransmitters are stored in synaptic vesicles and storage organelles of secretory cells. Transport of the monoamines serotonin, doparnine, norepinephrine, epinephrine, and histamine into storage organelles in a variety of cells is catalyzed by vesicular monoamine transporters (VMATs). Accumulation of the neurotransmitter depends o n the proton electrochemical gradient generated by the vesicular H+-adenosine triphosphatase and involves the Advances in Pharmacology, Volume 42 Copyright 0 1998 by Academic Press. All rights of reproduction in any form reserved 1054-3589198 $25.00
2 19
3. Marek, K. L., Seibly, J. P., Zoghbi, er ill. (1996). ['Z31]P-CIT SPECT imaging demonstrates bilateral loss of dopamine transporters in hemi-Parkinson's disease. Neurology 46,231-237. 4. Laruelle, M., Abi-Dargham, A,, van Dyck, C. H., er al. (1995).SPECT imaging of striatal dopamine release after amphetamine challenge in humans. J. Nucl. Med. 36, 1182-1190. 5. Laruelle, M., Abi-Dargham, A,, van Dyck, C., etal. (1996).SPECT imagingof amphetamineinduced dopamine release in drug free schizophrenic subjects. Proc. Natl. Acad. Sci. U.S.A. 93, 9235-9240.
D. F. Wong," G. Ricaurte," G. Grunder, R. Rothman,t S. Naidu,* H. Singer," J. Harris,* F. Yokoi," V. Villemagne," S. Szymanski," A. Gjedde,$ and M. Kuhad *Department of Radiology Johns Hopkins University Baltimore, Maryland 2 I287 +National Institute of Drug Abuse Baltimore, Maryland 2 I224 SAarhus University 8000 Aarhus, Denmark §Neuroscience Branch Emory University Atlanta, Georgia 30322
Dopamine Transporter Changes in Neuropsychiatric Disorders The dopamine transporter (DAT) protein is a member of Na+-dependent membrane transporters with very high affinity and substrate specificity. Reuptake of dopamine (DA) into the presynaptic neuron by means of DAT is believed to be the primary mechanism for termination of dopaminergic neurotransmission. Moreover, DAT is the key target for psychostimulants like amphetamine or cocaine as well as for neurotoxins like 1-methyl-4-phenylpyridine (MPP'). The highest concentrations of DATs are found in the basal ganglia, corresponding to the amount of DA nerve terminals in this brain region. Numerous studies demonstrating parallel losses of DA levels and DAT after lesions of nigrostriatal DA neurons suggest that the density of DAT is an excellent marker of the structural integrity of the dopaminergic system. In vivo imaging of DAT has been performed mainly in patients with Parkinson's disease to demonstrate the marked loss of nigrostriatal DA nerve terminals in this disorder. However, positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging of DAT have been shown to be useful in various other neurodegenerative disorders, including Advances in Pharmacology, Volume 42 Copyright 0 1998 by Academic Press. All rights of reproduction in any form reserved 1054-3589/98 $25.00
220
D. F. Wong et al.
Lesch-Nyhan disease (LND), Rett syndrome, Tourette's syndrome, stimulant abuse, and progressive supranuclear palsy. Using PET and ["CIWIN 35 428 as the radiotracer (l),we have recently reported a marked 50-63% reduction of tracer binding to DATs in the caudate and a 64-75% reduction in the putamen of six patients with classic LND compared with 10 normal controls (2).The almost total absence of hypoxanthineguanine phosphoribosyl transferase activity leads to hyperuricemia, choreoathetosis, dystonia, and compulsive self-injury, which characterize this devastating X-linked disease of infantile onset. A postmortem study of three LND patients and the results of animal studies had suggested the link between diminished DA function and self-injurious behavior in LND. The observed difference in the caudate-cerebellum ratio between the LND patients and the controls was even greater when we performed a partial volume correction of caudate time activity curves, which was necessary because volumetric magnetic resonance imaging studies had detected a 30% reduction in caudate volume in our patient sample. These results were confirmed soon thereafter in a PET study with ['8F]fluorodopa (3).The ratio of specific-to-nonspecificbinding of this tracer as an index of dopa decarboxylase activity was lowered in various brain regions of 12 patients with LND compared with normal controls. The ratio was diminished to between 31% in the putamen and 57% in the ventral tegmental area. Rett syndrome is a severe neurodevelopmental disease of females, characterized by microcephaly with cognitive retardation and autistic behavior, abnormalities of movement and muscle tone, and seizures. Postmortem studies suggest involvement of the basal forebrain cholinergic as well as nigrostriatal dopaminergic systems, with reduced melanin content and tyrosine hydroxylase activity in the substantia nigra. We have studied 12 patients with Rett syndrome with a single injection of [llC]WIN35 428 (2).When compared with age- (n = 11)or age/gender-matched (n = 5) healthy controls, we found a significant reduction in binding potential (k3/k4)of up to 45% both in the caudate and in the putamen of the patients. Interestingly, while we found low to low-normal values for the receptor density (Bmax) of postsynaptic D2-like DA receptors in the caudate in 12 patients with Rett syndrome measured with ["CINMSP, Chiron et al. (4)have reported markedly increased specific binding of [1231]iodolisuride, a SPECT tracer for the D2like DA receptor, in 11children with Rett syndrome. These authors concluded that the dopaminergic deficiency in Rett syndrome, which could be confirmed by our aforementioned findings in vivo, consecutively leads to an upregulation of postsynaptic receptors. The divergence of these findings is presently unexplained. Tourette's syndrome is a disorder that is usually characterized by complex cognitive and behavioral features such as obsessions and compulsions, impulsivity, coprolalia, self-injurious behavior, and involuntary motor and vocal tics. An increase in numbers of DATs has been reported in Tourette's syndrome from postmortem studies (5).This finding was corroborated by SPECT studies using the ligand ['231]P-CITin a small number of patients (6).In five neurolepticfree adult patients with Tourette's syndrome, striatal [1z31]/3-CITbinding was a mean of 37% higher than in the age- and gender-matched healthy controls. However, our PET studies with ["CIWIN 35 428 showed inconsistent results; although early findings pointed to increased numbers of DATs in patients with clinical Tourette's syndrome (7), this result is yet to be confirmed consistently in a larger patient sample. Moreover, imaging of presynaptic DA metabolism
D A T Changes in Neuropsychiatric Disorders
22 I
with ['*F]fluoro-dopa revealed no abnormality in presynaptic dopaminergic function in 10 patients with this disorder, compared with normal subjects (8). Because seven of these patients were treated with neuroleptic drugs, these results must be considered cautiously. Also, striatal [ "Clraclopride and ["CINMSP binding potentials, respectively, in PET studies (8, 9), as well as striatal uptake of [LZ31]IBZM in SPECT investigations ( l o ) , were reported to be normal in patients with Tourette's syndrome, compared with normal subjects. It is unclear why some studies suggest a defect in dopaminergic (especially presynaptic) function and some do not. One explanation could be that the patient population is biologically heterogeneous. It is now well established that the psychostimulant cocaine exhibits its psychotropic action via DAT. Volkow et al. (11)have recently shown that there is a direct relationship between the subjective effects of cocaine and DAT occupancy and that commonly abused cocaine doses block between 60-80Y0 of DATs. It may be possible to develop cocaine antagonists for the treatment of cocaine addiction, that will prevent cocaine binding without blocking DAT. Preliminary baboon studies with cocaine antagonists are being carried out by our group to measure DAT occupancy as a prelude to treatment trials in humans. Papio anubis baboons underwent two ["CIWIN 3.5 428 PET scans, one baseline (with saline) and a second with GBR 12909, either 1 mg/kg or 3 mg/kg, 90 min before the second tracer injection. When occupancy of the DAT was determined as percentage change in binding potential (k3/k4),we found a marked occupancy of DAT in the range of SO-70%. A marked reduction of striatal DAT densities has been reported in methamphetamine treated animals ( 12). In baboon studies with methamphetamine treatment, we could demonstrate a dose-related reduction in DAT densities. These studies were followed by postmortem analysis of neurochemical parameters. In recent years, the synthetic amphetamine analogue methcathinone ( 2 methylamino-1-phenylpropanone,ephedrone,"Cat") has emerged as a recreational drug of abuse. In animals, methcathinone, like methamphetamine, produces toxic effects on brain DA and serotonin neurons. Moreover, our studies in human subjects with a history of methcathinone abuse suggest a DAT decline as well (13). We employed ["CIWIN 35 428 imaging in five subjects who abused Cat. Preliminary analysis revealed a -26% and a - 17% decrement in caudate and putamen DAT, respectively, compared with age-matched controls. Of the three neurodevelopmental disorders studied, there seems to be a progression from markedly low to borderline elevated in LND, Rett syndrome, and Tourette's syndrome. These observations undoubtedly relate to degrees of involvement of the dopamine neuronal loss/transporter loss, and/or transporter upregulation in these young adults. This suggests that a dopaminergic involvement is justified in all of these disorders, and the rationale for the degree and direction has yet to be elucidated. These findings are illustrated for the putamen in Figure 1. Studies involving methcathinone and methamphetamine abuse confirmed the prior studies that significant DAT loss can occur in these drug abuse paradigms. Baboon studies with a neurochemical correlate will determine the doseresponse curve. The human studies with methcathinone document the dopaminergic damage in such substance abusers. The preliminary studies in baboons demonstrating DAT occupancy are an important means of screening drugs capable of blocking cocaine's actions at the DAT and will be an important target of cocaine treatment strategies in the
222
D. F. Wong et a/.
'"1 .
7.5
2 22
5
2.5
n LN
RETT
NOR
TS
FIGURE I
Mean 2 SEM DAT binding of ["CIWIN 35 428 for six LN, three RETT, 10 normals, and six Tourette subjects. DAT is significantly reduced for the LN compared with the other groups. LN, Lesch-Nyhan disease; RETT, Rett syndrome; NOR, normals; TS, Tourette's syndrome.
future. Thus, in analogy to receptor imaging studies that have been used to screen neuroleptics for antipsychotic action, it is likely that such imaging studies will be very useful in imaging DAT occupancy for such drug development. Acknowledgments Supported by NIH grants DA09482, HD24061, DA09487, MH42821, MD24448, Tourette Syndrome Assoc.
References 1. Wong, D. F., Yung B, Dannals, R. F., Shaya, E. K., Ravert, H. T., Chen, C. A., Chan, B., Folio, T., Scheffel, U., Ricaurte, G. A., Neumeyer, J. L., Wagner, H. N. Jr., and Kuhar, M. J. (1993). In uivo imaging of baboon and human dopamine transporters by positron emission tomography using ["CIWIN 35,428. Synapse 15, 130-142. 2. Wong, D. F., Harris, J.C., Naidu, S., Yokoi, F., Marenco, S., Dannals, R. F., Ravert, H. T., Yaster, M., Evans, A., Rousset, O., Bryan, R. N., Gjedde, A., Kuhar, M. J., and Breese, G. R. (1996).Dopamine transporters are markedly reduced in Lesch-Nyhan disease in vivo. Proc. Natl. Acad. Sci. U.S.A. 93, 5539-5543. 3 . Ernst, M., Zametkin, A. J., Matochik, J. A., Pascualvaca, D., Jons, P. H., Hardy, K., Hankerson, J. G., Doudet, D. J., and Cohen, R. M. (1996). Presynaptic dopaminergic deficits in Lesch-Nyhan disease. N. Engl. I. Med. 334, 1568-1572. 4. Chiron, C., Bulteau, C., Loc'h, C., Raynaud, C., Garreau, B., Syrota, A., and Maziere, B. (1993). Dopaminergic D2 receptor SPECT imaging in Ratt syndrome: increase of specific binding in striatum. I. Nucl. Med. 34, 1717-1721. 5. Singer, H. S., Hahn, I. H., and Moran, T. H. (1991). Abnormal dopamine uptake sites in postmortem striatum from patients with Tourette's syndrome. Ann. Neurol. 30,558-562.
Molecular. Biochemical Studies of Rat VMATI
223
6. Malison, R. T., McDougle, C. I., van Dyck, C. H., Scahill, L., Baldwin, R. M., Seibyl, J. P., Price, L. H., Leckman, J. F., and Innis, R. B. (1995).[123I]beta-CIT SPECT imaging of striatal doparnine transporter binding in Tourette's disorder. Am. J. Psycbiutry 152, 1359-1361. 7. Wong, D. F., Singer, H., Marenco, S., Brown, J., Yung, B., Yokoi, F., Chan, B., Matthews, W., Musachio, J., and Dannals, R. (1994).Dopamine transporter reuptake sites measured by ["CIWIN 35,428 PET imaging are elevated in Tourette syndrome. 1. Nucl. Med. 35, 130P. (Abstract). 8. Turjanski, N., Sawle, G. V., Playford, E. D., Weeks, R., Lammertsma, A. A., Lees, A. J., and Brooks, D. J. (1994).PET studies of the presynaptic and postsynaptic dopaminergic system in Tourette's syndrome. J . Neurol. Neurosurg. Psychiatry 57, 688-692. 9. Singer, H. S., Wong, D.F., Brown, J. E., Brandt, J., Krafft, L., Shaya, E., Dannals, R. F., and Wagner, H. N. Jr. (1992). Positron emission tomography evaluation of dopamine D2 receptors in adults with Tourette syndrome. Adv. NeuPol. 58, 233-239. 10. George, M. S., Robertson, M. M., Costa, D. C., Ell, P. J., Trimble, M. R., Pilowsky, L., Verhoeff, N. P. (1994). Dopamine receptor availability in Tourette's syndrome. Psychiatry Res. 55, 193-203. 11. Volkow, N. D., Wang, G. J., Fischman, M. W., Foltin, R. W., Fowler, J. S., Abumrad, N. N., Vitkun, S., Logan, J., Gatley, S. J., Pappas, N., Hitzemann, R., and Shea, C. E. (1997). Relationship between subjective effects of cocaine and dopamine transporter occupancy. Nature 386, 827-830. 12. Seiden, L. S., Ricaurte, G. A. Neurotoxicity of methamphetamine and related drugs. In Psychopharrnacology-A Generation of Progress. (Meltzer, H. Y., ed.), pp. 359-366. Raven Press, New York, NY. 13. Ricaurte, G., Wong, D. F., Szaho, Z . , Yokoi, F., Scheffel, U., Matthews, W., Ravert, M., Dannals R., and Naidu, S. (1996).Reductions in brain dopamine and serotonintransporters detected in humans previously exposed to repeated high doses of methcathinone using PET. Soc. Neurosci. 22, 1915 (Ahstract)
Shimon Schuldiner, Sonia Steiner-Mordoch, and Rodrigo Yelin Alexander Silberman Institute of Life Sciences Hebrew University Jerusalem, 9 I904 Israel
Molecular and Biochemical Studies of Rat Vesicular Monoamine Transporter Classical neurotransmitters are stored in synaptic vesicles and storage organelles of secretory cells. Transport of the monoamines serotonin, doparnine, norepinephrine, epinephrine, and histamine into storage organelles in a variety of cells is catalyzed by vesicular monoamine transporters (VMATs). Accumulation of the neurotransmitter depends o n the proton electrochemical gradient generated by the vesicular H+-adenosine triphosphatase and involves the Advances in Pharmacology, Volume 42 Copyright 0 1998 by Academic Press. All rights of reproduction in any form reserved 1054-3589198 $25.00