- Email: [email protected]
Methamphetamine administration causes overexpression of nNOS in the mouse striatum
Brain Research 851 Ž1999. 254–257 www.elsevier.comrlocaterbres
Short communication
Methamphetamine administration causes overexpression of nNOS in the mouse striatum Xiaolin Deng, Jean Lud Cadet
)
Molecular Neuropsychiatry Section, NIH r NIDA-IRP, Addiction Research Center, 5500 Nathan Shock DriÕe, Baltimore, MD 21224, USA Accepted 7 September 1999
Abstract The accumulated evidence suggests that the overproduction of nitric oxide ŽNO. is involved in methamphetamine ŽMETH.-induced neurotoxicity. Using NADPH-diaphorase histochemistry, neuronal nitric oxide synthase ŽnNOS. and inducible nitric oxide synthase ŽiNOS. antibody immunohistochemistry, the possible overexpression of nNOS and iNOS was investigated in the brains of mice treated with METH. The number of positive cells or the density of positive fibers was assessed at 1 h, 24 h and 1 week after METH injections. There were no clear positive iNOS cells and fibers demonstrated in the brains of mice after METH treatment. In contrast, METH caused marked increases in nNOS in the striatum and hippocampus at 1 and 24 h post-treatment. The nNOS expression normalized by 1 week. There were no statistical changes in nNOS expression in the frontal cortex, the cerebellar cortex, nor in the substantia nigra. These results provide further support for the idea that NO is involved in the neurotoxic effects of METH. q 1999 Published by Elsevier Science B.V. All rights reserved. Keywords: Methamphetamine; Neurotoxicity; Nitric oxide synthase
Methamphetamine ŽMETH. is a psychostimulant which is also a neurotoxicant w2,11,12x. For example, the administration of this drug causes significant depletion of dopamine ŽDA., serotonin Ž5-HT. and of their metabolites w12x. In the mice, METH-induced toxicity is mostly on striatal DA systems w3x. Several laboratories have been investigating the cellular and molecular mechanisms involved in the toxic effects of this drug. The accumulated evidence suggests that reactive oxygen species ŽROS. are involved in its neurotoxicity w2x. In addition to ROS, glutamate is thought to participate in the abnormalities caused by the drug w14x. Because glutamate has been shown to cause its toxic effects through increased production of nitric oxide ŽNO. w4x, a number of studies were carried out to assess if there was any relationship between METH-induced neurotoxicity and NO production. Both in vitro w13x and in vivo w1,5x studies have subsequently demonstrated that the use of NO synthase blockers can provide significant attenuation of the toxic effects of METH. Moreover, nNOS-deficient mice are also protected against METH-induced dopaminergic neurotoxicity w10x. We thus wanted to know
)
Corresponding author. [email protected]
Fax:
q 1-410-550-2745;
E-mail:
if METH could cause activation of either inducible NOS ŽiNOS. or of neuronal NOS ŽnNOS. in the brains of mice. Male CD-1 mice were used in these experiments. All mice were given four injections of 10 mgrkg of METH Žtotal dosage per animal was 40 mgrkg. or vehicle Žsaline. at 2 h intervals via the intraperitoneal route. All animal use procedures were according to the NIH Guide for the Care and Use of Laboratory Animals and were approved by the local Animal Care Committee. One hour, 24 h and 1 week following drug injections, the animals were anesthetized with pentobarbital, and perfused intracardially with saline followed by 40 ml of 4% paraformaldehyde in 0.1 M phosphate buffer ŽPB. at 48C. Subsequently, their brains were removed, post-fixed for 4 h in 4% paraformaldehyde, subsequently allowed to equilibrate in 30% sucrose for overnight. Thirty-micron coronal sections were cut in a cryostat. The sections were collected in PBS for subsequent procedures. Briefly, free-floating sections were rinsed with 0.1 M PB and then incubated in a solution containing 0.3% Triton X-100 ŽFisher Scientific, Fairlawn, NJ., 1 mgrml NADPH and 0.5 mgrml nitroblue tetrazolium Žboth from Sigma, St. Louis, MO. in 0.1 M PB at 378C for 50 min in the dark. After the reaction, the sections were mounted onto microscope slides, dehydrated and then coverslipped.
0006-8993r99r$ - see front matter q 1999 Published by Elsevier Science B.V. All rights reserved. PII: S 0 0 0 6 - 8 9 9 3 Ž 9 9 . 0 2 0 8 7 - 9
X. Deng, J.L. Cadetr Brain Research 851 (1999) 254–257
255
Fig. 1. Representative photomicrographs of NADPH-diaphorase-stained striatal sections. The animals were treated with saline ŽA., or with METH and then sacrificed at 1 h ŽB., 24 h ŽC. or 1 week ŽD. after drug administration. METH caused marked increases in the number of positive cells at the 1- and 24-h timepoints; these reverted back to normal after 1 week. Scale bar s 80 mm.
Fig. 2. Representative photomicrographs of NADPH-diaphorase-positive cells in hippocampal sections of saline-treated ŽA., or METH-treated mice sacrificed at 1 h ŽB., 24 h ŽC. or 1 week ŽD. after drug administration. There were obvious increases at the 1- and 24-h timepoints but not after 1 week. Scale bar s 100 mm.
256
X. Deng, J.L. Cadetr Brain Research 851 (1999) 254–257
Free-floating sections were also used for nNOS and iNOS immunostaining. Briefly, sections were exposed to 1% hydrogen peroxide for 20 min, then incubated for 30 min in 1% bovine serum albumin ŽBSA. –0.3% Triton X-100, followed by incubation with the primary antibody: nNOS ŽCalbiochem–Novabiochem, Polyclonal, 1:500. and iNOS ŽChemicon International, Polyclonal, 1:500.. The rest of the reaction was carried out according to the procedure described in the ABC kit ŽVector Laboratories.. The sections were reacted with 3,3X-diaminobenzidine ŽDAB. and hydrogen peroxide to visualize the peroxidase reaction, then mounted on microscope slides. For quantitative assessments, NADPH-diaphorase-positive cells were counted in the frontal cortex and the striatum. In addition, optical density ŽO.D.. of NADPH-diaphorase intense areas from the pyramidal layer of the hippocampus, the cerebellar cortex, and the substantia nigra was quantified by NIH image. The data were analyzed by ANOVA followed by Fisher’s protected least significant difference ŽPLSD. using Statview 4.02. Criteria for significance were set at the 0.05 level. Noticeable differences in NADPH-diaphorase staining were observed in the striatum and the pyramidal layer of hippocampus at 1 and 24 h after METH administration. In the striatum, there were marked increases in stained cells. The positive cells were easily identified to be of neuronal origin ŽFigs. 1 and 3.. In the hippocampus, increased reactivity was observed in the pyramidal layer ŽFig. 2.. O.D. values measured in pyramidal layers showed a significant increase at 1 and 24 h after METH administration ŽFig. 3.. There were no significant differences in the number of positive cells in the cerebral cortex, nor in the O.D. values measured in the cerebellar cortex and substantia nigra after METH treatment ŽFig. 3.. Results obtained from nNOS antibody immunohistochemistry were similar to those observed from NADPH-diaphorase histochemistry Ždata not shown.. In contrast, there were no observable METH-induced iNOS-positive cells or fibers in the brains of METH-treated mice Žnot shown.. The main finding from this investigation is that METH injections can cause increased expression of nNOS in the striatum and in hippocampal pyramidal neurons at 1 and 24 h post-drug-administration. These findings are consistent with recent observations documenting a role for NO in the neurotoxic effects of METH w1,5,13x. The present data provide further direct evidence that the drug can actually cause increases in the number of cells expressing nNOS in the striatum and in the hippocampus of the brains of mice. nNOS is known to participate in many normal and pathophysiologic events in the brain w4x. Although nNOS was, at first, reported to be mainly an enzyme that was expressed constitutively, several lines of evidence have led to the conclusion that this enzyme can be regulated during processes that lead to plasticity or cellular damage. These
Fig. 3. Quantitative assessment of the increases in NADPH-diaphorase positive staining in the five brain regions. The mice were treated and histochemical staining was carried out as described in the text. U P - 0.01 in comparison to results obtained from the same region of saline-treated mice.
events include increased nNOS upregulation during peripheral nerve regeneration w7x, after lipopolysaccharide injection w8x, or after methylmercury administration w9x. These observations support the view that nNOS can be dynamically controlled by toxic injuries to the nervous system. The manner by which METH might cause increases in nNOS activity may occur according to the following scenario. For example, METH administration has been reported to be associated with the production of ROS such as superoxide radicals and hydrogen peroxides in the striatum Žfor review, see Ref. w2x.. Hydrogen peroxide, because of its high permeability, might enter into corticostriatal glutamatergic terminals. This might lead to glutamate release which has been reported to occur during METH administration w15x. Stimulation of glutamate receptors located on post-synaptic striatal or hippocampal cells would cause calcium entry in these cells. Increased calcium into these cells could then lead to the increased nNOS activation. This scenario is consistent with the observation that nNOS
X. Deng, J.L. Cadetr Brain Research 851 (1999) 254–257
is co-localized with NMDA receptors in the striatum and hippocampus w16x. Nevertheless, the possibility that upregulation of the enzyme could occur through other mechanisms, such as transcriptional and translational events, needs also to be considered w6x. In summary, using histochemical and immunocytochemical techniques, we have demonstrated that METH can cause significant increases in the number of cells that express nNOS in the striatum and in the hippocampus of mice injected with the drug. No such increases were seen in iNOS expression. When taken together with the data obtained with NOS inhibitors w5,13x and NOS knock-out mice w10x, the present observations further argue for a very important role of NO produced by NOS-expressing neurons in the toxic effects of METH.
w6x w7x
w8x
w9x
w10x
w11x w12x
References w13x w1x S.F. Ali, Y. Itzhak, Effects of 7-nitroindazole, an NOS inhibitor on methamphetamine-induced dopaminergic and serotonergic neurotoxicity in mice, Ann. N.Y. Acad. Sci. 844 Ž1998. 122–130. w2x J.L. Cadet, C. Brannock, Free radicals and the pathobiology of brain dopamine systems, Neurochem. Int. 32 Ž1998. 117–131. w3x J.L. Cadet, P. Sheng, S.F. Ali, R. Rothman, E. Carlson, C. Epstein, Attenuation of methamphetamine-induced neurotoxicity in copperrzinc superoxide dismutase transgenic mice, J. Neurochem. 62 Ž1994. 380–383. w4x V.L. Dawson, T.M. Dawson, Nitric oxide neurotoxicity, J. Chem. Neuroanat. 10 Ž1996. 179–190. w5x D.A. Di Monte, J.E. Royland, M.W. Jakowec, J.W. Langston, Role of nitric oxide in methamphetamine neurotoxicity: protection by
w14x
w15x
w16x
257
7-nitroindazole, an inhibitor of neuronal nitric oxide synthase, J. Neurochem. 67 Ž1996. 2443–2450. D.A. Geller, T.R. Billiar, Molecular biology of nitric oxide synthases, Cancer Metastasis Rev. 17 Ž1998. 7–32. T. Gonzalez-Hernandez, A. Rustioni, Expression of three forms of nitric oxide in peripheral nerve regeneration, J. Neurosci. Res. 55 Ž1999. 198–207. S. Harada, T. Imaki, N. Chikada, M. Naruse, H. Demura, Distinct distribution and time-course changes in neuronal nitric oxide synthase and inducible NOS in the paraventricular nucleus following lipopolysaccharide injection, Brain Res. 821 Ž1999. 322–332. M. Ikeda, H. Komachi, I. Sato, T. Himi, T. Yuasa T, S. Murota, Induction of neuronal nitric oxide by methylmercury in the cerebellum, J. Neurosci. Res. 55 Ž1999. 352–356. Y. Itzhak, C. Gandia, P.L. Huang, S.F. Ali, Resistance of neuronal nitric oxide synthase-deficient mice to methamphetamine-induced dopaminergic neurotoxicity, J. Pharmacol. Exp. Ther. 284 Ž1998. 1040–1047. J.B. Murray, Psychophysiological aspects of amphetamine– methamphetamine abuse, J. Psychol. 132 Ž1998. 227–237. L.S. Seiden, K.E. Sabol, Methamphetamine and methylenedioxymethamphetamine neurotoxicity: possible mechanisms of cell destruction, NIDA Res. Monogr. 163 Ž1996. 251–276. P. Sheng, C. Cerruti, S.F. Ali, J.L. Cadet, Nitric oxide is a mediator of methamphetamine ŽMETH.-induced neurotoxicity. In vitro evidence from primary cultures of mesencephalic cells, Ann. N.Y. Acad. Sci. 801 Ž1996. 174–186. P.K. Sonsalla, D.S. Albers, G.D. Zeevalk, Role of glutamate in neurodegeneration of dopamine neurons in several animal models of Parkinsonism, Amino Acids 14 Ž1998. 69–74. S.E. Stephans, B.K. Yamamoto, Methamphetamine-induced neurotoxicity: roles for glutamate and dopamine efflux, Synapse 17 Ž1994. 203–209. S.W. Weiss, D.S. Albers, M.J. Iadarola, T.M. Dawson, V.L. Dawson, D.G. Standaert, NMDAR1 glutamate receptor subunit isoforms in neostriatal, neocortical, and hippocampal nitric oxide synthase neurons, J. Neurosci. 18 Ž1998. 1725–1734.
Short communication
Methamphetamine administration causes overexpression of nNOS in the mouse striatum Xiaolin Deng, Jean Lud Cadet
)
Molecular Neuropsychiatry Section, NIH r NIDA-IRP, Addiction Research Center, 5500 Nathan Shock DriÕe, Baltimore, MD 21224, USA Accepted 7 September 1999
Abstract The accumulated evidence suggests that the overproduction of nitric oxide ŽNO. is involved in methamphetamine ŽMETH.-induced neurotoxicity. Using NADPH-diaphorase histochemistry, neuronal nitric oxide synthase ŽnNOS. and inducible nitric oxide synthase ŽiNOS. antibody immunohistochemistry, the possible overexpression of nNOS and iNOS was investigated in the brains of mice treated with METH. The number of positive cells or the density of positive fibers was assessed at 1 h, 24 h and 1 week after METH injections. There were no clear positive iNOS cells and fibers demonstrated in the brains of mice after METH treatment. In contrast, METH caused marked increases in nNOS in the striatum and hippocampus at 1 and 24 h post-treatment. The nNOS expression normalized by 1 week. There were no statistical changes in nNOS expression in the frontal cortex, the cerebellar cortex, nor in the substantia nigra. These results provide further support for the idea that NO is involved in the neurotoxic effects of METH. q 1999 Published by Elsevier Science B.V. All rights reserved. Keywords: Methamphetamine; Neurotoxicity; Nitric oxide synthase
Methamphetamine ŽMETH. is a psychostimulant which is also a neurotoxicant w2,11,12x. For example, the administration of this drug causes significant depletion of dopamine ŽDA., serotonin Ž5-HT. and of their metabolites w12x. In the mice, METH-induced toxicity is mostly on striatal DA systems w3x. Several laboratories have been investigating the cellular and molecular mechanisms involved in the toxic effects of this drug. The accumulated evidence suggests that reactive oxygen species ŽROS. are involved in its neurotoxicity w2x. In addition to ROS, glutamate is thought to participate in the abnormalities caused by the drug w14x. Because glutamate has been shown to cause its toxic effects through increased production of nitric oxide ŽNO. w4x, a number of studies were carried out to assess if there was any relationship between METH-induced neurotoxicity and NO production. Both in vitro w13x and in vivo w1,5x studies have subsequently demonstrated that the use of NO synthase blockers can provide significant attenuation of the toxic effects of METH. Moreover, nNOS-deficient mice are also protected against METH-induced dopaminergic neurotoxicity w10x. We thus wanted to know
)
Corresponding author. [email protected]
Fax:
q 1-410-550-2745;
E-mail:
if METH could cause activation of either inducible NOS ŽiNOS. or of neuronal NOS ŽnNOS. in the brains of mice. Male CD-1 mice were used in these experiments. All mice were given four injections of 10 mgrkg of METH Žtotal dosage per animal was 40 mgrkg. or vehicle Žsaline. at 2 h intervals via the intraperitoneal route. All animal use procedures were according to the NIH Guide for the Care and Use of Laboratory Animals and were approved by the local Animal Care Committee. One hour, 24 h and 1 week following drug injections, the animals were anesthetized with pentobarbital, and perfused intracardially with saline followed by 40 ml of 4% paraformaldehyde in 0.1 M phosphate buffer ŽPB. at 48C. Subsequently, their brains were removed, post-fixed for 4 h in 4% paraformaldehyde, subsequently allowed to equilibrate in 30% sucrose for overnight. Thirty-micron coronal sections were cut in a cryostat. The sections were collected in PBS for subsequent procedures. Briefly, free-floating sections were rinsed with 0.1 M PB and then incubated in a solution containing 0.3% Triton X-100 ŽFisher Scientific, Fairlawn, NJ., 1 mgrml NADPH and 0.5 mgrml nitroblue tetrazolium Žboth from Sigma, St. Louis, MO. in 0.1 M PB at 378C for 50 min in the dark. After the reaction, the sections were mounted onto microscope slides, dehydrated and then coverslipped.
0006-8993r99r$ - see front matter q 1999 Published by Elsevier Science B.V. All rights reserved. PII: S 0 0 0 6 - 8 9 9 3 Ž 9 9 . 0 2 0 8 7 - 9
X. Deng, J.L. Cadetr Brain Research 851 (1999) 254–257
255
Fig. 1. Representative photomicrographs of NADPH-diaphorase-stained striatal sections. The animals were treated with saline ŽA., or with METH and then sacrificed at 1 h ŽB., 24 h ŽC. or 1 week ŽD. after drug administration. METH caused marked increases in the number of positive cells at the 1- and 24-h timepoints; these reverted back to normal after 1 week. Scale bar s 80 mm.
Fig. 2. Representative photomicrographs of NADPH-diaphorase-positive cells in hippocampal sections of saline-treated ŽA., or METH-treated mice sacrificed at 1 h ŽB., 24 h ŽC. or 1 week ŽD. after drug administration. There were obvious increases at the 1- and 24-h timepoints but not after 1 week. Scale bar s 100 mm.
256
X. Deng, J.L. Cadetr Brain Research 851 (1999) 254–257
Free-floating sections were also used for nNOS and iNOS immunostaining. Briefly, sections were exposed to 1% hydrogen peroxide for 20 min, then incubated for 30 min in 1% bovine serum albumin ŽBSA. –0.3% Triton X-100, followed by incubation with the primary antibody: nNOS ŽCalbiochem–Novabiochem, Polyclonal, 1:500. and iNOS ŽChemicon International, Polyclonal, 1:500.. The rest of the reaction was carried out according to the procedure described in the ABC kit ŽVector Laboratories.. The sections were reacted with 3,3X-diaminobenzidine ŽDAB. and hydrogen peroxide to visualize the peroxidase reaction, then mounted on microscope slides. For quantitative assessments, NADPH-diaphorase-positive cells were counted in the frontal cortex and the striatum. In addition, optical density ŽO.D.. of NADPH-diaphorase intense areas from the pyramidal layer of the hippocampus, the cerebellar cortex, and the substantia nigra was quantified by NIH image. The data were analyzed by ANOVA followed by Fisher’s protected least significant difference ŽPLSD. using Statview 4.02. Criteria for significance were set at the 0.05 level. Noticeable differences in NADPH-diaphorase staining were observed in the striatum and the pyramidal layer of hippocampus at 1 and 24 h after METH administration. In the striatum, there were marked increases in stained cells. The positive cells were easily identified to be of neuronal origin ŽFigs. 1 and 3.. In the hippocampus, increased reactivity was observed in the pyramidal layer ŽFig. 2.. O.D. values measured in pyramidal layers showed a significant increase at 1 and 24 h after METH administration ŽFig. 3.. There were no significant differences in the number of positive cells in the cerebral cortex, nor in the O.D. values measured in the cerebellar cortex and substantia nigra after METH treatment ŽFig. 3.. Results obtained from nNOS antibody immunohistochemistry were similar to those observed from NADPH-diaphorase histochemistry Ždata not shown.. In contrast, there were no observable METH-induced iNOS-positive cells or fibers in the brains of METH-treated mice Žnot shown.. The main finding from this investigation is that METH injections can cause increased expression of nNOS in the striatum and in hippocampal pyramidal neurons at 1 and 24 h post-drug-administration. These findings are consistent with recent observations documenting a role for NO in the neurotoxic effects of METH w1,5,13x. The present data provide further direct evidence that the drug can actually cause increases in the number of cells expressing nNOS in the striatum and in the hippocampus of the brains of mice. nNOS is known to participate in many normal and pathophysiologic events in the brain w4x. Although nNOS was, at first, reported to be mainly an enzyme that was expressed constitutively, several lines of evidence have led to the conclusion that this enzyme can be regulated during processes that lead to plasticity or cellular damage. These
Fig. 3. Quantitative assessment of the increases in NADPH-diaphorase positive staining in the five brain regions. The mice were treated and histochemical staining was carried out as described in the text. U P - 0.01 in comparison to results obtained from the same region of saline-treated mice.
events include increased nNOS upregulation during peripheral nerve regeneration w7x, after lipopolysaccharide injection w8x, or after methylmercury administration w9x. These observations support the view that nNOS can be dynamically controlled by toxic injuries to the nervous system. The manner by which METH might cause increases in nNOS activity may occur according to the following scenario. For example, METH administration has been reported to be associated with the production of ROS such as superoxide radicals and hydrogen peroxides in the striatum Žfor review, see Ref. w2x.. Hydrogen peroxide, because of its high permeability, might enter into corticostriatal glutamatergic terminals. This might lead to glutamate release which has been reported to occur during METH administration w15x. Stimulation of glutamate receptors located on post-synaptic striatal or hippocampal cells would cause calcium entry in these cells. Increased calcium into these cells could then lead to the increased nNOS activation. This scenario is consistent with the observation that nNOS
X. Deng, J.L. Cadetr Brain Research 851 (1999) 254–257
is co-localized with NMDA receptors in the striatum and hippocampus w16x. Nevertheless, the possibility that upregulation of the enzyme could occur through other mechanisms, such as transcriptional and translational events, needs also to be considered w6x. In summary, using histochemical and immunocytochemical techniques, we have demonstrated that METH can cause significant increases in the number of cells that express nNOS in the striatum and in the hippocampus of mice injected with the drug. No such increases were seen in iNOS expression. When taken together with the data obtained with NOS inhibitors w5,13x and NOS knock-out mice w10x, the present observations further argue for a very important role of NO produced by NOS-expressing neurons in the toxic effects of METH.
w6x w7x
w8x
w9x
w10x
w11x w12x
References w13x w1x S.F. Ali, Y. Itzhak, Effects of 7-nitroindazole, an NOS inhibitor on methamphetamine-induced dopaminergic and serotonergic neurotoxicity in mice, Ann. N.Y. Acad. Sci. 844 Ž1998. 122–130. w2x J.L. Cadet, C. Brannock, Free radicals and the pathobiology of brain dopamine systems, Neurochem. Int. 32 Ž1998. 117–131. w3x J.L. Cadet, P. Sheng, S.F. Ali, R. Rothman, E. Carlson, C. Epstein, Attenuation of methamphetamine-induced neurotoxicity in copperrzinc superoxide dismutase transgenic mice, J. Neurochem. 62 Ž1994. 380–383. w4x V.L. Dawson, T.M. Dawson, Nitric oxide neurotoxicity, J. Chem. Neuroanat. 10 Ž1996. 179–190. w5x D.A. Di Monte, J.E. Royland, M.W. Jakowec, J.W. Langston, Role of nitric oxide in methamphetamine neurotoxicity: protection by
w14x
w15x
w16x
257
7-nitroindazole, an inhibitor of neuronal nitric oxide synthase, J. Neurochem. 67 Ž1996. 2443–2450. D.A. Geller, T.R. Billiar, Molecular biology of nitric oxide synthases, Cancer Metastasis Rev. 17 Ž1998. 7–32. T. Gonzalez-Hernandez, A. Rustioni, Expression of three forms of nitric oxide in peripheral nerve regeneration, J. Neurosci. Res. 55 Ž1999. 198–207. S. Harada, T. Imaki, N. Chikada, M. Naruse, H. Demura, Distinct distribution and time-course changes in neuronal nitric oxide synthase and inducible NOS in the paraventricular nucleus following lipopolysaccharide injection, Brain Res. 821 Ž1999. 322–332. M. Ikeda, H. Komachi, I. Sato, T. Himi, T. Yuasa T, S. Murota, Induction of neuronal nitric oxide by methylmercury in the cerebellum, J. Neurosci. Res. 55 Ž1999. 352–356. Y. Itzhak, C. Gandia, P.L. Huang, S.F. Ali, Resistance of neuronal nitric oxide synthase-deficient mice to methamphetamine-induced dopaminergic neurotoxicity, J. Pharmacol. Exp. Ther. 284 Ž1998. 1040–1047. J.B. Murray, Psychophysiological aspects of amphetamine– methamphetamine abuse, J. Psychol. 132 Ž1998. 227–237. L.S. Seiden, K.E. Sabol, Methamphetamine and methylenedioxymethamphetamine neurotoxicity: possible mechanisms of cell destruction, NIDA Res. Monogr. 163 Ž1996. 251–276. P. Sheng, C. Cerruti, S.F. Ali, J.L. Cadet, Nitric oxide is a mediator of methamphetamine ŽMETH.-induced neurotoxicity. In vitro evidence from primary cultures of mesencephalic cells, Ann. N.Y. Acad. Sci. 801 Ž1996. 174–186. P.K. Sonsalla, D.S. Albers, G.D. Zeevalk, Role of glutamate in neurodegeneration of dopamine neurons in several animal models of Parkinsonism, Amino Acids 14 Ž1998. 69–74. S.E. Stephans, B.K. Yamamoto, Methamphetamine-induced neurotoxicity: roles for glutamate and dopamine efflux, Synapse 17 Ž1994. 203–209. S.W. Weiss, D.S. Albers, M.J. Iadarola, T.M. Dawson, V.L. Dawson, D.G. Standaert, NMDAR1 glutamate receptor subunit isoforms in neostriatal, neocortical, and hippocampal nitric oxide synthase neurons, J. Neurosci. 18 Ž1998. 1725–1734.