Position
Chief,
Molecular Neuropsychiatry Branch
Chief,
Molecular Neuropsychiatry Section
Associate,
Contact
Biomedical Research Center251 Bayview Boulevard
Suite 200
Room 07A721A
Baltimore, MD 21224
Phone: 667-312-5049
Email: jcadet@intra.nida.nih.gov
Education
Residency - Department of Psychiatry at Columbia University College of Physicians and Surgeons
Residency - Department of Neurology at Mount Sinai Medical Center in NYC
M.D. - Columbia University College of Physicians and Surgeons
Research Interests
Research in our section focuses on studies the molecular and cellular mechanisms of psychostimulant addiction and toxicity. Dr. Cadet’s group has provided recent evidence that methamphetamine (METH) self-administration is accompanied with markers of toxicity in striatal dopaminergic systems. These results are consistent with the idea that catecholamines, especially, dopamine can activate neurodegenerative processes in the mammalian brain. We have also shown recently that METH preconditioning protects against METH toxicity. This occurs by upregulation of neurotrophic factors such as BDNF and/or downregulation of glutamatergic systems. Preliminary studies have shown that these changes are secondary to epigenetic modifications that include histone hypoacetylation and DNA methylation. The laboratory is thus pursuing investigations to further identify epigenetic markers that are involved in METH self-administration and METH preconditioning.
Publications
Selected Publications
2016
Torres, Oscar V; Ladenheim, Bruce; Jayanthi, Subramaniam; McCoy, Michael T; Krasnova, Irina N; Vautier, Francois A; Cadet, Jean Lud
In: Neurotox Res, vol. 30, no. 1, pp. 32–40, 2016, ISSN: 1476-3524 (Electronic); 1029-8428 (Linking).
@article{Torres2016,
title = {An Acute Methamphetamine Injection Downregulates the Expression of Several Histone Deacetylases (HDACs) in the Mouse Nucleus Accumbens: Potential Regulatory Role of HDAC2 Expression.},
author = { Oscar V Torres and Bruce Ladenheim and Subramaniam Jayanthi and Michael T McCoy and Irina N Krasnova and Francois A Vautier and Jean Lud Cadet},
url = {https://www.ncbi.nlm.nih.gov/pubmed/26721795},
doi = {10.1007/s12640-015-9591-3},
issn = {1476-3524 (Electronic); 1029-8428 (Linking)},
year = {2016},
date = {2016-07-01},
journal = {Neurotox Res},
volume = {30},
number = {1},
pages = {32--40},
address = {Molecular Neuropsychiatry Research Branch, DHHS/NIH/NIDA Intramural Research Program, National Institutes of Health, 251 Bayview Boulevard, Baltimore, MD, 21224, USA.},
abstract = {Methamphetamine (METH) administration alters gene expression in the nucleus accumbens (NAc). We recently demonstrated that an acute METH injection produced prolonged increases in the expression of immediate early genes in the NAc of HDAC2-deficient mice, suggesting that HDAC2 might be an important regulator of gene expression in the rodent brain. Here, we tested the possibility that HDAC2 deletion might also impact METH-induced changes in the expression of various HDAC classes in the NAc. Wild-type (WT) and HDAC2 knockout (KO) mice were given a METH (20 mg/kg) injection, and NAc tissue was collected at 1, 2, and 8 h post treatment. We found that METH decreased HDAC3, HDAC4, HDAC7, HDAC8, and HDAC11 mRNA expression but increased HDAC6 mRNA levels in the NAc of WT mice. In contrast, the METH injection increased HDAC3, HDAC4, HDAC7, HDAC8, and HDAC11 mRNA levels in HDAC2KO mice. These observations suggest that METH may induce large-scale transcriptional changes in the NAc by regulating the expression of several HDACs, in part, via HDAC2-dependent mechanisms since some of the HDACs showed differential responses between the two genotypes. Our findings further implicate HDACs as potential novel therapeutic targets for neurotoxic complications associated with the abuse of certain psychostimulants.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Methamphetamine (METH) administration alters gene expression in the nucleus accumbens (NAc). We recently demonstrated that an acute METH injection produced prolonged increases in the expression of immediate early genes in the NAc of HDAC2-deficient mice, suggesting that HDAC2 might be an important regulator of gene expression in the rodent brain. Here, we tested the possibility that HDAC2 deletion might also impact METH-induced changes in the expression of various HDAC classes in the NAc. Wild-type (WT) and HDAC2 knockout (KO) mice were given a METH (20 mg/kg) injection, and NAc tissue was collected at 1, 2, and 8 h post treatment. We found that METH decreased HDAC3, HDAC4, HDAC7, HDAC8, and HDAC11 mRNA expression but increased HDAC6 mRNA levels in the NAc of WT mice. In contrast, the METH injection increased HDAC3, HDAC4, HDAC7, HDAC8, and HDAC11 mRNA levels in HDAC2KO mice. These observations suggest that METH may induce large-scale transcriptional changes in the NAc by regulating the expression of several HDACs, in part, via HDAC2-dependent mechanisms since some of the HDACs showed differential responses between the two genotypes. Our findings further implicate HDACs as potential novel therapeutic targets for neurotoxic complications associated with the abuse of certain psychostimulants.
2011
Beauvais, Genevieve; Atwell, Kenisha; Jayanthi, Subramaniam; Ladenheim, Bruce; Cadet, Jean Lud
Involvement of dopamine receptors in binge methamphetamine-induced activation of endoplasmic reticulum and mitochondrial stress pathways. Journal Article
In: PLoS One, vol. 6, no. 12, pp. e28946, 2011, ISSN: 1932-6203 (Electronic); 1932-6203 (Linking).
@article{Beauvais2011,
title = {Involvement of dopamine receptors in binge methamphetamine-induced activation of endoplasmic reticulum and mitochondrial stress pathways.},
author = { Genevieve Beauvais and Kenisha Atwell and Subramaniam Jayanthi and Bruce Ladenheim and Jean Lud Cadet},
url = {https://www.ncbi.nlm.nih.gov/pubmed/22174933},
doi = {10.1371/journal.pone.0028946},
issn = {1932-6203 (Electronic); 1932-6203 (Linking)},
year = {2011},
date = {2011-12-13},
journal = {PLoS One},
volume = {6},
number = {12},
pages = {e28946},
address = {Molecular Neuropsychiatry Research Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, Maryland, United States of America.},
abstract = {Single large doses of methamphetamine (METH) cause endoplasmic reticulum (ER) stress and mitochondrial dysfunctions in rodent striata. The dopamine D(1) receptor appears to be involved in these METH-mediated stresses. The purpose of this study was to investigate if dopamine D(1) and D(2) receptors are involved in ER and mitochondrial stresses caused by single-day METH binges in the rat striatum. Male Sprague-Dawley rats received 4 injections of 10 mg/kg of METH alone or in combination with a putative D(1) or D(2) receptor antagonist, SCH23390 or raclopride, respectively, given 30 min prior to each METH injection. Rats were euthanized at various timepoints afterwards. Striatal tissues were used in quantitative RT-PCR and western blot analyses. We found that binge METH injections caused increased expression of the pro-survival genes, BiP/GRP-78 and P58(IPK), in a SCH23390-sensitive manner. METH also caused up-regulation of ER-stress genes, Atf2, Atf3, Atf4, CHOP/Gadd153 and Gadd34. The expression of heat shock proteins (HSPs) was increased after METH injections. SCH23390 completely blocked induction in all analyzed ER stress-related proteins that included ATF3, ATF4, CHOP/Gadd153, HSPs and caspase-12. The dopamine D(2)-like antagonist, raclopride, exerted small to moderate inhibitory influence on some METH-induced changes in ER stress proteins. Importantly, METH caused decreases in the mitochondrial anti-apoptotic protein, Bcl-2, but increases in the pro-apoptotic proteins, Bax, Bad and cytochrome c, in a SCH23390-sensitive fashion. In contrast, raclopride provided only small inhibition of METH-induced changes in mitochondrial proteins. These findings indicate that METH-induced activation of striatal ER and mitochondrial stress pathways might be more related to activation of SCH23390-sensitive receptors.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Single large doses of methamphetamine (METH) cause endoplasmic reticulum (ER) stress and mitochondrial dysfunctions in rodent striata. The dopamine D(1) receptor appears to be involved in these METH-mediated stresses. The purpose of this study was to investigate if dopamine D(1) and D(2) receptors are involved in ER and mitochondrial stresses caused by single-day METH binges in the rat striatum. Male Sprague-Dawley rats received 4 injections of 10 mg/kg of METH alone or in combination with a putative D(1) or D(2) receptor antagonist, SCH23390 or raclopride, respectively, given 30 min prior to each METH injection. Rats were euthanized at various timepoints afterwards. Striatal tissues were used in quantitative RT-PCR and western blot analyses. We found that binge METH injections caused increased expression of the pro-survival genes, BiP/GRP-78 and P58(IPK), in a SCH23390-sensitive manner. METH also caused up-regulation of ER-stress genes, Atf2, Atf3, Atf4, CHOP/Gadd153 and Gadd34. The expression of heat shock proteins (HSPs) was increased after METH injections. SCH23390 completely blocked induction in all analyzed ER stress-related proteins that included ATF3, ATF4, CHOP/Gadd153, HSPs and caspase-12. The dopamine D(2)-like antagonist, raclopride, exerted small to moderate inhibitory influence on some METH-induced changes in ER stress proteins. Importantly, METH caused decreases in the mitochondrial anti-apoptotic protein, Bcl-2, but increases in the pro-apoptotic proteins, Bax, Bad and cytochrome c, in a SCH23390-sensitive fashion. In contrast, raclopride provided only small inhibition of METH-induced changes in mitochondrial proteins. These findings indicate that METH-induced activation of striatal ER and mitochondrial stress pathways might be more related to activation of SCH23390-sensitive receptors.
Krasnova, Irina N; Ladenheim, Bruce; Hodges, Amber B; Volkow, Nora D; Cadet, Jean Lud
Chronic methamphetamine administration causes differential regulation of transcription factors in the rat midbrain. Journal Article
In: PLoS One, vol. 6, no. 4, pp. e19179, 2011, ISSN: 1932-6203 (Electronic); 1932-6203 (Linking).
@article{Krasnova2011,
title = {Chronic methamphetamine administration causes differential regulation of transcription factors in the rat midbrain.},
author = { Irina N Krasnova and Bruce Ladenheim and Amber B Hodges and Nora D Volkow and Jean Lud Cadet},
url = {https://www.ncbi.nlm.nih.gov/pubmed/21547080},
doi = {10.1371/journal.pone.0019179},
issn = {1932-6203 (Electronic); 1932-6203 (Linking)},
year = {2011},
date = {2011-04-25},
journal = {PLoS One},
volume = {6},
number = {4},
pages = {e19179},
address = {Molecular Neuropsychiatry Research Branch, DHHS/NIH/NIDA Intramural Research Program, Bethesda, Maryland, United States of America.},
abstract = {Methamphetamine (METH) is an addictive and neurotoxic psychostimulant widely abused in the USA and throughout the world. When administered in large doses, METH can cause depletion of striatal dopamine terminals, with preservation of midbrain dopaminergic neurons. Because alterations in the expression of transcription factors that regulate the development of dopaminergic neurons might be involved in protecting these neurons after toxic insults, we tested the possibility that their expression might be affected by toxic doses of METH in the adult brain. Male Sprague-Dawley rats pretreated with saline or increasing doses of METH were challenged with toxic doses of the drug and euthanized two weeks later. Animals that received toxic METH challenges showed decreases in dopamine levels and reductions in tyrosine hydroxylase protein concentration in the striatum. METH pretreatment protected against loss of striatal dopamine and tyrosine hydroxylase. In contrast, METH challenges caused decreases in dopamine transporters in both saline- and METH-pretreated animals. Interestingly, METH challenges elicited increases in dopamine transporter mRNA levels in the midbrain in the presence but not in the absence of METH pretreatment. Moreover, toxic METH doses caused decreases in the expression of the dopamine developmental factors, Shh, Lmx1b, and Nurr1, but not in the levels of Otx2 and Pitx3, in saline-pretreated rats. METH pretreatment followed by METH challenges also decreased Nurr1 but increased Otx2 and Pitx3 expression in the midbrain. These findings suggest that, in adult animals, toxic doses of METH can differentially influence the expression of transcription factors involved in the developmental regulation of dopamine neurons. The combined increases in Otx2 and Pitx3 expression after METH preconditioning might represent, in part, some of the mechanisms that served to protect against METH-induced striatal dopamine depletion observed after METH preconditioning.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Methamphetamine (METH) is an addictive and neurotoxic psychostimulant widely abused in the USA and throughout the world. When administered in large doses, METH can cause depletion of striatal dopamine terminals, with preservation of midbrain dopaminergic neurons. Because alterations in the expression of transcription factors that regulate the development of dopaminergic neurons might be involved in protecting these neurons after toxic insults, we tested the possibility that their expression might be affected by toxic doses of METH in the adult brain. Male Sprague-Dawley rats pretreated with saline or increasing doses of METH were challenged with toxic doses of the drug and euthanized two weeks later. Animals that received toxic METH challenges showed decreases in dopamine levels and reductions in tyrosine hydroxylase protein concentration in the striatum. METH pretreatment protected against loss of striatal dopamine and tyrosine hydroxylase. In contrast, METH challenges caused decreases in dopamine transporters in both saline- and METH-pretreated animals. Interestingly, METH challenges elicited increases in dopamine transporter mRNA levels in the midbrain in the presence but not in the absence of METH pretreatment. Moreover, toxic METH doses caused decreases in the expression of the dopamine developmental factors, Shh, Lmx1b, and Nurr1, but not in the levels of Otx2 and Pitx3, in saline-pretreated rats. METH pretreatment followed by METH challenges also decreased Nurr1 but increased Otx2 and Pitx3 expression in the midbrain. These findings suggest that, in adult animals, toxic doses of METH can differentially influence the expression of transcription factors involved in the developmental regulation of dopamine neurons. The combined increases in Otx2 and Pitx3 expression after METH preconditioning might represent, in part, some of the mechanisms that served to protect against METH-induced striatal dopamine depletion observed after METH preconditioning.
2010
Cadet, Jean Lud; Jayanthi, Subramaniam; McCoy, Michael T; Beauvais, Genevieve; Cai, Ning Sheng
Dopamine D1 receptors, regulation of gene expression in the brain, and neurodegeneration. Journal Article
In: CNS Neurol Disord Drug Targets, vol. 9, no. 5, pp. 526–538, 2010, ISSN: 1996-3181 (Electronic); 1871-5273 (Linking).
@article{Cadet2010,
title = {Dopamine D1 receptors, regulation of gene expression in the brain, and neurodegeneration.},
author = { Jean Lud Cadet and Subramaniam Jayanthi and Michael T McCoy and Genevieve Beauvais and Ning Sheng Cai},
url = {https://www.ncbi.nlm.nih.gov/pubmed/20632973#},
issn = {1996-3181 (Electronic); 1871-5273 (Linking)},
year = {2010},
date = {2010-11-01},
journal = {CNS Neurol Disord Drug Targets},
volume = {9},
number = {5},
pages = {526--538},
address = {Molecular Neuropsychiatry Research Branch, DHHS/NIH/NIDA Intramural Research Program, Baltimore, MD 21224, USA. jcadet@intra.nida.nih.gov},
abstract = {Dopamine (DA), the most abundant catecholamine in the basal ganglia, participates in the regulation of motor functions and of cognitive processes such as learning and memory. Abnormalities in dopaminergic systems are thought to be the bases for some neuropsychiatric disorders including addiction, Parkinson's disease, and Schizophrenia. DA exerts its arrays of functions via stimulation of D1-like (D1 and D5) and D2-like (D2, D3, and D4) DA receptors which are located in various regions of the brain. The DA D1 and D2 receptors are very abundant in the basal ganglia where they exert their functions within separate neuronal cell types. The present paper focuses on a review of the effects of stimulation of DA D1 receptors on diverse signal transduction pathways and gene expression patterns in the brain. We also discuss the possible involvement of the DA D1 receptors in DA-mediated toxic effects observed both in vitro and in vivo. Future studies using more selective agonist and antagonist agents and the use of genetically modified animals should help to further clarify the role of these receptors in the normal physiology and in pathological events that involve DA.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Dopamine (DA), the most abundant catecholamine in the basal ganglia, participates in the regulation of motor functions and of cognitive processes such as learning and memory. Abnormalities in dopaminergic systems are thought to be the bases for some neuropsychiatric disorders including addiction, Parkinson's disease, and Schizophrenia. DA exerts its arrays of functions via stimulation of D1-like (D1 and D5) and D2-like (D2, D3, and D4) DA receptors which are located in various regions of the brain. The DA D1 and D2 receptors are very abundant in the basal ganglia where they exert their functions within separate neuronal cell types. The present paper focuses on a review of the effects of stimulation of DA D1 receptors on diverse signal transduction pathways and gene expression patterns in the brain. We also discuss the possible involvement of the DA D1 receptors in DA-mediated toxic effects observed both in vitro and in vivo. Future studies using more selective agonist and antagonist agents and the use of genetically modified animals should help to further clarify the role of these receptors in the normal physiology and in pathological events that involve DA.
Krasnova, Irina N; Justinova, Zuzana; Ladenheim, Bruce; Jayanthi, Subramaniam; McCoy, Michael T; Barnes, Chanel; Warner, John E; Goldberg, Steven R; Cadet, Jean Lud
In: PLoS One, vol. 5, no. 1, pp. e8790, 2010, ISSN: 1932-6203 (Electronic); 1932-6203 (Linking).
@article{Krasnova2010,
title = {Methamphetamine self-administration is associated with persistent biochemical alterations in striatal and cortical dopaminergic terminals in the rat.},
author = { Irina N Krasnova and Zuzana Justinova and Bruce Ladenheim and Subramaniam Jayanthi and Michael T McCoy and Chanel Barnes and John E Warner and Steven R Goldberg and Jean Lud Cadet},
url = {https://www.ncbi.nlm.nih.gov/pubmed/20098750},
doi = {10.1371/journal.pone.0008790},
issn = {1932-6203 (Electronic); 1932-6203 (Linking)},
year = {2010},
date = {2010-01-20},
journal = {PLoS One},
volume = {5},
number = {1},
pages = {e8790},
address = {National Institute on Drug Abuse, National Institutes of Health, Baltimore, Maryland, United States of America.},
abstract = {Methamphetamine (meth) is an illicit psychostimulant that is abused throughout the world. Repeated passive injections of the drug given in a single day or over a few days cause significant and long-term depletion of dopamine and serotonin in the mammalian brain. Because meth self-administration may better mimic some aspects of human drug-taking behaviors, we examined to what extent this pattern of drug treatment might also result in damage to monoaminergic systems in the brain. Rats were allowed to intravenously self-administer meth (yoked control rats received vehicle) 15 hours per day for 8 days before being euthanized at either 24 hours or at 7 and 14 days after cessation of drug taking. Meth self-administration by the rats was associated with a progressive escalation of daily drug intake to 14 mg/kg per day. Animals that self-administered meth exhibited dose-dependent decreases in striatal dopamine levels during the period of observation. In addition, there were significant reductions in the levels of striatal dopamine transporter and tyrosine hydroxylase proteins. There were also significant decreases in the levels of dopamine, dopamine transporter, and tyrosine hydroxylase in the cortex. In contrast, meth self-administration caused only transient decreases in norepinephrine and serotonin levels in the two brain regions, with these values returning to normal at seven days after cessation of drug taking. Importantly, meth self-administration was associated with significant dose-dependent increases in glial fibrillary acidic protein in both striatum and cortex, with these changes being of greater magnitude in the striatum. These results suggest that meth self-administration by rats is associated with long-term biochemical changes that are reminiscent of those observed in post-mortem brain tissues of chronic meth abusers.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Methamphetamine (meth) is an illicit psychostimulant that is abused throughout the world. Repeated passive injections of the drug given in a single day or over a few days cause significant and long-term depletion of dopamine and serotonin in the mammalian brain. Because meth self-administration may better mimic some aspects of human drug-taking behaviors, we examined to what extent this pattern of drug treatment might also result in damage to monoaminergic systems in the brain. Rats were allowed to intravenously self-administer meth (yoked control rats received vehicle) 15 hours per day for 8 days before being euthanized at either 24 hours or at 7 and 14 days after cessation of drug taking. Meth self-administration by the rats was associated with a progressive escalation of daily drug intake to 14 mg/kg per day. Animals that self-administered meth exhibited dose-dependent decreases in striatal dopamine levels during the period of observation. In addition, there were significant reductions in the levels of striatal dopamine transporter and tyrosine hydroxylase proteins. There were also significant decreases in the levels of dopamine, dopamine transporter, and tyrosine hydroxylase in the cortex. In contrast, meth self-administration caused only transient decreases in norepinephrine and serotonin levels in the two brain regions, with these values returning to normal at seven days after cessation of drug taking. Importantly, meth self-administration was associated with significant dose-dependent increases in glial fibrillary acidic protein in both striatum and cortex, with these changes being of greater magnitude in the striatum. These results suggest that meth self-administration by rats is associated with long-term biochemical changes that are reminiscent of those observed in post-mortem brain tissues of chronic meth abusers.
2008
Sekine, Yoshimoto; Ouchi, Yasuomi; Sugihara, Genichi; Takei, Nori; Yoshikawa, Etsuji; Nakamura, Kazuhiko; Iwata, Yasuhide; Tsuchiya, Kenji J; Suda, Shiro; Suzuki, Katsuaki; Kawai, Masayoshi; Takebayashi, Kiyokazu; Yamamoto, Shigeyuki; Matsuzaki, Hideo; Ueki, Takatoshi; Mori, Norio; Gold, Mark S; Cadet, Jean L
Methamphetamine causes microglial activation in the brains of human abusers. Journal Article
In: J Neurosci, vol. 28, no. 22, pp. 5756–5761, 2008, ISSN: 1529-2401 (Electronic); 0270-6474 (Linking).
@article{Sekine2008,
title = {Methamphetamine causes microglial activation in the brains of human abusers.},
author = { Yoshimoto Sekine and Yasuomi Ouchi and Genichi Sugihara and Nori Takei and Etsuji Yoshikawa and Kazuhiko Nakamura and Yasuhide Iwata and Kenji J Tsuchiya and Shiro Suda and Katsuaki Suzuki and Masayoshi Kawai and Kiyokazu Takebayashi and Shigeyuki Yamamoto and Hideo Matsuzaki and Takatoshi Ueki and Norio Mori and Mark S Gold and Jean L Cadet},
url = {https://www.ncbi.nlm.nih.gov/pubmed/18509037},
doi = {10.1523/JNEUROSCI.1179-08.2008},
issn = {1529-2401 (Electronic); 0270-6474 (Linking)},
year = {2008},
date = {2008-05-28},
journal = {J Neurosci},
volume = {28},
number = {22},
pages = {5756--5761},
address = {Molecular Neuropsychiatry Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Department of Health and Human Services, Baltimore, Maryland 21224, USA.},
abstract = {Methamphetamine is a popular addictive drug whose use is associated with multiple neuropsychiatric adverse events and toxic to the dopaminergic and serotonergic systems of the brain. Methamphetamine-induced neuropathology is associated with increased expression of microglial cells that are thought to participate in either pro-toxic or protective mechanisms in the brain. Although reactive microgliosis has been observed in animal models of methamphetamine neurotoxicity, no study has reported on the status of microglial activation in human methamphetamine abusers. The present study reports on 12 abstinent methamphetamine abusers and 12 age-, gender-, and education-matched control subjects who underwent positron emission tomography using a radiotracer for activated microglia, [(11)C](R)-(1-[2-chlorophenyl]-N-methyl-N-[1-methylpropyl]-3-isoquinoline carboxamide) ([(11)C](R)-PK11195). Compartment analysis was used to estimate quantitative levels of binding potentials of [(11)C](R)-PK11195 in brain regions with dopaminergic and/or serotonergic innervation. The mean levels of [(11)C](R)-PK11195 binding were higher in methamphetamine abusers than those in control subjects in all brain regions (>250% higher; p < 0.01 for all). In addition, the binding levels in the midbrain, striatum, thalamus, and orbitofrontal and insular cortices (p < 0.05) correlated inversely with the duration of methamphetamine abstinence. These results suggest that chronic self-administration of methamphetamine can cause reactive microgliosis in the brains of human methamphetamine abusers, a level of activation that appears to subside over longer periods of abstinence.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Methamphetamine is a popular addictive drug whose use is associated with multiple neuropsychiatric adverse events and toxic to the dopaminergic and serotonergic systems of the brain. Methamphetamine-induced neuropathology is associated with increased expression of microglial cells that are thought to participate in either pro-toxic or protective mechanisms in the brain. Although reactive microgliosis has been observed in animal models of methamphetamine neurotoxicity, no study has reported on the status of microglial activation in human methamphetamine abusers. The present study reports on 12 abstinent methamphetamine abusers and 12 age-, gender-, and education-matched control subjects who underwent positron emission tomography using a radiotracer for activated microglia, [(11)C](R)-(1-[2-chlorophenyl]-N-methyl-N-[1-methylpropyl]-3-isoquinoline carboxamide) ([(11)C](R)-PK11195). Compartment analysis was used to estimate quantitative levels of binding potentials of [(11)C](R)-PK11195 in brain regions with dopaminergic and/or serotonergic innervation. The mean levels of [(11)C](R)-PK11195 binding were higher in methamphetamine abusers than those in control subjects in all brain regions (>250% higher; p < 0.01 for all). In addition, the binding levels in the midbrain, striatum, thalamus, and orbitofrontal and insular cortices (p < 0.05) correlated inversely with the duration of methamphetamine abstinence. These results suggest that chronic self-administration of methamphetamine can cause reactive microgliosis in the brains of human methamphetamine abusers, a level of activation that appears to subside over longer periods of abstinence.
Krasnova, I N; Li, S M; Wood, W H; McCoy, M T; Prabhu, V V; Becker, K G; Katz, J L; Cadet, J L
Transcriptional responses to reinforcing effects of cocaine in the rat hippocampus and cortex. Journal Article
In: Genes Brain Behav, vol. 7, no. 2, pp. 193–202, 2008, ISSN: 1601-183X (Electronic); 1601-183X (Linking).
@article{Krasnova2008,
title = {Transcriptional responses to reinforcing effects of cocaine in the rat hippocampus and cortex.},
author = { I N Krasnova and S M Li and W H Wood and M T McCoy and V V Prabhu and K G Becker and J L Katz and J L Cadet},
url = {https://www.ncbi.nlm.nih.gov/pubmed/17640290},
doi = {10.1111/j.1601-183X.2007.00338.x},
issn = {1601-183X (Electronic); 1601-183X (Linking)},
year = {2008},
date = {2008-03-01},
journal = {Genes Brain Behav},
volume = {7},
number = {2},
pages = {193--202},
address = {Molecular Neuropsychiatry Branch, National Institute on Drug Abuse, NIH/DHHS, Baltimore, MD 21224, USA.},
abstract = {The psychostimulant effects of cocaine are thought to result from its ability to block dopamine (DA) uptake and increase DA levels in ventral striatum. In addition, cocaine causes biochemical changes in the brain areas involved in learning and memory, including hippocampus and cortex, whose role in drug reinforcement is now being actively investigated. Thus, we studied molecular events in the hippocampus and frontal cortex of rats treated with cocaine conditioned place preference (CPP) paradigm. After exposure to cocaine conditioning (cocaine paired), cocaine alone (cocaine non-paired) or saline rats were tested for place conditioning. Cocaine (10 mg/kg) caused increases in time spent in the drug-paired compartment. By using microarray analyses, we examined gene expression in the hippocampi and frontal cortices of cocaine-paired rats, cocaine non-paired and saline-treated controls. Our study revealed that 214 transcripts were differentially regulated in the hippocampi of cocaine-paired rats. These include genes that play roles in protein phosphorylation, RNA processing and protein synthesis, ubiquitin-dependent protein degradation and cytoskeleton organization. In contrast, 39 genes were differently expressed in the frontal cortex. Our data support the possibility that molecular changes in the hippocampus might participate in the formation and maintenance of memory patterns induced by cocaine in the brain. Differences in the transcriptional responses in the hippocampus and cortex suggest the primary importance of the hippocampus for recent memory processing associated with cocaine-induced CPP.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The psychostimulant effects of cocaine are thought to result from its ability to block dopamine (DA) uptake and increase DA levels in ventral striatum. In addition, cocaine causes biochemical changes in the brain areas involved in learning and memory, including hippocampus and cortex, whose role in drug reinforcement is now being actively investigated. Thus, we studied molecular events in the hippocampus and frontal cortex of rats treated with cocaine conditioned place preference (CPP) paradigm. After exposure to cocaine conditioning (cocaine paired), cocaine alone (cocaine non-paired) or saline rats were tested for place conditioning. Cocaine (10 mg/kg) caused increases in time spent in the drug-paired compartment. By using microarray analyses, we examined gene expression in the hippocampi and frontal cortices of cocaine-paired rats, cocaine non-paired and saline-treated controls. Our study revealed that 214 transcripts were differentially regulated in the hippocampi of cocaine-paired rats. These include genes that play roles in protein phosphorylation, RNA processing and protein synthesis, ubiquitin-dependent protein degradation and cytoskeleton organization. In contrast, 39 genes were differently expressed in the frontal cortex. Our data support the possibility that molecular changes in the hippocampus might participate in the formation and maintenance of memory patterns induced by cocaine in the brain. Differences in the transcriptional responses in the hippocampus and cortex suggest the primary importance of the hippocampus for recent memory processing associated with cocaine-induced CPP.
2005
Thiriet, Nathalie; Deng, Xiaolin; Solinas, Marcello; Ladenheim, Bruce; Curtis, Wendy; Goldberg, Steven R; Palmiter, Richard D; Cadet, Jean Lud
Neuropeptide Y protects against methamphetamine-induced neuronal apoptosis in the mouse striatum. Journal Article
In: J Neurosci, vol. 25, no. 22, pp. 5273–5279, 2005, ISSN: 1529-2401 (Electronic); 0270-6474 (Linking).
@article{Thiriet2005,
title = {Neuropeptide Y protects against methamphetamine-induced neuronal apoptosis in the mouse striatum.},
author = { Nathalie Thiriet and Xiaolin Deng and Marcello Solinas and Bruce Ladenheim and Wendy Curtis and Steven R Goldberg and Richard D Palmiter and Jean Lud Cadet},
url = {https://www.ncbi.nlm.nih.gov/pubmed/15930374},
doi = {10.1523/JNEUROSCI.4893-04.2005},
issn = {1529-2401 (Electronic); 0270-6474 (Linking)},
year = {2005},
date = {2005-06-01},
journal = {J Neurosci},
volume = {25},
number = {22},
pages = {5273--5279},
address = {Centre National de la Recherche Scientifique 6187, University of Poitiers, 86000 Poitiers, France.},
abstract = {Methamphetamine (METH) is an illicit drug that causes neuronal apoptosis in the mouse striatum, in a manner similar to the neuronal loss observed in neurodegenerative diseases. In the present study, injections of METH to mice were found to cause the death of enkephalin-positive projection neurons but not the death of neuropeptide Y (NPY)/nitric oxide synthase-positive striatal interneurons. In addition, these METH injections were associated with increased expression of neuropeptide Y mRNA and changes in the expression of the NPY receptors Y1 and Y2. Administration of NPY in the cerebral ventricles blocked METH-induced apoptosis, an effect that was mediated mainly by stimulation of NPY Y2 receptors and, to a lesser extent, of NPY Y1 receptors. Finally, we also found that neuropeptide Y knock-out mice were more sensitive than wild-type mice to METH-induced neuronal apoptosis of both enkephalin- and nitric oxide synthase-containing neurons, suggesting that NPY plays a general neuroprotective role within the striatum. Together, our results demonstrate that neuropeptide Y belongs to the class of factors that maintain neuronal integrity during cellular stresses. Given the similarity between the cell death patterns induced by METH and by disorders such as Huntington's disease, our results suggest that NPY analogs might be useful therapeutic agents against some neurodegenerative processes.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Methamphetamine (METH) is an illicit drug that causes neuronal apoptosis in the mouse striatum, in a manner similar to the neuronal loss observed in neurodegenerative diseases. In the present study, injections of METH to mice were found to cause the death of enkephalin-positive projection neurons but not the death of neuropeptide Y (NPY)/nitric oxide synthase-positive striatal interneurons. In addition, these METH injections were associated with increased expression of neuropeptide Y mRNA and changes in the expression of the NPY receptors Y1 and Y2. Administration of NPY in the cerebral ventricles blocked METH-induced apoptosis, an effect that was mediated mainly by stimulation of NPY Y2 receptors and, to a lesser extent, of NPY Y1 receptors. Finally, we also found that neuropeptide Y knock-out mice were more sensitive than wild-type mice to METH-induced neuronal apoptosis of both enkephalin- and nitric oxide synthase-containing neurons, suggesting that NPY plays a general neuroprotective role within the striatum. Together, our results demonstrate that neuropeptide Y belongs to the class of factors that maintain neuronal integrity during cellular stresses. Given the similarity between the cell death patterns induced by METH and by disorders such as Huntington's disease, our results suggest that NPY analogs might be useful therapeutic agents against some neurodegenerative processes.
Krasnova, Irina N; Ladenheim, Bruce; Cadet, Jean Lud
Amphetamine induces apoptosis of medium spiny striatal projection neurons via the mitochondria-dependent pathway. Journal Article
In: FASEB J, vol. 19, no. 7, pp. 851–853, 2005, ISSN: 1530-6860 (Electronic); 0892-6638 (Linking).
@article{Krasnova2005,
title = {Amphetamine induces apoptosis of medium spiny striatal projection neurons via the mitochondria-dependent pathway.},
author = { Irina N Krasnova and Bruce Ladenheim and Jean Lud Cadet},
url = {https://www.ncbi.nlm.nih.gov/pubmed/15731293},
doi = {10.1096/fj.04-2881fje},
issn = {1530-6860 (Electronic); 0892-6638 (Linking)},
year = {2005},
date = {2005-05-01},
journal = {FASEB J},
volume = {19},
number = {7},
pages = {851--853},
address = {Molecular Neuropsychiatry Branch, NIDA-IRP, DHHS/NIH, Baltimore, Maryland, USA.},
abstract = {Amphetamine (AMPH) is a psychostimulant whose chronic abuse may cause impairments in attention and memory in humans. These cognitive deficits might be related to neurotoxic effects of the drug. One such toxic effect is the well-described destruction of striatal dopaminergic terminals in mammals. In the present study, we investigated the possibility that AMPH might also cause neuronal apoptosis in the rodent striatum. Administration of a dose of the drug (10 mg/kg, 4 times, every 2 h) that is toxic to dopaminergic terminals resulted in the appearance of striatal cells that were positive for cleaved caspase-3 and for terminal deoxynucleotidyl transferase-mediated biotin-dUTP nick-end labeling (TUNEL), observations that are indicative of an ongoing apoptotic process. Dual immunofluorescence staining revealed that cleaved caspase-3-positive cells express calbindin and DARPP-32, but not somatostatin, parvalbumin, or cholinergic markers. In addition, AMPH also caused increased expression of p53 and Bax at both transcript and protein levels; in contrast, Bcl-2 levels were decreased after the AMPH injections. Moreover, Bax knockout mice showed resistance to AMPH-induced apoptotic cell death but not to AMPH-induced destruction of dopaminergic terminals. When taken together, these observations indicate that injections of doses of AMPH that are known to destroy striatal dopamine terminals can also cause apoptotic death of postsynaptic medium spiny projection neurons via mitochondria-dependent mechanisms.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Amphetamine (AMPH) is a psychostimulant whose chronic abuse may cause impairments in attention and memory in humans. These cognitive deficits might be related to neurotoxic effects of the drug. One such toxic effect is the well-described destruction of striatal dopaminergic terminals in mammals. In the present study, we investigated the possibility that AMPH might also cause neuronal apoptosis in the rodent striatum. Administration of a dose of the drug (10 mg/kg, 4 times, every 2 h) that is toxic to dopaminergic terminals resulted in the appearance of striatal cells that were positive for cleaved caspase-3 and for terminal deoxynucleotidyl transferase-mediated biotin-dUTP nick-end labeling (TUNEL), observations that are indicative of an ongoing apoptotic process. Dual immunofluorescence staining revealed that cleaved caspase-3-positive cells express calbindin and DARPP-32, but not somatostatin, parvalbumin, or cholinergic markers. In addition, AMPH also caused increased expression of p53 and Bax at both transcript and protein levels; in contrast, Bcl-2 levels were decreased after the AMPH injections. Moreover, Bax knockout mice showed resistance to AMPH-induced apoptotic cell death but not to AMPH-induced destruction of dopaminergic terminals. When taken together, these observations indicate that injections of doses of AMPH that are known to destroy striatal dopamine terminals can also cause apoptotic death of postsynaptic medium spiny projection neurons via mitochondria-dependent mechanisms.
Jayanthi, Subramaniam; Deng, Xiaolin; Ladenheim, Bruce; McCoy, Michael T; Cluster, Andrew; Cai, Ning-Sheng; Cadet, Jean Lud
Calcineurin/NFAT-induced up-regulation of the Fas ligand/Fas death pathway is involved in methamphetamine-induced neuronal apoptosis. Journal Article
In: Proc Natl Acad Sci U S A, vol. 102, no. 3, pp. 868–873, 2005, ISSN: 0027-8424 (Print); 0027-8424 (Linking).
@article{Jayanthi2005,
title = {Calcineurin/NFAT-induced up-regulation of the Fas ligand/Fas death pathway is involved in methamphetamine-induced neuronal apoptosis.},
author = { Subramaniam Jayanthi and Xiaolin Deng and Bruce Ladenheim and Michael T McCoy and Andrew Cluster and Ning-Sheng Cai and Jean Lud Cadet},
url = {https://www.ncbi.nlm.nih.gov/pubmed/15644446},
doi = {10.1073/pnas.0404990102},
issn = {0027-8424 (Print); 0027-8424 (Linking)},
year = {2005},
date = {2005-01-18},
journal = {Proc Natl Acad Sci U S A},
volume = {102},
number = {3},
pages = {868--873},
address = {Molecular Neuropsychiatry Branch, National Institute on Drug Abuse Intramural Research Program, National Institutes of Health, Department of Health and Human Services, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA.},
abstract = {Methamphetamine $[$METH ("speed")$]$ is an abused psychostimulant that can cause psychotic, cognitive, and psychomotor impairment in humans. These signs and symptoms are thought to be related to dysfunctions in basal ganglionic structures of the brain. To identify possible molecular bases for these clinical manifestations, we first used cDNA microarray technology to measure METH-induced transcriptional responses in the striatum of rats treated with an apoptosis-inducing dose of the drug. METH injection resulted in increased expression of members of the Jun, Egr, and Nur77 subfamilies of transcription factors (TFs), changes that were confirmed by quantitative PCR. Because pathways linked to these factors are involved in the up-regulation of Fas ligand (FasL), FasL mRNA was quantified and found to be increased. Immunohistochemical studies also revealed METH-induced increased FasL protein expression in striatal GABAergic neurons that express enkephalin. Moreover, there were METH-mediated increases in calcineurin, as well as shuttling of nuclear factor of activated T cells (NFAT)c3 and NFATc4 from the cytosol to the nucleus of METH-treated rats, mechanisms also known to be involved in FasL regulation. Furthermore, METH induced cleavage of caspase-3 in FasL- and Fas-containing neurons. Finally, the METH-induced changes in the FasL-Fas death pathway were attenuated by pretreatment with the dopamine D1 receptor antagonist, SCH23390, which also caused attenuation of METH-induced apoptosis. These observations indicate that METH causes some of its neurodegenerative effects, in part, via stimulation of the Fas-mediated cell death pathway consequent to FasL up-regulation mediated by activation of multiple TFs.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Methamphetamine $[$METH ("speed")$]$ is an abused psychostimulant that can cause psychotic, cognitive, and psychomotor impairment in humans. These signs and symptoms are thought to be related to dysfunctions in basal ganglionic structures of the brain. To identify possible molecular bases for these clinical manifestations, we first used cDNA microarray technology to measure METH-induced transcriptional responses in the striatum of rats treated with an apoptosis-inducing dose of the drug. METH injection resulted in increased expression of members of the Jun, Egr, and Nur77 subfamilies of transcription factors (TFs), changes that were confirmed by quantitative PCR. Because pathways linked to these factors are involved in the up-regulation of Fas ligand (FasL), FasL mRNA was quantified and found to be increased. Immunohistochemical studies also revealed METH-induced increased FasL protein expression in striatal GABAergic neurons that express enkephalin. Moreover, there were METH-mediated increases in calcineurin, as well as shuttling of nuclear factor of activated T cells (NFAT)c3 and NFATc4 from the cytosol to the nucleus of METH-treated rats, mechanisms also known to be involved in FasL regulation. Furthermore, METH induced cleavage of caspase-3 in FasL- and Fas-containing neurons. Finally, the METH-induced changes in the FasL-Fas death pathway were attenuated by pretreatment with the dopamine D1 receptor antagonist, SCH23390, which also caused attenuation of METH-induced apoptosis. These observations indicate that METH causes some of its neurodegenerative effects, in part, via stimulation of the Fas-mediated cell death pathway consequent to FasL up-regulation mediated by activation of multiple TFs.
