Biomedical subjects

J L Cadet

Publications and source records attributed to J L Cadet.

At least 37 records · Page 2Linked to original sources

PubMed2001

Involvement of free radicals in MDMA-induced neurotoxicity in mice.

3,4-methylenedioxymethamphetamine (MDMA) or ecstasy) is a substituted amphetamine with stimulating and hallucinogenic properties. Administration of MDMA leads to the formation of metabolites responsible for its toxic effects on serotonergic neurons in rats and non-human primates and on dopaminergic neurons in mice. Our findings indicate that overexpression of the human superoxide dismutase gene (Cu/Zn-SOD) abolishes certain effects of MDMA such as the decreased level of dopamine, DOPAC and 5-HT in the striatum, inactivation of certain antioxidant enzymes (CU/ZN-SPD, catalase or glutathione peroxidase) or peroxidation of lipids. These data are in agreement with the implication of free radicals and consequenty of oxidative stress in the mode of action of MDMA.

Animals↗

PubMed2001

Profile of genes showing increased expression following dopamine and methamphetamine exposure in an immortalized neuronal cell line.

Methamphetamine (METH) is a drug of abuse with well-described neurodegenerative effects. Some of the METH-induced degenerative manifestations are thought to be due to increased dopamine (DA) release in the cytoplasm of nerve terminals and subsequent extravasation in the synaptic cleft. Using an immortalized neural cell line, we have made use of the comprehensive cDNA array technology in order to compare and contrast the molecular effects of DA and METH. We found that the two compounds do have many similar but also different effects. Since these neural cells produce no DA, these results demonstrate that many of the METH-induced responses attributed to DA might, in fact, be intrinsic to METH itself. More biochemical studies are needed to investigate DA-independent METH deleterious events in the central nervous system.

Animals↗

PubMed2000

Methamphetamine-induced apoptosis is attenuated in the striata of copper-zinc superoxide dismutase transgenic mice.

Administration of methamphetamine caused significant increases in terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells, in poly (ADP-ribose) polymerase (PARP) cleavage, as well as in caspase-3 activity in the striata of C57BL/6J mice. In contrast, all these effects were markedly suppressed in the copper-zinc superoxide dismutase transgenic mice. These results indicate that superoxide radicals might be important factors in METH-induced cell death.

Animals↗

PubMed2000

Direct interactions of methamphetamine with the nucleus.

Possible direct effects of methamphetamine (METH) on transcription factors AP-1 and cAMP response element-binding protein (CREB) in the nucleus were assessed by electrophoretic mobility-shift assay. In vitro addition of METH to nuclear extract from brain tissue increased DNA-binding activities of both transcription factors. In addition, injections of METH to mice induced increases in the binding of AP-1 and CREB, which were depleted by preincubating the nuclear extract with anti-METH antibody. We also examined the cellular distribution of METH in mesencephalic neuronal cells using an immunofluorescence experiment with anti-METH antibody. METH-like immunoreactivity was seen to accumulate in the cytosol 4-6 h after the METH treatment. Furthermore, METH-positive signals were also observed in the nuclei of the METH-treated cells. The present study is the first demonstration that METH can have direct effects on DNA-binding protein complex by redistributing not only in the cytosol but also into the nucleus.

Animals↗

PubMed2000

Differential effects of cocaine and cocaine alcohol on neurocognitive performance.

OBJECTIVE: To investigate the dose-related effects of cocaine with or without alcohol use on the CNS by measuring performance on neurobehavioral tests. BACKGROUND: Chronic use of cocaine is associated with persistent decrements in cognitive function that are most pronounced in heavy users. Specific neurobehavioral deficits in areas such as executive function and impulsivity would make it difficult for the cocaine abuser to discontinue using drugs. Because alcohol is often used in conjunction with cocaine, the CNS effects of alcohol when taken with cocaine deserve further investigation. METHOD: The authors evaluated the dose-related effects of cocaine and alcohol use on performance in a variety of neuropsychological tests after 1 to 3 days of abstinence and again after 4 weeks of abstinence. Fifty-six chronic cocaine abusers who had used cocaine during the past 24 to 48 hours volunteered to perform a battery of neuropsychological tests on two separate occasions during a period of enforced abstinence. In addition to using cocaine, most of the volunteers consumed alcohol. Approximately half of the participants consumed more than 10 alcohol-containing drinks per week. RESULTS: After controlling for the effects of age, sex, and intelligence on performance, the authors found dose-related associations between neurobehavioral performance and cocaine dose and alcohol dose. When the influences of cocaine and alcohol on neurobehavioral performance were taken separately, cocaine and alcohol each selectively affected performance on different neurobehavioral tests after 1 to 3 days of abstinence, with these effects persisting after 4 weeks of abstinence. CONCLUSION: The concomitant use of cocaine and alcohol may have additive negative effects on the brain as compared to the use of only one of these two substances.

Adult↗

PubMed2000

Bcl-2 overexpression attenuates dopamine-induced apoptosis in an immortalized neural cell line by suppressing the production of reactive oxygen species.

Parkinson's disease is a neurodegenerative disease that is consequent to the loss of brain dopamine (DA) cells. These abnormalities are thought, in part, to be a manifestation of increased free radical production during the metabolism of catecholamines. The antiapoptic agent, bcl-2, has been shown to protect cells against the toxic effects of reactive oxygen species (ROS). Thus, we tested whether bcl-2 could attenuate the toxic effects of DA on immortalized neural cells. Our results show that DA caused dose-dependent cell death. The use of confocal microscopy and flow cytometry demonstrated that DA caused cell death through an apoptotic process. Moreover, DA caused a marked increase in ROS in these cells. Furthermore, overexpression of bcl-2 caused significant protection against DA-induced apoptosis. These results are discussed in terms of their support for a role of bcl-2 in the development of Parkinson's disease.

Apoptosis↗

PubMed2000

Caffeine withdrawal increases cerebral blood flow velocity and alters quantitative electroencephalography (EEG) activity.

RATIONALE: Cessation of daily caffeine consumption produces a withdrawal syndrome comprised of subjective symptoms and functional impairment. Few controlled studies have examined the physiological effects of caffeine withdrawal. OBJECTIVE: The present study examined the effect of caffeine withdrawal on cerebral blood flow velocity and quantitative EEG. METHODS: Ten volunteers reporting moderate caffeine intake (mean 333 mg/day) participated in this double-blind study. Subjects completed several tests when maintaining their normal diet (baseline period) and during two 1-day periods during which they consumed caffeine-free diets and received capsules containing placebo (placebo test session) or caffeine (caffeine test session) in amounts equal to their baseline daily caffeine consumption. Blood flow velocity was determined for four arteries: right and left middle (MCA), and right and left anterior (ACA) cerebral arteries using pulsed transcranial Doppler sonography. EEG was recorded for 3 min from eight scalp sites while subjects sat, with eyes closed, in a sound-attenuated electronically shielded chamber. Subjective effects were assessed with questionnaires. RESULTS: Results showed an effect of the placebo (21-h withdrawal) condition compared to the caffeine condition. Placebo significantly increased the mean velocity, systolic velocity and diastolic velocity (cm/s) in all four cerebral arteries. In the MCA, the pulsatility index was significantly decreased following placebo. Placebo significantly increased EEG theta power. Placebo also produces subjective effect changes, including increases in heavy feelings in arms and legs and decreases in ability to concentrate. The caffeine and baseline conditions produced similar results on both the physiological and subjective measures. CONCLUSION: Cessation of daily caffeine consumption produced changes in cerebral blood flow velocity and quantitative EEG. These changes may be related to classic caffeine withdrawal symptoms of headache, drowsiness and decreased alertness.

Adult↗

PubMed2000

Effects of methamphetamine-induced neurotoxicity on the development of neural circuitry: a hypothesis.

Exposure of the developing brain to methamphetamine has well-studied biochemical and behavioral consequences. We review: (1) the effects of methamphetamine on mature serotonergic and dopaminergic pathways; (2) the mechanisms of methamphetamine neurotoxicity and (3) the role of serotonergic and dopaminergic signaling in sculpting developing neural circuitry. Consideration of these data suggest the types of neural circuit alterations that may result from exposure of the developing brain to methamphetamine and that may underlie functional defects.

Animals↗

PubMed2000

Serum withdrawal potentiates the toxic effects of methamphetamine in vitro.

Methamphetamine (METH) has been shown to cause neurotoxic damage both in vitro and in vivo. The mechanisms of action are thought to involve the production of pathophysiologic concentration of free radicals. The present study was undertaken to assess the toxic effects of METH caused dose-dependent increased production of reactive oxygen species (ROS) and cell death. Cell death caused by METH was characterized by cytoplasmic vacuolar formation, shrinkage of cytoplasm and nuclear dissolution. Flow cytometric evaluation also revealed that this toxin causes changes similar to those observed in cells undergoing apoptosis. When taken together these observations suggest the METH can cause these cells to die via apoptosis. Further experiments indicated that growth of these cells in low (1%) serum or in the absence of serum markedly enhanced the apoptotic effects of METH. These data provide further support for the ideas that METH can cause ROS-mediated apoptosis.

Animals↗

PubMed2000

Methamphetamine-induced neurotoxicity is attenuated in transgenic mice with a null mutation for interleukin-6.

Increasing evidence implicates apoptosis as a major mechanism of cell death in methamphetamine (METH) neurotoxicity. The involvement of a neuroimmune component in apoptotic cell death after injury or chemical damage suggests that cytokines may play a role in METH effects. In the present study, we examined if the absence of IL-6 in knockout (IL-6-/-) mice could provide protection against METH-induced neurotoxicity. Administration of METH resulted in a significant reduction of [(125)I]RTI-121-labeled dopamine transporters in the caudate-putamen (CPu) and cortex as well as depletion of dopamine in the CPu and frontal cortex of wild-type mice. However, these METH-induced effects were significantly attenuated in IL-6-/- animals. METH also caused a decrease in serotonin levels in the CPu and hippocampus of wild-type mice, but no reduction was observed in IL-6-/- animals. Moreover, METH induced decreases in [(125)I]RTI-55-labeled serotonin transporters in the hippocampal CA3 region and in the substantia nigra-reticulata but increases in serotonin transporters in the CPu and cingulate cortex in wild-type animals, all of which were attenuated in IL-6-/- mice. Additionally, METH caused increased gliosis in the CPu and cortices of wild-type mice as measured by [(3)H]PK-11195 binding; this gliotic response was almost completely inhibited in IL-6-/- animals. There was also significant protection against METH-induced DNA fragmentation, measured by the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeled (TUNEL) cells in the cortices. The protective effects against METH toxicity observed in the IL-6-/- mice were not caused by differences in temperature elevation or in METH accumulation in wild-type and mutant animals. Therefore, these observations support the proposition that IL-6 may play an important role in the neurotoxicity of METH.

Amphetamine↗

PubMed2000

Gender differences in the EEG of abstinent cocaine abusers.

Gender differences in the EEG were explored in cocaine-abusing individuals not seeking treatment. Twenty currently abstinent cocaine-abusing females aged 21-41 were studied. Their cocaine use history was matched to 20 currently abstinent cocaine-abusing males. Twelve female and 20 male non-drug-abusing individuals served as a control group. Resting eyes closed EEG was recorded from 8 leads. The males who used cocaine had elevated EEG beta (p<0.0125) and reduced alpha (p<0.0125) when compared to the cocaine-abusing females and control subjects. These findings suggest that the EEG of cocaine-abusing women may be more normal than that of cocaine-abusing men. Such gender-specific differences for cocaine-abusing populations may require gender-specific treatment to improve outcome.

Adult↗

PubMed2000

Protective effect of supplemental superoxide dismutase on survival of neuronal cells during starvation. Requirement for cytosolic distribution.

There is evidence that raising cellular levels of Cu2+/Zn2+ superoxide dismutase (SOD1) can protect neurons from oxidative injury. We compared a novel method of elevating neuronal SOD activity using a recombinant hybrid protein composed of the atoxic neuronal binding domain of tetanus toxin (C fragment or TTC) and human SOD1 (hSOD1) with increasing cellular SOD levels through overexpression. Fetal murine cortical neurons or N18-RE-105 cells were incubated with the TTC-hSOD1 hybrid protein and compared to cells constitutively expressing hSOD1 for level of SOD activity, cellular localization of hSOD1, and capacity to survive glucose and pyruvate starvation. Cells incubated with TTC-hSOD1 showed a threefold increase in cellular SOD activity over control cells. This level of increase was comparable to fetal cortical neurons from transgenic mice constitutively expressing hSOD1 and transfected N18-RE-105 cells expressing a green fluorescent protein-hSOD1 fusion protein (GFP-hSOD1). Human SOD1 was distributed diffusely throughout the cytoplasm of the transgenic murine neurons and transfected N18-RE-105 cells. In contrast, cells incubated with TTC-hSOD1 showed hSOD1 localized to the cell surface and intra-cytoplasmic vesicles. The cells expressing hSOD1 showed enhanced survival in glucose- and pyruvate-free medium. Neither cortical neurons nor N18-RE-105 cells incubated in TTC-hSOD1 showed increased survival during starvation. Access to the site where toxic superoxides are generated or their targets may be necessary for the protective function of SOD1.

Animals↗

PubMed2000

African-American teen smokers: issues to consider for cessation treatment.

Previous reports have indicated ethnic differences in both tobacco-related morbidity and treatment outcome for smoking cessation among adults. We assessed smoking-related characteristics in African-American and non-African American teenagers applying to a cessation trial. 115 teens (15.9 +/- 1.8 years, 68% females, 27% African-American) responded via telephone to media ads. Self-reported sociodemographic, medical and smoking-related data were obtained to determine pre-eligibility for a full intake screen prior to trial participation. Compared to non-African American, African American teen applicants were older (16.4 +/- 1.7 years versus 15.6 +/- 1.6; p = 0.015), had lower Fagerström Test for Nicotine Dependence (FTND) scores (5.3 +/- 2.3 versus 6.1 +/- 1.8; p = 0.018, ANOVA controlling for age) and smoked fewer cigarettes on the weekend (27 +/- 16 versus 38 +/- 17; p = 0.001). African American teens reported similar duration of smoking (3.3 +/- 1.4 versus 3.1 +/- 1.5 years) and time elapsed between first cigarette ever smoked and daily smoking (0.7 +/- 0.9 versus 0.6 +/- 0.7 years). African American and non-African American teens had similar motivation to quit scores and frequency of reported health problems (e.g., asthma, psychiatric conditions). These data suggest that cessation treatment programs designed for African American youth should include lower Fagerstrom-defined levels, and possibly other criteria for tobacco dependence. These observations also highlight the importance of ethnocultural issues in treatment research programs.

Adolescent↗

PubMed1999

Methamphetamine administration causes overexpression of nNOS in the mouse striatum.

The accumulated evidence suggests that the overproduction of nitric oxide (NO) is involved in methamphetamine (METH)-induced neurotoxicity. Using NADPH-diaphorase histochemistry, neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS) 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.

Animals↗

PubMed1999

Null mutation of c-fos causes exacerbation of methamphetamine-induced neurotoxicity.

Methamphetamine neurotoxicity has been demonstrated in rodents and nonhuman primates. These neurotoxic effects may be associated with mechanisms involved in oxidative stress and the activation of immediate early genes (IEG). It is not clear, however, whether these IEG responses are involved in a methamphetamine-induced toxic cascade or in protective mechanisms against the deleterious effects of the drug. As a first step toward clarifying this issue further, the present study was thus undertaken to assess the toxic effects of methamphetamine in heterozygous and homozygous c-fos knock-out as well as wild-type mice. Administration of methamphetamine caused significant reduction in [(125)I]RTI-121-labeled dopamine uptake sites, dopamine transporter protein, and tyrosine hydroxylase-like immunohistochemistry in the striata of wild-type mice. These decreases were significantly exacerbated in heterozygous and homozygous c-fos knock-out mice, with the homozygous showing greater loss of striatal dopaminergic markers. Moreover, in comparison with wild-type animals, both genotypes of c-fos knock-out mice showed more DNA fragmentation, measured by the number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeled nondopaminergic cells in their cortices and striata. In contrast, wild-type mice treated with methamphetamine demonstrated a greater number of glial fibrillary acidic protein-positive cells than did c-fos knock-out mice. These data suggest that c-fos induction in response to toxic doses of methamphetamine might be involved in protective mechanisms against this drug-induced neurotoxicity.

Animals↗

PubMed1999

Dual mechanism of Fas-induced cell death in neuroglioma cells: a role for reactive oxygen species.

ApoI/Fas belongs to the tumor necrosis factor receptor (TNFR) superfamily and mediates cell death in various cell types. A dual mode of Fas-triggered cell death has been reported depending on cell types used in the experiments. The present study was carried out to test the possible role of reactive oxygen species in this dual mechanism in neuroglioma cells. Anti-Fas antibody caused dose-dependent and time-dependent increase in cell death measured by lactate dehydrogenase (LDH) release in control neuroglioma cells and in cells that were transfected with catalase cDNA. However, cells transfected with copper/zinc superoxide dismutase (Cu/ZnSOD) cDNA showed marked attenuation of Fas-induced LDH release. Moreover, flow cytometry and confocal microscopy revealed that Fas-induced cell death in control cells occur mostly through an apoptotic process. This process was also completely abrogated in cells overexpressing catalase or copper/zinc superoxide dismutase (Cu/ZnSOD). Further experiments revealed that Fas-induced cell death was associated with increased formation of superoxide anions in control neuroglioma cells and in cells overexpressing catalase. These increases were significantly suppressed by Cu/ZnSOD overexpression. These data indicate that Fas-mediated cell death in neuroglioma cells occur, in part, through the production of reactive oxygen species (ROS). These observations also suggest that Fas-induced cell death in these cells occur through apoptosis and necrosis. Thus overexpression of Cu/ZnSOD caused the suppression of both types of Fas-induced cell death whereas catalase prevented apoptotic but not necrotic cell death. These observations are discussed in terms of their support for a role for both peroxides and superoxide radicals in Fas-induced cell death.

Apoptosis↗

PubMed1999

Effects of antihistamines on 3, 4-methylenedioxymethamphetamine-induced depletion of serotonin in rats.

This study investigated the effects of chlorpheniramine (CPA, 10-25 mg/kg), diphenhydramine (DIPH, 20 mg/kg), tripelennamine (TRIP, 20 mg/kg), and pyrilamine (PYRI, 20 mg/kg) on 3, 4-methylenedioxymethamphetamine (MDMA, 20 mg/kg x 2)-induced hyperthermia and depletion of indoles in rat brains, on the uptake of serotonin and dopamine into rat synaptosomes, on the binding affinity of CPA for biogenic amine transporters in the synaptosomes of rat brain, and on the scavenging hydroxyl free radicals activity. Rats were treated with two injections of MDMA, CPA, DIPH, TRIP, PYRI, and saline, alone or in combination of MDMA with one of the antihistamines, 6 h apart and sacrificed 5 days later. Rectal temperature was measured prior to and hourly following the drug injections for 13 h. As compared to saline controls, MDMA increased body temperature and decreased levels of indoles, measured by HPLC, in several brain regions of rats. CPA attenuated and DIPH had no effect on MDMA-induced hyperthermia, yet both attenuated the depletion of indoles, whereas PYRI and TRIP potentiated these effects. CPA inhibited the binding of [(3)H]paroxetine and [(3)H]nisoxetine to the synaptosomes of cerebral cortex and of [(3)H]win 35,428 to the synaptosomes of striatum. CPA, DIPH, TRIP, and PYRI inhibited [(3)H]serotonin uptake. CPA, PYRI, and TRIP, but not DIPH, scavenge hydroxyl radicals. Possible mechanisms of the different effects of the antihistamines on MDMA-induced hyperthermia and depletion of serotonin are discussed. Published 1999 Wiley-Liss, Inc.

Adrenergic Uptake Inhibitors↗

PubMed1999

Chronic methylphenidate alters locomotor activity and dopamine transporters differently from cocaine.

Continuous infusion of cocaine produces partial behavioral tolerance to its locomotor activating effects, while daily injections produce sensitization. Methylphenidate binds with a similar affinity to cocaine at the dopamine transporter, but has a much lower affinity for the serotonin transporter than does cocaine. This study was done to compare the effects of chronic methylphenidate with chronic cocaine. The pattern of locomotor activity over a 7 day treatment period was significantly different from cocaine. Methylphenidate elevated activity on each day, compared to saline, yet neither tolerance to a continuous infusion of the drug, nor sensitization to repeated daily injections was produced. We have previously shown that neither of these treatments with cocaine produces significant alterations in dopamine transporter density 1 day after the end of treatment. In contrast, methylphenidate injections significantly decreased dopamine transporters in rostral caudate putamen, with no change in nucleus accumbens. Continuous infusion of methylphenidate had no effect on dopamine transporters in either brain region. These findings provide further evidence that different classes of dopamine uptake inhibitors may interact with the dopamine transporter in qualitatively different manners. Furthermore, it is possible that the inhibition of serotonin uptake by cocaine may contribute to the adaptations in behavioral activity that are seen during chronic treatment.

Animals↗