Biomedical subjects

J L Cadet

Publications and source records attributed to J L Cadet.

At least 73 records · Page 4Linked to original sources

PubMed1998

The neuropsychiatry of chronic cocaine abuse.

This review integrates findings from neuropsychological, PET, and MRI studies in human subjects and neurochemical findings in animals to make inferences about neuropsychiatric consequences of chronic abuse of cocaine. It also aims to develop insights into brain-behavioral relationships that may explain the perpetuation of addictive behaviors. Such insights promise to lead to a better understanding of the neuropsychiatry of cocaine abuse and to promote the development of more efficacious treatments. The authors present evidence suggesting that cocaine abusers have specific dysfunction of executive functions (decision making, judgment) and that this behavior is associated with dysfunction of specific prefrontal brain regions, the orbitofrontal cortex, and anterior cingulate gyrus. Suggestions for future research and treatment are also discussed.

Aged↗

PubMed1998

Delta opioid peptide [D-Ala2,D-leu5]enkephalin blocks the long-term loss of dopamine transporters induced by multiple administrations of methamphetamine: involvement of opioid receptors and reactive oxygen species.

Delta opioid peptide [D-Ala2,D-leu5]enkephalin (DADLE) can prolong organ preservation and increases myocardial tolerance to ischemia. Our study examined the protective property of DADLE against methamphetamine- (METH) induced dopaminergic terminal damage in the central nervous system. Because the neurotoxicity of METH involves reactive oxygen species, we also examined if DADLE might be an antioxidative agent in vitro. DADLE at 2 and 4 mg/kg (i.p.), given 30 min before each METH administration (5 or 10 mg/kg, i.p., four injections in a day at 2-hr intervals), dose-dependently blocked the METH-induced long-term dopamine transporter loss. The opioid antagonist naltrexone blocked this action of DADLE in both aspects of striata but tends not to affect the effects of DADLE in the nucleus accumbens. DADLE did not alter changes in body temperature induced by METH. The reduction of striatal dopaminergic content and tyrosine hydroxylase activity caused by METH, however, were not blocked by DADLE. In vitro, DADLE was approximately equipotent to glutathione in inhibiting both superoxide anion formation induced by xanthine oxidase and hydroxyl radical formation evoked by ferrous/citrate complex. DADLE was only slightly less potent than glutathione in inhibiting the iron/ascorbate-induced brain lipid peroxidation. These results suggest that DADLE can protect the terminal membranes of dopaminergic neurons against METH-induced insult but not the loss of dopaminergic content and tyrosine hydroxylase activity and that this action of DADLE might involve opioid receptors as well as the sequestration of free radical.

Animals↗

PubMed1997

Cocaine dependence. A clinical syndrome requiring neuroprotection.

Cocaine use has increased the frequency of medical complications among younger individuals. Neurological and neurovascular complications include strokes, seizures, transient ischemic attacks, and headaches. Subclinical deficits in cerebral perfusion and EEG have been noted in this population. Although these subclinical deficits may be an indication of increased risk of medical complications, the prophalactic treatment of cocaine abusers with neuroprotective agents has not yet been advocated. Blood flow of the anterior and medial cerebral arteries was measured by transcranial Doppler sonography in cocaine abusers (n = 70) and control subjects (n = 20) to determine whether cocaine abusers might have reduced cerebral blood flow in large cerebral arteries. Blood flow was measured within three days of and again about 28 days after admission of subjects to an inpatient research ward to determine whether blood flow improved with monitored abstinence. The mean, systolic, and diastolic velocities as well as the Pulsatility Index (PI) in both arteries differed between the control and cocaine abusers (p < 0.05). After about a month of abstinence, blood flow for the cocaine-dependent subjects increased. These preliminary findings suggest that blood flow is reduced in cocaine abusers and that there is a slight improvement with abstinence. Further research is needed to determine whether blood flow in abstinent cocaine abusers can be increased by pharmacological manipulations.

Adult↗

PubMed1997

Subclinical neurological and neurovascular deficits in cocaine dependence. Gender and psychosocial considerations.

Neurological and neurovascular deficits were reported in cocaine abusers. In order to examine the contribution of cocaine use severity as well as other psychosocial factors to these deficits, we examined the following measures in a sample of cocaine abusers (n = 70): blood flow (transcranial Doppler sonography), and psychosocial measures (the Norbeck Social Support Questionnaire, the Symptom Check List 90R, the Beck Hopelessness Scale, and the Ellison Wellness Scale). Blood flow in the anterior and medial cerebral arteries was lower in the cocaine abusers than in the control subjects. Both cocaine use and psychosocial measures significantly predicted decreases in blood flow.

Adult↗

PubMed1997

Overexpression of superoxide dismutase and catalase in immortalized neural cells: toxic effects of hydrogen peroxide.

Hydrogen peroxide (H2O2) is a known toxicant which causes its damage via the production of hydroxyl radicals. It has been reported to cause both necrotic and apoptotic cell death. The present study was undertaken to evaluate the mode of H2O2-induced cell death and to assess if overexpression of catalase could protect against its toxicity. H2O2 causes cell death of immortalized CSM 14.1 neural cells in a dose-dependent manner. H2O2-induced death was associated with DNA laddering as shown by agarose gel electrophoresis. Stable overexpression of catalase by transfection of a vector containing human cDNA into these cells markedly attenuated H2O2-induced toxic effects. Transfection of a vector containing a SOD cDNA afforded no protection. These results indicate that H2O2 can lead to the activation of endonuclease enzyme that breaks DNA into oligosomes. These cells which overexpress catalase or SOD will help to determine the specific role of H2O2 or O2- in the deleterious effects of a number of toxins.

Catalase↗

PubMed1997

Differential toxic effects of methamphetamine (METH) and methylenedioxymethamphetamine (MDMA) in multidrug-resistant (mdr1a) knockout mice.

The toxic effects of methamphetamine (METH) (2.5, 5.0 and 10.0 mg/kg) and methylenedioxymethamphetamine (MDMA) (5.0, 10.0 and 20.0 mg/kg) on dopaminergic systems were assessed in the striatum and of the nucleus accumbens in mdr1a wild-type and knockout mice. METH caused significant dose-dependent decreases of dopamine (DA) and DA transporters (DAT) in the striatum and the nucleus accumbens (NAc) of both wild-type and knockout mice. The lowest doses of METH (2.5 mg/kg) caused only small changes in the wild-type, but marked. decreases in the mdr1a knockout mice. The two higher doses (5 mg/kg and 10 mg/kg) caused similar changes in both strains of mice. In contrast to METH, MDMA caused greater percentage decreases in DAT in the wild-type mice. For example, the lowest dose (5 mg/kg) caused significant decreases in DAT in the NAc of wild-type but not of mdr1a knockout mice. The highest dose (20 mg/kg) caused similar changes in both the strains. These results suggest that METH and MDMA interact differentially with P-glycoproteins. These observations document, for the first time, a role for these proteins in the entry of METH and MDMA into the brain via the blood-brain barrier, with P-glycoprotein possibly facilitating the entry of MDMA but interfering with that of METH into the brain.

Animals↗

PubMed1997

Methamphetamine-induced serotonin neurotoxicity is attenuated in p53-knockout mice.

Methamphetamine (METH) is a drug of abuse that causes deleterious effects to brain monoaminergic systems. The tumor suppressor gene, p53, is thought to play an important role in cell death. In the present study, we have assessed the participation of p53 in METH-induced serotonergic neurotoxicity, by using the mice lacking the gene for p53 protein. Three dosages (2.5, 5.0 and 10.0 mg/kg x 4) of METH were administered to wild-type (p53+/+), heterozygous (p53+/-) and homozygous (p53-/-) p53-knockout mice. The two lower doses caused no significant changes in serotonin (5-HT) transporters in any of the groups. The highest dose (10.0 mg/kg) caused significant decreases in striatal 5-HT transporters in wild-type (-31%) and heterozygous (-18%) mice. In contrast, 5-HT transporters were not significantly decreased in homozygous mice. These results suggest that the tumor suppressor, p53, plays an important role in METH-induced serotonergic neurotoxicity in mice brain. These data provide further evidence for a role of p53 in the neurotoxic effects of METH.

Analysis of Variance↗

PubMed1997

Neurophysiological signs of cocaine dependence: increased electroencephalogram beta during withdrawal.

To determine whether a central nervous system marker of cocaine dependence might exist, the resting electroencephalogram (EEG) of 33 drug-free, cocaine-dependent men (DSM-III-R criteria) was compared with two control groups [nondrug group (n = 10) and drug group who abused drugs, but were not cocaine dependent (n = 20)]. The EEG was recorded from eight sites after about 10 days of monitored abstinence (range 4-15 days) on a closed research ward for the drug-using individuals. The EEG was recorded for the nondrug control group as outpatients. The drug history was determined by the drug history questionnaire and a medical screening interview. The percent of EEG beta activity for the cocaine-dependent subjects was greater than that of both control groups (p < .05) as well as a normative database (HZI: Tarrytown, NY). The percent of EEG beta in frontal and central areas of the cocaine-dependent individuals was correlated with the frequency of cocaine use during the last 30 days. High levels of EEG beta may be a neurophysiological withdrawal sign in cocaine-dependent men.

Adult↗

PubMed1997

Methamphetamine induces apoptosis in immortalized neural cells: protection by the proto-oncogene, bcl-2.

Methamphetamine (METH) is an amphetamine analog that produces degeneration of the dopaminergic system in mammals. The neurotoxic effects of the drug are thought to be mediated by oxygen-based free radicals. In the present report, we have used immortalized neural cells obtained from rat mesencephalon in order to further assess the role of oxidative stress in METH-induced neurotoxicity. We thus tested if the anti-death proto-oncogene, bcl-2 could protect against METH-induced cytotoxicity. METH caused dose-dependent loss of cellular viability in control cells while bcl-2-expressing cells were protected against these deleterious effects. Using flow cytometry, immunofluorescent staining, and DNA electrophoresis, we also show that METH exposure can cause DNA strand breaks, chromatin condensation, nuclear fragmentation, and DNA laddering. All these changes were prevented by bcl-2 expression. These observations provide further support for the involvement of oxidative stress in the toxic effects of amphetamine analogs. They also document that METH-induced cytotoxicity is secondary to apoptosis. These findings may be of relevance to the cause(s) of Parkinson's disease which involves degeneration of the nigrostriatal dopaminergic pathway.

Analysis of Variance↗

PubMed1997

Kainate-induced hippocampal DNA damage is attenuated in superoxide dismutase transgenic mice.

Peripheral administration of kainic acid (KA) can cause cell death in the hippocampus of rodents. This is thought to involve oxidative stress. In the present study, we tested the possibility that KA-induced neuronal cell death might be attenuated in CuZn superoxide dismutase transgenic (SOD-Tg) mice. Acute administration of KA causes animal death in a dose-dependent fashion; this was attenuated in SOD-Tg mice. Similarly, KA caused dose-dependent neuronal cell death in the hippocampus of wild-type mice; this cell death was attenuated in the SOD-Tg mice, in a gene-dosage-dependent fashion, with homozygous mice showing complete protection even at the highest dose (45 mg/kg) of KA used in this study. These results provide further support for the involvement of oxygen-based radicals in the toxic effects of KA.

Animals↗

PubMed1997

p53-knockout mice are protected against the long-term effects of methamphetamine on dopaminergic terminals and cell bodies.

p53-knockout mice provide a useful model to test the role of p53 in the neurotoxic effects of drugs in vivo. To test the involvement of p53 in methamphetamine (METH)-induced toxicity, wild-type mice, as well as heterozygous and homozygous p53-knockout male mice, were administered four injections of three different doses (2.5, 5.0, and 10.0 mg/kg) of the drug given at 2-h intervals within the space of 1 day. METH caused a marked dose-dependent loss of dopamine transporters in both the striatum and the nucleus accumbens of wild-type mice killed 2 weeks after drug administration. However, this METH-induced decrease in dopamine transporters was attenuated in both homozygous and heterozygous p53-knockout mice, with homozygous animals showing significantly greater protection. The possibility for p53 involvement in METH-induced toxicity was also supported by the observation that METH caused marked increases in p53-like immunoreactivity in the striata of wild-type mice and very little change in heterozygous p53-knockout mice, whereas no p53-like immunostaining was detected in the homozygous p53-knockout mice. Further support for p53 involvement was provided by the fact that METH treatment caused significant decreases in dopamine transporter mRNA and the number of tyrosine hydroxylase-positive cells in the substantia nigra pars compacta and the ventral tegmental area of wild-type but not homozygous p53-knockout mice killed 2 weeks after cessation of METH administration. These results provide concordant evidence for a role of the tumor suppressor, p53, in the long-term deleterious effects of a drug acting on brain dopamine systems.

Animals↗

PubMed1997

Differential regulation of dopamine transporter after chronic self-administration of bupropion and nomifensine.

Inhibition of dopamine (DA) transporter function is thought to be the principal mechanism underlying cocaine's addictive effects. In contrast to cocaine, several other inhibitors of DA transporter function are not considered to possess abuse liability. One of the neuroadaptive changes to chronic cocaine self-administration is the up-regulation of DA transporters. In the present study, we investigated the reinforcing and neuroadaptive effects of two other DA reuptake inhibitors, namely bupropion and nomifensine. Drug-naive rats readily acquired and subsequently maintained consistent self-administration of 3 and 1 mg/kg/infusion doses of bupropion and nomifensine, respectively, during 2-hr daily sessions over a prolonged period. Similarly, self-administration responding at low doses of bupropion (0.75 and 1.5 mg/kg/infusion) and nomifensine (0.1 and 0.3 mg/kg/infusion) showed some consistency during the initial weeks of testing which gradually declined or tended to decline to levels similar to that of the water control group during the later weeks of testing. Bupropion self-administration dose-dependently up-regulated DA transporters in caudate putamen and nucleus accumbens. In contrast, nomifensine self-administration did not alter DA transporter levels. These data provide evidence for heterogeneity among DA reuptake inhibitors, with some of these drugs being able to up-regulate DA transporters after their self-administration, whereas others lack this neuroadaptive response.

Animals↗

PubMed1996

Differential reinforcing effects of cocaine and GBR-12909: biochemical evidence for divergent neuroadaptive changes in the mesolimbic dopaminergic system.

The dopamine (DA) transporter is thought to be the primary mediator of reinforcing effects of cocaine. In the present study, an intravenous drug self-administration procedure, in vitro autoradiography, and HPLC methods were used to investigate possible differences in reinforcing and neuroadaptive responses to cocaine versus GBR-12909, a selective inhibitor of the DA transporter with a postulated therapeutic use in cocaine abuse. Drug-naive rats readily acquired and subsequently maintained cocaine self-administration behavior during 2 hr daily sessions over a prolonged period. In contrast, although GBR-12909 was initially self-administered, both cocaine-naive and cocaine-trained rats failed to maintain self-administration behavior for GBR-12909 over prolonged periods of time. After self-administration responding decreased with GBR-12909, rats showed a delay of 6.6 +/- 1.3 sessions in reacquiring consistent cocaine self-administration. Moreover, when GBR-12909 was again substituted for cocaine, they failed to self-administer GBR-12909, even during the initial days of testing. In contrast, after extinction of self-administration responding by water substitution, rats readily self-administered both cocaine and GBR-12909. Cocaine self-administration upregulated DA transporters, whereas water-substituted cocaine withdrawal upregulated both DA transporters and D1 receptors. Unlike cocaine, GBR-12909 self-administration by itself altered neither DA transporters nor D1 or D2 receptors. Nevertheless, substitution of GBR-12909 for cocaine reversed the cocaine-induced upregulation of DA transporters and reduced DA and dihydroxyphenylacetic acid levels in the mesolimbic system. These data suggest that cocaine and GBR-12909 differentially affect dopaminergic systems and also cause different reinforcing and neuroadaptive effects. GBR-12909-like compounds may be useful pharmacotherapeutic agents for cocaine addiction. Upregulation of DA transporters and D1 receptors might play important roles in the neuroadaptive cascade that leads to cocaine addiction and withdrawal.

Adaptation, Physiological↗

PubMed1996

Nitric oxide is a mediator of methamphetamine (METH)-induced neurotoxicity. In vitro evidence from primary cultures of mesencephalic cells.

METH is a monoaminergic toxic that destroys dopamine terminals in vivo. Oxidative mechanisms associated with DA metabolism are thought to play an important role in its toxic effects. These ideas were supported by the demonstration that CuZn-superoxide dismutase (CuZnSOD) transgenic mice were protected against the toxic effects of the drug. In the present study, we sought to determine if nitric oxide (NO) production was also involved in METH-induced neurotoxicity using primary cultures obtained from fetal rat mesencephalon. METH caused dose- and time-dependent cell death in vitro. Blockade of nitric oxide (NO) formation with several nitric oxide (NO) synthase blockers attenuated METH-mediated toxicity. Moreover, inhibition of ADP-ribosylation with nicotinamide and benzamide also provided protection against the toxicity of the drug. These results, together with our previous results in transgenic mice, support a role for free radicals in METH-induced toxic effects.

Animals↗

PubMed1996

The dopamine-depleting effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in CD-1 mice are gender-dependent.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is a selective dopaminergic neurotoxin affecting the nigrostriatal system in a variety of species including, rodents, nonhuman primates and humans. There exists, however, a great deal of variability in the sensitivity of different species to the effects of MPTP. The present study was designed to determine whether a significant difference in gender susceptibility to the toxin in CD-1 mice might also exist. A dosing regiment of 30 mg/kg MPTP once a day for 3 days (90 mg/kg total dose) in 4-month-old male and female CD-1 mice led to a significant depletion of striatal dopamine in both sexes. Two way ANOVA analysis of a time-course generated by measuring striatal dopamine at 4, 12 and 24 h after each dose of MPTP revealed that the initial dopamine reduction is significantly greater in male CD-1 mice (P < 0.001). Further, dopamine levels were reduced to a greater extent in male mice 5 days after the last dose (31% vs. 59% of control; P < 0.02). HPLC analysis using fluorescence detection revealed no difference in the striatal nor the cerebellar levels of MPP+ between the two sexes, however, accumulation of larger amounts of MPP+ was observed in the livers of the female mice. These findings suggest that, while female CD-1 mice are more resistant to the dopamine-depleting effects of MPTP, this gender difference is not due to decreased or accumulation of striatal MPP+.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1996

Autoradiographic evidence for methamphetamine-induced striatal dopaminergic loss in mouse brain: attenuation in CuZn-superoxide dismutase transgenic mice.

Methamphetamine (METH) has long-lasting neurotoxic effects on the nigrostriatal dopamine (DA) system of rodents. METH-induced neurotoxicity is thought to involve release of DA in presynaptic DA terminals, which is associated with increased formation of oxygen-based free radicals. We have recently shown that METH-induced striatal DA depletion is attenuated in transgenic (Tg) mice that express the human CuZn-superoxide dismutase (SOD) enzyme. That study did not specifically address the issue of loss of DA terminals. In the present study, we have used receptor autoradiographic studies of [(125)I]RTI-121-labeled DA uptake sites to evaluate the effects of several doses of METH on striatal DA terminals of Non-Tg as well as of heterozygous and homozygous SOD-Tg mice. In Non-Tg mice, METH caused decreases in striatal DA uptake sites in a dose-dependent fashion. The loss of DA terminals was more prominent in the lateral region than in the medial subdivisions of the striatum. In SOD-Tg mice, the loss of DA terminals caused by METH was attenuated in a gene dosage-dependent fashion, with the homozygous mice showing the greatest protection. Female mice were somewhat more resistant than male mice against these deleterious effects of METH. These results provide further evidence for a role of superoxide radicals in the long-term effects of METH. They also suggest the notion of a gender-specific handling of oxidative stress.

Animals↗

PubMed1996

Chronic cocaine use as a neuropsychiatric syndrome: a model for debate.

In humans, chronic cocaine abuse is associated with changes in the central nervous system (CNS). Neuropathological changes include cerebrovascular events, EEG abnormalities, vasculitis, seizures, and decrements in neurobehavioral performance. The acute administration of cocaine is associated with acute psychotic episodes and paranoid states while withdrawal from the drug is often associated with depressed mood. The mechanistic basis of these behavioral states is not known. Given the structural and functional changes associated with cocaine use, we propose that the chronic heavy use of cocaine may result in a neuropsychiatric syndrome which might be associated with neuropsychological changes that are not obvious during routine clinical evaluation of drug-using individuals. This disconnection syndrome, because of its sublety, might have deleterious effects on both acute and long-term therapeutic interventions with these subjects. An approach which deals with cocaine abuse as a neuropsychiatric disorder might be more beneficial to the long-term goal of treating these patients. This approach entails a neurobehavioral evaluation which will be comprised of a thorough neurological and psychiatric examination, neuropsychological testing, and imaging studies. The results of this evaluation would provide a more rational basis for cognitive and/or pharmacological therapies.

Cocaine↗

PubMed1996

AP-1 DNA-binding activation by methamphetamine involves oxidative stress.

Methamphetamine (METH) caused dose-dependent increases in AP-1 DNA-binding activity in both nontransgenic (Non-Tg) and CuZn-SOD transgenic (SOD-Tg) mice. However, the increases in SOD-Tg mice were less prominent than those observed in Non-Tg animals. The time-course of METH-induced AP-1 changes was similar in both strains of mice. AP-1 binding activity showed an initial increase at 1 h, peaked at 3 h, and then gradually declined. AP-1 binding activity was back to normal by the 72-h time point. Regional analyses of METH effects revealed increases in the caudate putamen and cerebellum, with the striatum showing relatively higher METH-induced AP-1 DNA-binding activation. These regional effects were also attenuated in the SOD-Tg mice. These data indicate that METH-induced stimulation of AP-1 DNA-binding depends on cellular redox status. These results are consistent with in vitro studies that have reported that several transcription factors are regulated through redox mechanisms.

Animals↗