Biomedical subjects

J L Cadet

Publications and source records attributed to J L Cadet.

At least 55 records · Page 3Linked to original sources

PubMed1999

Reversal by [D-Ala2,D-Leu5]enkephalin of the dopamine transporter loss caused by methamphetamine.

A single administration of 40 mg/kg (i.p.) of methamphetamine caused a loss of dopamine transporter in the striatum of albino Swiss (CD-1) mouse for at least 3 weeks. The administration of a single dose of [D-Ala2,D-Leu5]enkephalin (DADLE) (18 mg/kg, i.p.), given at day 14 after the administration of methamphetamine, caused a significant, transient restoration of dopamine transporter level in the striatum. These results suggest that delta-opioid peptide DADLE is able to reverse the neuronal damage caused by methamphetamine.

Animals↗

PubMed1999

Neuroadaptations in the dopaminergic system after active self-administration but not after passive administration of methamphetamine.

Methamphetamine is a strong and long-lasting stimulant that can be easily synthesized and is effective when taken either orally, intravenously, or smoked as 'ice'. Due to it's escalating abuse, a clear need exists for laboratory procedures to evaluate motivational components of methamphetamine abuse and their underlying neurobiological mechanisms. In the present experiment, we utilized a 'yoked' procedure in which rats were run simultaneously in groups of three, with two rats serving as yoked controls which received an injection of either 0.1 mg/kg methamphetamine or saline which was not contingent on responding each time a response-contingent injection of 0.1 mg/kg methamphetamine was self-administered by the third paired rat. Rats that had actively self-administered methamphetamine for 5 weeks and were then withdrawn from methamphetamine for 24 h showed marked decreases in somatodendritic dopamine D2 autoreceptors levels in the ventral tegmental area (34%) and medial (31%) and dorsal (21%) part of the substantia nigra zona compacta with a corresponding down-regulation of dopamine D1 receptors in the shell of the nucleus accumbens (15%), as measured by in vitro quantitative autoradiography. Since the decreases in levels of dopamine D1 and D2 receptors which occurred in rats self-administering methamphetamine did not occur in littermates that received either yoked injections of methamphetamine or saline, these changes likely reflect motivational states that were present when methamphetamine injection depended on active drug self-administration behavior.

Animals↗

PubMed1999

[D-Ala2, D-Leu5]enkephalin blocks the methamphetamine-induced c-fos mRNA increase in mouse striatum.

The administration of methamphetamine caused an increase of c-fos mRNA in the striatum of the mouse. A systemic injection of the delta-opioid receptor agonist, [D-Ala2, D-Leu5]enkephalin (DADLE), attenuated the c-fos mRNA increase induced by methamphetamine. These results suggest that endogenous delta-opioid peptides might counteract certain genomic influences exerted by psychostimulants such as methamphetamine.

Animals↗

PubMed1999

Chronic exposure to antibodies directed against anti-opiate peptides alter delta-opioid receptor levels.

The development of addictive states in response to chronic opioid use may be regulated partially by the release of endogenous peptides. These anti-opiate peptides (AOP) are secreted or released into the CNS and produce diverse actions that counterbalance the effects of prolonged opiate exposure. Though the mechanism(s) by which these peptides exert their physiological properties remain largely unknown, there is some indication that AOP's modulate opioid receptor levels. In this study, we investigated the effects of chronically infused alpha-melanocyte stimulating hormone (alpha-MSH), dynorphin(1-8) (DYN(1-8)), dynorphin A (DYNA), and NPFF antibodies on delta-opioid receptor expression in rat brains. Quantitative autoradiographic experiments revealed that antibodies directed against alpha-MSH and DYNA produced significant increases in delta receptor levels in the caudate, claustrum, and cingulate cortex of the rat brain. Conversely, NPFF monoclonal antibodies caused significant decreases in the caudate, nucleus accumbens, olfactory tubercle, and cingulate cortex. These results suggest that the density of delta-opioid receptors is affected by changes in the levels of the anti-opioid peptides in the extracelluar fluid in the rat brain.

Animals↗

PubMed1999

Overexpression of human copper/zinc superoxide dismutase in transgenic mice attenuates oxidative stress caused by methylenedioxymethamphetamine (Ecstasy).

Administration of 3,4-methylenedioxymethamphetamine (4 x 20 mg/kg) to non-transgenic CD-1 mice caused marked depletion in dopamine, 3,4-dihydroxyphenylacetic acid and 5-hydroxytryptamine in the caudate-putamen. There were no significant changes in serotonergic markers in the hippocampus and frontal cortex. Homozygous and heterozygous copper/zinc superoxide dismutase transgenic mice show partial protection against the toxic effects of 3,4-methylenedioxymethamphetamine on striatal dopaminergic markers. In addition, 3,4-methylenedioxymethamphetamine injections caused marked decreases in copper/zinc superoxide dismutase activity in the frontal cortex, caudate-putamen and hippocampus of wild-type mice. Moreover, there were concomitant 3,4-methylenedioxymethamphetamine-induced decreases in catalase activity in the caudate-putamen and hippocampus, decreases in glutathione peroxidase activity in the frontal cortex as well as increases in lipid peroxidation in the frontal cortex, caudate-putamen, and hippocampus of wild-type mice. In contrast, administration of 3,4-methylenedioxymethamphetamine to homozygous superoxide dismutase transgenic mice caused no significant changes in antioxidant enzyme activities nor in lipid peroxidation. These results provide further substantiation of a role for oxygen-based radicals in 3,4-methylenedioxymethamphetamine-induced neurotoxicity. The present data also suggest that free radicals generated during 3,4-methylenedioxymethamphetamine administration may perturb antioxidant enzymes. Consequently, there might be further overproduction of free radicals with associated peroxidative damage to cell membranes and associated terminal degeneration.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1999

Neurovascular deficits in cocaine abusers.

The nature of the neurological and cerebrovascular deficits in cocaine abusers and whether they persist in abstinence is unclear. Blood flow velocity of the anterior and middle cerebral arteries was measured by transcranial Doppler sonography in cocaine abusers (n = 50) and control subjects (n = 25). Blood flow velocity was measured within 3 days and again after about 28 days after being admitted to an inpatient research ward to determine whether blood flow velocity improved during monitored abstinence conditions. The mean, systolic, and diastolic velocities as well as the pulsatility index in middle and anterior cerebral arteries significantly differed between controls and cocaine abusers (p < .05). Cerebrovascular resistance is increased in cocaine abusers and the increase persists for over a month of abstinence. Further research is needed to determine whether cerebrovascular resistance can be improved by pharmacological manipulations and whether improved blood flow relates to improved treatment outcome.

Adult↗

PubMed1999

The regulation of cerebral blood flow during intravenous cocaine administration in cocaine abusers.

Cocaine abuse is associated with heightened risk of life-threatening neurological complications such as strokes, seizures, and transient ischemic attacks. We used transcranial Doppler (TCD) sonography, a continuous measure of cerebral blood flow velocity, to better understand the changes in cerebral hemodynamics produced by cocaine administration, which may lead to an increased risk for stroke in cocaine abusers. Heart rate and blood pressure were also measured. Blood flow velocity of seven cocaine abusers was studied during placebo, 10-, 25-, and 50-mg intravenous (i.v.) injections of cocaine. A significant increase in mean and systolic velocity which lasted for about two minutes was observed with all doses of cocaine, with no change in the placebo condition. This increase in systolic velocity indicates that cocaine produces an immediate and brief period of vasoconstriction in large arteries of the brain. The present results elucidate the time course of cocaine's acute cerebrovascular effects and provide a better understanding of etiology of cocaine-related stroke and transient ischemic attacks.

Adult↗

PubMed1999

Dose-related neurobehavioral effects of chronic cocaine use.

Although cocaine use is a significant public health problem, there is a paucity of scientific data on long-term neurobehavioral effects. This study examined the dose-related association between chronic cocaine use and neurobehavioral performance. A battery of neuropsychological tests was administered to 30 abstinent chronic cocaine abusers and 21 non-drug-using control subjects matched for age, education, and intelligence. After controlling for age, education, and intellectual ability, greater use of cocaine (grams per week) was associated with larger decrements on tests measuring executive functioning, visuoperception, psychomotor speed, and manual dexterity. These results suggest that chronic cocaine use is associated with persistent decrements in cognitive function that are most pronounced in heavy users. Knowledge of specific cognitive processing deficits in chronic cocaine users would be useful for designing individually tailored drug treatment programs.

Adult↗

PubMed1999

Relative rates of AIDS among racial/ethnic groups by exposure categories.

The relative rates of acquired immunodeficiency syndrome (AIDS) were calculated among racial/ethnic populations using Centers for Disease Control and Prevention HIV (human immunodeficiency virus)/Surveillance reports assuming that racial/ethnic distributions reflect that of the US Census Data from 1990. For comparison, a rate of 1 was assigned to whites in each calculation. The overall relative rates were whites--1, African Americans--4.7, Hispanics--3, Asian/Pacific Islanders--0.4, and Native Americans--0.5. Acquired immunodeficiency syndrome surveillance data show higher rates of AIDS for African Americans and Hispanics compared with whites, Asians/Pacific Islanders, and Native Americans. The relative rates for African Americans and Hispanics compared with whites were highest for injecting drug users, heterosexual contact, and pediatric patients. These results led us to explore possible explanations for increased AIDS reporting in African Americans and Hispanics. We then explored available national datasets regarding those variables. The analyses indicate that variables such as access and receptivity to HIV prevention and treatment efforts, race/ethnicity, sexual behaviors, sexually transmitted diseases, socioeconomic status, and substance abuse interact in a complex fashion to influence HIV transmission and progression to AIDS in affected communities.

Acquired Immunodeficiency Syndrome↗

PubMed1998

Methamphetamine-induced increase in striatal NF-kappaB DNA-binding activity is attenuated in superoxide dismutase transgenic mice.

Methamphetamine injection (x4 with 2-h interval) caused dose-dependent activation of striatal NF-kappaB activity. Striatal NF-kappaB binding increased significantly at 1-3 h after the last injection of methamphetamine (10 mg/kg, i.p. x4). This induction of striatal NF-kappaB activity was significantly attenuated in Cu, Zn-superoxide dismutase transgenic mice in a gene dosage-dependent fashion. The present results suggest that reactive oxygen species generated by methamphetamine injections can activate striatal NF-kappaB DNA-binding during this drug-induced toxic process.

Animals↗

PubMed1998

Superoxide radicals are mediators of the effects of methamphetamine on Zif268 (Egr-1, NGFI-A) in the brain: evidence from using CuZn superoxide dismutase transgenic mice.

Administration of methamphetamine (METH) to mammals is known to cause deleterious effects to brain monoaminergic systems. These toxic effects are thought to be due to oxidative stress. Acute administration of METH causes activation of immediate-early genes (IEGs) such as c-fos and Zif268 mRNA in rodent brains. However, the exact mechanisms involved in these changes have not been completely clarified. As a first step towards assessing a possible role for free radicals in METH-induced changes in IEGs, we have used CuZn superoxide dismutase (SOD) transgenic (Tg) mice and have quantified the effects of METH on c-fos and Zif268 mRNAs by in situ hybridization techniques. Mice were injected with 25 mg/kg of METH and sacrificed at various time points afterwards. There were significant METH-induced increases in both c-fos and Zif268 mRNAs in the frontal cortex and striatum of both strains of animals. Interestingly, the increases in Zif268 were markedly attenuated in the CuZn SOD-Tg mice; the increases in c-fos were also attenuated, but to a significantly lesser degree. These results indicate that superoxide radicals might play an important role in the activation of Zif268 after METH administration. Because IEGs are modulators of gene expression, these results also raise the possibility that oxidative mechanisms might be important factors in neuroadaptive changes caused by stimulant drugs.

Animals↗

PubMed1998

Methamphetamine-induced changes in antioxidant enzymes and lipid peroxidation in copper/zinc-superoxide dismutase transgenic mice.

The present study was conducted to investigate the effects of methamphetamine (METH)-induced toxicity on brain cortical and striatal antioxidant defense systems. Because METH-induced toxicity is attenuated in copper/zinc-superoxide dismutase transgenic (Cu/Zn-SOD-Tg) mice, we sought to determine if METH had differential effect on antioxidant enzymes on these mice in comparison to non-Tg mice. METH (4 x 1) mg/kg) induced a significant decrease in Cu/Zn-SOD activity in the cortical region without altering striatal enzymatic activity in non-Tg mice; whereas homozygous SOD-Tg mice showed a significant increase in the striatum. In addition, METH caused decrease in catalase (CAT) activity in the striatum of non-Tg mice and significant increase in the cortex of homozygous SOD-Tg mice. METH also induced decreases in glutathione peroxidase (GSH-Px) in both cortical and striatal regions of non-Tg mice and in the striatum of heterozygous SOD-Tg mice. Lipid peroxidation was increased in both cortices and striata of non-Tg and heterozygous SOD-Tg, mice, whereas the homozygous SOD-Tg mice were not affected. These results are discussed in terms of their substantiation of a role for oxygen-based radicals in METH-induced toxicity in rodents.

Animals↗

PubMed1998

Effects of toxic doses of methamphetamine (METH) on dopamine D1 receptors in the mouse brain.

Methamphetamine (METH) is a drug of abuse that causes marked DA depletion in the mammalian dopaminergic systems. These are characterized by marked decreases in presynaptic markers including dopamine (DA) levels and DA transporters. Very little research has been carried out to evaluate possible postsynaptic effects of this drug. In the present study, we assessed the status of METH on striatal DA D1 receptors labeled with [3H]SCH23390 after toxic doses of METH that were shown to cause marked depletion of various markers of presynaptic DA systems in mice [J. Neurochem. 69 (1997) 780]. Our results show that these doses of METH caused 30% decrease in striatal DA D1 receptors. In contrast, p53 knockout mice that show protection against the toxic effects of METH show no significant decreases in DA D1 receptors. These results suggest that toxic doses of METH that cause loss of presynaptic DA markers might also affect postsynaptic elements. We discuss the possibility that these changes might be secondary to toxic effects of METH on intrinsic striatal cell bodies.

Animals↗

PubMed1998

Melatonin attenuates methamphetamine-induced toxic effects on dopamine and serotonin terminals in mouse brain.

Methamphetamine (METH) is a drug of abuse that causes deleterious effects to brain monoaminergic systems. These toxic effects are thought to be due to oxidative stress. The pineal hormone, melatonin, has been shown to have neuroprotective effects against toxic quinones and oxidative stress produced by catecholamines. The present study was thus undertaken to assess possible protective effects of melatonin against METH-induced neurotoxic effects on the striatum and the nucleus accumbens by using autoradiographic techniques. Four dosages (5, 20, 40, 80 mg/kg) of melatonin were administered to mice intraperitoneally 30 minutes prior to the injections of METH (4 x 5 mg/kg) given at 2-hour intervals. The lowest doses of melatonin (5 mg/kg) had no significant effects against METH-induced toxicity. However, the higher doses (40 or 80 mg/kg) of melatonin significantly attenuated METH-induced toxic effects on both dopamine and serotonin systems. These data provide further evidence for a possible role of oxidative stress in METH-induced toxicity.

Animals↗

PubMed1998

Regulation of mu binding sites after chronic administration of antibodies directed against specific anti-opiate peptides.

There is some indication that anti-opiate peptides (AOP) modulate opioid receptor systems by altering mu-receptor density. To further characterize this phenomenon, we investigated the effects of continuous infusion of anti-AOP IgG on mu binding sites in the brains of rats. Specifically, male Sprague-Dawley rats received intracerebroventricular (i.c.v.) infusions for 13 days of either control (rabbit) IgG or test IgGs: anti-dynorphin A IgG, anti-dynorphin A1-8 IgG, anti-alpha-MSH IgG, or the monoclonal anti-NPFF IgG. Administration of anti-NPFF IgG or the anti-dynorphin1-8 IgG significantly increased mu labeling by 40-70% in several brain regions at the caudate level. Contrary to these findings, anti-alpha-MSH IgG decreased (19-32%) [125I]-DAMGO labeling in several thalamic nuclei. The results suggest that the density of mu-opioid receptors is regulated in part by anti-opiate peptides in the extracellular fluid of the brain.

Animals↗

PubMed1998

Free radicals and the pathobiology of brain dopamine systems.

Oxygen is an essential element for normal life. However, reactive oxygen species (ROS) can also participate in deleterious reactions that can affect lipid, protein, and nucleic acid. Normal physiological function thus depends on a balance between these ROS and the scavenging systems that aerobic organisms have developed over millennia. Tilting of that balance towards a pro-oxidant state might result from both endogenous and exogenous causes. In the present paper, we elaborate on the thesis that the neurodegenerative effects of two drugs, namely methamphetamine (METH, ICE) and methylenedioxymethamphetamine (MDMA, Ecstasy) are due to ROS overproduction in monoaminergic systems in the brain. We also discuss the role of oxygen-based species in 6-hydroxydopamine (6-OHDA)-induced nigrostriatal dopaminergic degeneration and in Parkinson's disease. Studies are underway to identify specific cellular and molecular mechanisms that are regulated by oxygen species. These studies promise to further clarify the role of oxidative stress in neurodegeneration and in plastic changes that occur during the administration of addictive agents that affect the brain.

Animals↗

PubMed1998

Attenuation of 6-hydroxydopamine-induced dopaminergic nigrostriatal lesions in superoxide dismutase transgenic mice.

6-Hydroxydopamine is a neurotoxin that produces degeneration of the nigrostriatal dopaminergic pathway in rodents. Its toxicity is thought to involve the generation of superoxide anion secondary to its autoxidation. To examine the effects of the overexpression of Cu,Zn-superoxide dismutase activity on 6-hydroxydopamine-induced dopaminergic neuronal damage, we have measured the effects of 6-hydroxydopamine on striatal and nigral dopamine transporters and nigral tyrosine hydroxylase-immunoreactive neurons in Cu,Zn-superoxide dismutase transgenic mice. Intracerebroventricular injection of 6-hydroxydopamine (50 microg) in non-transgenic mice produced reductions in the size of striatal area and an enlargement of the cerebral ventricle on both sides of the brains of mice killed two weeks after the injection. In addition, 6-hydroxydopamine caused marked decreases in striatal and nigral [125I]RTI-121-labelled dopamine transporters not only on the injected side but also on the non-injected side of non-transgenic mice; this was associated with decreased cell number and size of tyrosine hydroxylase-immunoreactive dopamine neurons in the substantia nigra pars compacta on both sides in these mice. In contrast, superoxide dismutase transgenic mice were protected against these neurotoxic effects of 6-hydroxydopamine, with the homozygous transgenic mice showing almost complete protection. These results provide further support for a role of superoxide anion in the toxic effects of 6-hydroxydopamine. They also provide further evidence that reactive oxygen species may be the main determining factors in the neurodegenerative effects of catecholamines.

Animals↗

PubMed1998

Smaller volume of prefrontal lobe in polysubstance abusers: a magnetic resonance imaging study.

The present study was conducted to test the hypothesis that individuals with substance abuse disorder exhibit structural deficits in the prefrontal cortex. Volumes of the prefrontal lobe in subjects with histories of polysubstance abuse (n = 25) were measured and compared with those in normal volunteers (n = 14), using high-resolution volumetric magnetic resonance imaging (MRI). The research participants were men, 22 to 41 years of age. Polysubstance abusers were abstinent from drugs of abuse (except nicotine) for at least 15 days before MRI scanning. The total volumes of the prefrontal lobe (left and right hemispheres) were significantly smaller in the substance abuse group than in the control group. When the prefrontal lobe was segmented for gray and white matter, the deficit in the substance abusers was seen as significantly smaller volumes of gray but not of white matter. These results indicate that hypoplasia and/or atrophy in the prefrontal cortex accompany substance abuse and suggest that structural deficits in the prefrontal cortex may play an essential role in the neuropathological basis of functional impairments in substance abuse disorder, as demonstrated by functional brain imaging and cognitive studies.

Adult↗