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Results for “Methamphetamine”

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PubMed1991

Changes in sensitivity of dopamine autoreceptors in rat striatum after subchronic treatment with methamphetamine.

To determine the functional alterations of the release modulating striatal dopamine (DA) autoreceptors that might be associated with the behavioral sensitization to methamphetamine after pretreatment with methamphetamine, we investigated the effect of apomorphine and sulpiride on electrically evoked DA release from striatal slices of rats pretreated with methamphetamine. Apomorphine induced a dose-dependent inhibition of the DA release evoked from the striatal slices. Pretreatment with methamphetamine (6 mg/kg per day for 9 days) significantly reduced the inhibitory effect of apomorphine. On the other hand, sulpiride caused a dose-dependent increase in the DA release evoked from the striatal slices. The enhancement by sulpiride of the evoked DA release was diminished by pretreatment with methamphetamine. These results show that pretreatment with methamphetamine blunts the responsiveness of evoked DA release to the DA antagonists as well as to the DA agonists, indicating that DA autoreceptor subsensitivity is produced by pretreatment with methamphetamine.

Animals↗

PubMed1993

Suppressive effect of cycloheximide on behavioral sensitization to methamphetamine in mice.

The effect of a protein synthesis inhibitor, cycloheximide, on behavioral sensitization to methamphetamine was investigated in mice. As indicated by the sensitization tests, repeated injection of methamphetamine (2 mg/kg i.p.) at intervals of 3 and 4 days resulted in a progressive augmentation of the locomotor-stimulating effect of methamphetamine. This phenomenon, called locomotor sensitization, was attenuated by simultaneous treatment with cycloheximide (120 mg/kg i.p.) at the time of stimulant injection. In contrast, when mice were treated with cycloheximide 4 h after stimulant injection, locomotor activity was progressively augmented in the same way as observed in mice receiving repeated injections of methamphetamine alone. On challenge, it was noted that locomotor activity was significantly higher in mice injected repeatedly with the stimulant alone and in those mice treated with the inhibitor 4 h after the stimulant injection compared to the saline-treated control mice. However, mice that had been simultaneously treated with cycloheximide and methamphetamine showed almost the same locomotor activity as the saline-treated control mice. These observations indicated that the locomotor sensitization to methamphetamine was possibly suppressed by simultaneous treatment with cycloheximide. We then examined the dose- and time-dependent nature of the effect of cycloheximide on locomotor sensitization. The stimulation of locomotion observed after repeated injection of the stimulant at a dose of 1.5 mg/kg was significantly attenuated by simultaneous treatment with 120 or 240 mg/kg of cycloheximide, but not by treatment with 60 mg/kg of the inhibitor. However, all the treatments failed to suppress the development of locomotor sensitization elicited by 3 mg/kg of methamphetamine.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Early post-treatment with haloperidol retards induction of methamphetamine sensitization in mice.

The repeated administration of methamphetamine (2 mg/kg s.c.) at 3- to 4-day intervals induced sensitization to its ambulation-increasing effect in mice. When the simultaneous administration of methamphetamine with haloperidol (0.025, 0.1 and 0.4 mg/kg s.c.) was carried out, the acute ambulation-increasing effect as well as the development of sensitization were haloperidol-dose-dependently inhibited. Moreover, treatment with haloperidol (0.1 and 0.4 mg/kg) 3 h following each methamphetamine administration, which per se did not affect the acute ambulation increase caused by methamphetamine, could protect against the induction of methamphetamine sensitization in a dose-dependent manner, whereas treatment with haloperidol after 24 h did not show such protective action. The present results suggest that blockade of the dopamine receptors at an early period following each administration of methamphetamine may be responsible for the delay in development of methamphetamine sensitization as expressed by ambulatory activity of mice.

Animals↗

PubMed1984

Effect of methamphetamine on rat spinal cord. Dopamine receptor-mediated depression of monosynaptic reflex.

The experiments were performed on spinal rats transected at Cl. Intravenous administration of methamphetamine-HCl (MA-HCl, 2 mg/kg) and apomorphine-HCl (5 mg/kg) reduced the amplitude of the monosynaptic reflex (MSR), while the polysynaptic reflex was increased by methamphetamine. Depression of the monosynaptic reflex by both drugs was antagonized by haloperidol, but not by phentolamine. Depression of the monosynaptic reflex by methamphetamine was not antagonized by pretreatment with reserpine; however, the result was explained by the assumption that methamphetamine releases newly-synthesized dopamine or that methamphetamine may act directly on dopamine receptors. Depression of the monosynaptic reflex induced by methamphetamine was independent of peripheral changes in blood pressure. Oxygen tension in the spinal cord was slightly reduced by methamphetamine in rats treated with phentolamine and a change of pO2 in the spinal cord was ruled out as a possible mechanism of action. These results suggest that dopaminergic neurons in the spinal cord of the rat depress the transmission of monosynaptic spinal reflexes.

Animals↗

PubMed1986

Nigrostriatal dopamine actions on the D2 receptors mediate methamphetamine effects on the striatonigral substance P system.

Multiple administrations of methamphetamine to rats produced elevated concentrations of substance P-like immunoreactivity within the substantia nigra, an effect which is believed to be mediated by increases in dopaminergic activity induced by methamphetamine. The results reported here demonstrate that the effect of methamphetamine is mediated specifically by the dopamine pathway in the nigrostriatum. Thus, extensive destruction of dopamine neurons in the nigrostriatum by lesions induced by 6-hydroxydopamine or blockade of synthesis of dopamine with alpha-methyl-p-tyrosine prevented the increases in substance P-like immunoreactivity in the nigra, induced by methamphetamine. Similarly, the concurrent administration of the D2 receptor antagonist, sulpiride, also prevented the effects of methamphetamine on substance P-like immunoreactivity in a dose-dependent way. In addition, multiple administrations of the D2 agonist, RU24926, elevated, whereas the DI agonist, SKF38393, decreased the content of substance P-like immunoreactivity in the nigra. The effects of methamphetamine were not altered in rats with lesions induced by 5,7-dihydroxytryptamine. Thus, these findings suggest that the effect of methamphetamine on the striatonigral substance P pathway is mediated by nigrostriatal dopaminergic actions on D2 receptors.

5,7-Dihydroxytryptamine↗

PubMed1993

Inhibitory effect of 4-phenyltetrahydroisoquinoline on locomotion and dopamine release induced by micro-injection of methamphetamine into the nucleus accumbens of the rat.

The inhibitory effects of 4-phenyl-1,2,3,4-tetrahydroisoquinoline (4-PTIQ) on methamphetamine-induced increases in dopamine and locomotion were investigated. Methamphetamine hydrochloride (10 micrograms) microinjected into the nucleus accumbens increased both locomotor activity and extracellular dopamine levels, measured by the brain microdialysis method. 4-PTIQ hydrochloride (20 micrograms) co-injected with methamphetamine inhibited both the increase in dopamine and the locomotor activity. The uptake blocker cocaine hydrochloride (20 micrograms) co-injected with methamphetamine failed to inhibit the effect of methamphetamine. Thus 4-PTIQ but not cocaine inhibited the dopamine-releasing effect of methamphetamine, and 4-PTIQ is suggested to block methamphetamine-induced locomotion by inhibition of dopamine release.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1995

Roles of dopamine D1 receptors in striatal fos protein induction associated with methamphetamine behavioral sensitization in rats.

To elucidate the roles of dopamine D1 and D2 receptors in mediating strial Fos protein induction and behavioral sensitization after methamphetamine administration, we examined the effects of the D1 receptor antagonist SCH 23390 and D2 receptor antagonist sulpiride on these phenomena in rats. Intraperitoneal administration of 5.0 mg/kg methamphetamine produced a significant increase in Fos-immunoreactive cells in the medial striatum. Prior exposure to 5.0 mg/kg methamphetamine enhanced ipsilateral rotational behavior in response to subsequent methamphetamine administration in unilateral nigral-lesioned rats (sensitization). Pretreatment with SCH 23390 (0.32 mg/kg IP) suppressed significantly the expression of striatal Fos protein and the development of acute behavioral sensitization following a single injection of 5.0 mg/kg methamphetamine. Sulpiride (50 mg/kg IP) was also effective in suppressing methamphetamine behavioral sensitization, but did not affect the striatal Fos induction. These results suggest that dopamine D1 receptor-mediated mechanisms are involved in the striatal Fos protein induction associated with behavioral sensitization following exposure to methamphetamine.

Animals↗

PubMed1984

A fatal methamphetamine poisoning associated with hyperpyrexia.

After self-administration of 0.05 g of methamphetamine hydrochloride intravenously on three occasions at intervals of 3 h, a 25-year-old female methamphetamine abuser ingested approximately 1.5 g of methamphetamine hydrochloride, and was found dead 3-4 h later. Complete rigor mortis was observed 1-2 h after death and the rectal temperature was 38.4 degrees C 3-4 h after death. Distribution of methamphetamine and amphetamine in the body was analyzed by chemical ionization mass fragmentography. Amphetamine/methamphetamine concentrations (mumol/100 g) were 0.26/28.8 in blood, 0.64/68.2 in brain, 0.96/117.1 in liver, 0.53/50.6 in kidney, and 1.49/1045 in stomach contents. Total amount of methamphetamine hydrochloride in stomach contents was 11.6 mg. Amphetamine in tissues was a metabolite of methamphetamine, and amphetamine in stomach contents resulted from excretion into saliva and gastric mucous excretion. With rectal temperature at death estimated at more than 41 degrees C, it would seem that hyperpyrexia played an important role in causing death from methamphetamine poisoning.

Adult↗

PubMed2006

Attentional control and brain metabolite levels in methamphetamine abusers.

BACKGROUND: Methamphetamine abuse is associated with neurotoxicity to frontostriatal brain regions with concomitant deleterious effects on cognitive processes. METHODS: By using a computerized measure of selective attention and single-voxel proton magnetic resonance spectroscopy, we examined the relationship between attentional control and brain metabolite levels in the anterior cingulate cortex (ACC) and primary visual cortex (PVC) in 36 currently abstinent methamphetamine abusers and 16 non-substance-using controls. RESULTS: The methamphetamine abusers exhibited reduced attentional control (i.e., increased Stroop interference) compared with the controls (p = .04). Bonferroni-adjusted comparisons revealed that ACC levels of N-acetyl aspartate (NAA)-creatine and phosphocreatine (Cr) were lower and that levels of choline (Cho)-NAA were higher in the methamphetamine abusers compared with the controls, at the adjusted p value of .0125. Levels of NAA-Cr, but not of Cho-NAA, within the ACC correlated with measures of attentional control in the methamphetamine abusers (r = -.41; p = .01) but not in controls (r = .22; p = .42). No significant correlations were observed in the PVC (methamphetamine abusers, r = .19; p = .28, controls, r = .38; p = .15). CONCLUSIONS: Changes in neurochemicals within frontostriatal brain regions including ACC may contribute to deficits in attentional control among chronic methamphetamine abusers.

Adult↗

PubMed2005

Attenuation of methamphetamine-induced behavioral sensitization in mice by systemic administration of naltrexone.

Repeated intermittent exposure to psychostimulants was found to produce behavioral sensitization. The present study was designed to establish a mouse model and by which to investigate whether opioidergic system plays a role in methamphetamine-induced behavioral sensitization. Mice injected with 2.5 mg/kg of methamphetamine once a day for 7 consecutive days showed behavioral sensitization after challenge with 0.3125 mg/kg of the drug on day 11, whereas mice injected with a lower daily dose (1.25 mg/kg) did not. Mice received daily injections with either 1.25 or 2.5 mg/kg of methamphetamine showed behavioral sensitization after challenge with 1.25 mg/kg of the drug on days 11, 21, and 28. To investigate the role of opioidergic system in the induction and expression of behavioral sensitization, long-acting but non-selective opioid antagonist naltrexone was administrated prior to the daily injections of and challenge with methamphetamine, respectively. Our results show that the expressions of behavioral sensitization were attenuated by pretreatment with 10 or 20 mg/kg of naltrexone either during the induction period or before methamphetamine challenge when they were tested on days 11 and 21. These results indicate that repeated injection with methamphetamine dose-dependently induced behavioral sensitization in mice, and suggest the involvement of opioid receptors in the induction and expression of methamphetamine-induced behavioral sensitization.

Amphetamine-Related Disorders↗

PubMed2006

Prefrontal dopamine efflux during exposure to drug-associated contextual cues in rats with prior repeated methamphetamine.

Conditioned stimulus-reward response and prefrontal dopamine efflux under context previously paired with methamphetamine administration were assessed in rats with or without prior sensitizing regimen. Sensitizing pretreatment was administered with methamphetamine (1mg/kg, every other day for six sessions) for behavioral sensitization. The animals received methamphetamine (1mg/kg) or saline injection (each for six sessions) to pair with distinct contexts on alternate days to induce conditioned place preference. Then, dopamine outflows in the medial prefrontal cortex were analyzed on the next day via microdialysis study as animals exposed to the methamphetamine or saline-paired context, respectively. Prefrontal DA efflux increased in those rats without sensitizing pretreatment, while they occupied the methamphetamine-paired chamber. The rats with prior sensitizing regimen demonstrated more robust conditioned place preference than those without pretreatment, however, their dopamine efflux was attenuated, while remaining in methamphetamine-paired context. It is suggested that the attenuated responsiveness of mesocortical dopamine transmission in prior sensitized rats may, at least in part, be responsible for their augmented conditioned place preference, which resulted from activation of related brain areas that together strengthen the associative learning to drug-related stimuli. This paradigm may reflect a dysregulated prefrontal function in the methamphetamine abusers.

Animals↗

PubMed2004

Neurocognitive performance of methamphetamine users discordant for history of marijuana exposure.

Abuse of the stimulant drug methamphetamine is associated with neural injury and neuropsychological (NP) deficits, while the residual effects of marijuana use remain uncertain. We sought to determine if methamphetamine dependent persons who also met criteria for marijuana abuse or dependence evidenced different NP performance than those with dependence for methamphetamine alone. We examined three groups that did not differ significantly on important demographic factors: (1) subjects with a history of methamphetamine dependence and history of marijuana abuse/dependence (METH+/MJ+, n=27); (2) methamphetamine dependent subjects without history of marijuana abuse/dependence (METH+/MJ-, n=26); (3) a control group with minimal or no drug use (n=41). A comprehensive NP battery was administered and performance was quantified for five cognitive ability areas. The METH+/MJ- group generally demonstrated the greatest NP impairment, with statistically significant differences observed between the METH+/MJ- and control group in learning, retention/retrieval, and a summary score of global NP performance. The METH+/MJ+ group did not differ significantly from the control or METH+/MJ- group on any NP ability. However, there was a significant linear trend in the global NP score suggesting that the METH+/MJ+ performed intermediate to the control and METH+/MJ- groups. Based on these findings, we cannot conclude that there is a protective effect of marijuana use in methamphetamine users; however, marijuana use clearly did not appear to exacerbate methamphetamine neurotoxicity. Further investigations are needed to determine if the emerging literature, suggesting that certain cannabinoids might have neuroprotective actions, is generalizable to community-dwelling substance abusers.

Adult↗

PubMed2004

Behavioral sensitization to the discriminative stimulus effects of methamphetamine in rats.

Sensitization to the discriminative stimulus effects of psychostimulants is not fully understood. Therefore, the present study was designed to investigate the development of sensitization to the discriminative stimulus of methamphetamine in rats. A dose-response curve for methamphetamine and a generalization test for cocaine were recorded in rats trained to discriminate between 1.0 mg/kg methamphetamine and saline. A significant leftward shift of the dose-response curve for methamphetamine and of the dose-generalization curve for cocaine was observed following repeated administration of methamphetamine (2.0 mg/kg) instead of saline. These findings suggest that repeated administration of methamphetamine can produce behavioral sensitization to the discriminative stimulus effects of methamphetamine in rats.

Animals↗

PubMed2006

Differential effects of methamphetamine and cocaine on behavior and extracellular levels of dopamine and 3,4-dihydroxyphenylalanine in the nucleus accumbens of conscious rats.

The central dopamine system plays a prominent role in the effect of psychostimulants such as methamphetamine, cocaine and nicotine. l-3,4-Dihydroxyphenylalanine (DOPA), a precursor of dopamine, has been proposed as a neurotransmitter in the central nervous system. We have studied the effects of these psychostimulants on the release of DOPA and dopamine from the nucleus accumbens shell in conscious rats using in vivo microdialysis. Methamphetamine and cocaine increase the extracellular levels of dopamine. The effect of methamphetamine (1 mg/kg s.c.) on the release of dopamine was almost comparable to that of cocaine (10 mg/kg i.p.). However, methamphetamine increases, but cocaine decreases the extracellular levels of DOPA. In a behavioral study, methamphetamine (1 mg/kg s.c.) induced chewing, walking and sniffing behavior. Cocaine (10 mg/kg i.p.) produces weak effects on these behavioral parameters, when compared to the effects of methamphetamine (1 mg/kg s.c.). The behavioral changes produced by methamphetamine are suppressed by DOPA cyclohexyl ester (30 mg/kg i.p.), a competitive DOPA antagonist. Endogenous DOPA in the nucleus accumbens thus appears to be in involved in the behavioral responses to these psychomotor stimulants.

Animals↗

PubMed2006

Identification of N,N-dimethylamphetamine formed by methylation of methamphetamine in formalin-fixed liver tissue by multistage mass spectrometry.

Methamphetamine is methylated in the presence of unbuffered formalin solutions within hours at room temperature. The product, N,N-dimethylamphetamine, is also found in human liver exposed to methamphetamine followed by incubation with formalin. In the present study, a direct mass spectrometric method was developed to identify N,N-dimethylamphetamine in human liver before and after treatment with formalin. Human liver samples were obtained from four deaths that were investigated by the West Virginia Office of Chief Medical Examiner. Full toxicological analysis was conducted on samples from the decedents and methamphetamine was among the positive findings in each case. The method used to expose liver tissue to formaldehyde involved treating a small piece of liver from each case with formalin solution (20% v/v) for 24 h at room temperature. The formalin treated tissues were homogenized and the resulting suspension was sonicated for 5 min, and then centrifuged. Supernatant aliquots were directly analyzed by electrospray ionization (ESI) mass spectrometry without chromatographic isolation. Positive ion multistage mass spectra recorded in MS, MS/MS and MS/MS/MS (MS3) modes were used to confirm the presence of N,N-dimethylamphetamine and methamphetamine in the mixture. Liver tissue not treated with formalin did not contain a detectable level of N,N-dimethylamphetamine. Decreases in methamphetamine concentrations in liver tissue resulting from treatment with formalin were measured using deuterium-labeled methamphetamine as internal standard. The method can be completed in less than 2 h on thawed tissue. The results suggest that the process of fixing tissues with formalin may lead to false negative findings for methamphetamine.

Adult↗

PubMedDate not supplied

Behavioral and growth effects induced by low dose methamphetamine administration during the neonatal period in rats.

The investigation of methamphetamine exposure during neonatal development in rats has demonstrated that long-term spatial learning deficits are induced. A previous dose-response study showed that administration of 5 mg/kg methamphetamine, four times daily from postnatal days 11 to 20 produced these deficits, although the effects were not as severe as at higher doses of 10 or 15 mg/kg. This study examined concentrations of methamphetamine at or below 5mg/kg given over the same period of time. Five different concentrations of methamphetamine (i.e., 5, 2.5, 1.25, 0.625, or 0) were administered every 2 h four times daily from postnatal days 11 to 20. Body weights, zero maze performance, and Morris water maze learning were examined. A dose-dependent decrease in body weight was observed during the period of methamphetamine administration and these lower weights continued throughout adulthood for the 5, 2.5, and 1.25 mg/kg concentrations, although the adult decreases were negligible. No differences were noted in the zero maze. In the Morris water maze during the acquisition period, dose-dependent differences in spatial orientation were seen, however non-dose related deficits were observed for other parameters. During the shifted platform phase ("reversal"), a similar dose-dependent difference in spatial orientation was observed, although no other effects were noted during this phase. Females performed worse than males regardless of treatment or the phase of learning in the Morris water maze. These data suggest that even lower doses of methamphetamine can alter learning and memory in adulthood, although with less consistent results than with doses higher than 5 mg/kg/dose. These data would caution against even casual use of methamphetamine by women during pregnancy since even low doses could alter the ability of the child to learn.

Aging↗

PubMed2006

Methamphetamine-related sudden death with a concentration which was of a 'toxic level'.

We reviewed 32 cases where a forensic autopsy detected methamphetamine in the blood, and all of these autopsies were performed at two institutes between 1991 and 2003. In accordance with several criteria, the blood concentration in 11 cases was classified as above the toxic level, and 10 of these cases were diagnosed as methamphetamine poisoning. In 20 cases (62.5% of total cases), the blood concentration was of a 'toxic level', and 10, 2 and 1 of these cases were diagnosed as methamphetamine poisoning, cardiomyopathy and intracerebral hemorrhage, respectively. Since it is unclear how the effects of methamphetamine may contribute to the death of an individual, a diagnosis of the exact cause of death is often difficult to make in cases where the blood concentration of methamphetamine was of a 'toxic level'. Therefore, a diagnosis has to be carefully made in consideration of the pathological findings, the pharmacological effects of methamphetamine and the process until death in such cases. Additionally, the mechanism of methamphetamine-related death needs to be more fully studied to enable an appropriate diagnosis to be made easily.

Adult↗

PubMed2005

Methamphetamine and human immunodeficiency virus protein Tat synergize to destroy dopaminergic terminals in the rat striatum.

Dysfunction of the dopaminergic system accompanied by loss of dopamine in the striatum is a major feature of human immunodeficiency virus-1-associated dementia. Previous studies have shown that human immunodeficiency virus-1-associated dementia patients with a history of drug abuse have rapid neurological progression, prominent psychomotor slowing, more severe encephalitis and more severe dendritic and neuronal damage in the frontal cortex compared with human immunodeficiency virus-1-associated dementia patients without a history of drug abuse. In a previous study, we showed that methamphetamine and human immunodeficiency virus-1 protein Tat interact to produce a synergistic decline in dopamine levels in the rat striatum. The present study was carried out to understand the underlying cause for the loss of dopamine. Male Sprague-Dawley rats were administered saline, methamphetamine, Tat or Tat followed by methamphetamine 24 h later. Two and seven days later the animals were killed and tissue sections from striatum were processed for silver staining to examine terminal degeneration while sections from striatum and substantia nigra were processed for tyrosine hydroxylase immunoreactivity. Striatal tissue was also analyzed by Western blotting for tyrosine hydroxylase protein levels. Compared with controls, methamphetamine+Tat-treated animals showed extensive silver staining and loss of tyrosine hydroxylase immunoreactivity and protein levels in the ipsilateral striatum. There was no apparent loss of tyrosine hydroxylase in the substantia nigra. Markers for oxidative stress were significantly increased in striatal synaptosomes from Tat+methamphetamine group compared with controls. The results indicate that methamphetamine and Tat interact to produce an enhanced injury to dopaminergic nerve terminals in the striatum with sparing of the substantia nigra by a mechanism involving oxidative stress. These findings suggest a possible mode of interaction between methamphetamine and human immunodeficiency virus-1 infection to produce enhanced dopaminergic neurotoxicity in human immunodeficiency virus-1 infected/methamphetamine-abusing patients.

3,4-Dihydroxyphenylacetic Acid↗