SEARCH · PubMed Health

Results for “Methamphetamine”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 73 records · Page 4Linked to original sources

PubMed2001

Long-term effects of a high-dose methamphetamine regimen on subsequent methamphetamine-induced dopamine release in vivo.

Rats were treated with a high-dose methamphetamine (METH) regimen (40 mg/kg/injection, four times at 2-h intervals) or a saline regimen (four injections at 2-h intervals). Temperature related measures taken during the high-dose METH treatment were maximum core temperature and minimum chamber temperature. Fourteen rats (METH N=7; Saline N=7) were implanted with in-vivo dialysis probes 4-7 weeks post-regimen (average=6 weeks). The next day, they received a challenge dose of METH (4.0 mg/kg) and dopamine release was measured. Results showed a significant decrease in challenge-induced dopamine release in rats previously treated with the high-dose METH regimen. These findings demonstrate a functional deficit in the dopamine system 6 weeks after high-dose METH treatment. Temperature-related measures taken during the high-dose regimen were not correlated with METH-induced dopamine release 6 weeks later. An additional group of rats were sacrificed 6 weeks after the high-dose regimen (METH N=12; Saline N=10), and their brains was analyzed for dopamine and serotonin concentrations. Tissue concentrations of dopamine were significantly depleted in striatum and nucleus accumbens/olfactory tubercle, but not septum, hypothalamus, or ventral mid-brain 6 weeks after the high-dose regimen. Tissue concentrations of serotonin were also significantly depleted in striatum, nucleus accumbens/olfactory tubercle, hippocampus, somatosensory cortex, but not septum, hypothalamus or ventral mid-brain. Significant correlations between the temperature-related measures and post-mortem neurotransmitter tissue concentrations were region and transmitter dependent.

Animals↗

PubMed1997

Tolerance to the neurotoxic effect of methamphetamine in rats behaviorally sensitized to methamphetamine or amphetamine.

A series of experiments was conducted to examine whether rats behaviorally sensitized to methamphetamine (MA) would show supersensitivity or tolerance to the MA-induced neurotoxic effects on dopaminergic and serotonergic nerve terminals in the striatum (ST), nucleus accumbens (NA) and medial frontal cortex (MFC). Moderate to high doses of MA (3, 4 and 5 mg HCl salt/kg, s.c., at 2 h intervals, four injections) dose-relatedly decreased the contents of dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in ST, and the content of 5-HIAA in NA and that of 5-HT in MFC. These neurotoxic effects in ST were significantly attenuated in rats behaviorally sensitized to MA (4 mg HCl salt/kg, s.c., for 10 days). To examine the possibility that the attenuation in the toxic effects in sensitized rats was due to an accelerated metabolism from MA to amphetamine (AMPH), a high dose of MA (5 mg HCl salt/kg, s.c., at 2 h intervals, four injections) was administered to rats behaviorally sensitized to AMPH (4 mg HCl salt/kg, s.c., for 10 days). It was revealed that the MA-induced decrease in the striatal contents of DOPAC, homovanillic acid (HVA), 5-HT and 5-HIAA were attenuated in rats behaviorally sensitized to AMPH. The MA-induced decrease in the striatal DA content tended to be attenuated in AMPH-sensitized rats. These data suggest that rats behaviorally sensitized to MA or AMPH develop tolerance to MA-induced striatal dopaminergic and serotonergic neurotoxicity. It is speculated that the mechanism of tolerance might be mediated by an altered central response rather than peripheral metabolism.

Amphetamine↗

PubMed1998

Effect of melatonin on methamphetamine- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurotoxicity and methamphetamine-induced behavioral sensitization.

Methamphetamine (METH)- and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurotoxicity is thought to be associated with the formation of free radicals. Since evidence suggests that melatonin may act as a free radical scavenger and antioxidant, the present study was undertaken to investigate the effect of melatonin on METH- and MPTP-induced neurotoxicity. In addition, the effect of melatonin on METH-induced locomotor sensitization was investigated. The administration of METH (5 mg kg(-1) x 3) or MPTP (20 mg kg(-1) x 3) to Swiss Webster mice resulted in 45-57% depletion in the content of striatal dopamine and its metabolites, 3,4-dihydroxyphenylacetic acid and homovanillic acid, and 57-59% depletion in dopamine transporter binding sites. The administration of melatonin (10 mg kg(-1)) before each of the three injections of the neurotoxic agents (on day 1), and thereafter for two additional days, afforded a full protection against METH-induced depletion of dopamine and its metabolites and dopamine transporter binding sites. In addition, melatonin significantly diminished METH-induced hyperthermia. However, the treatment with melatonin had no significant effect on MPTP-induced depletion of the dopaminergic markers tested. In the set of behavioral experiments, we found that the administration of 1 mg kg(-1) METH to Swiss Webster mice for 5 days resulted in marked locomotor sensitization to a subsequent challenge injection of METH, as well as context-dependent sensitization (conditioning). The pretreatment with melatonin (10 mg kg(-1)) prevented neither the sensitized response to METH nor the development of conditioned locomotion. Results of the present study indicate that melatonin has a differential effect on the dopaminergic neurotoxicity produced by METH and MPTP. Since it is postulated that METH-induced hyperthermia is related to its neurotoxic effect, while regulation of body temperature is unrelated to MPTP-induced neurotoxicity or METH-induced locomotor sensitization, the protective effect of melatonin observed in the present study may be due primarily to diminishing METH-induced hyperthermia.

Animals↗

PubMed2002

Methamphetamine-induced dopaminergic neurotoxicity in mice: long-lasting sensitization to the locomotor stimulation and desensitization to the rewarding effects of methamphetamine.

High doses of methamphetamine (METH) cause the depletion of striatal dopaminergic markers; however, little is known about the behavioral consequences of METH-induced neurotoxicity. In the present study, the authors investigated the effect of a neurotoxic dose of METH (5 mg/kg; every 3 h x3) on the subsequent response of Swiss Webster mice to (a) the psychomotor-stimulating effect of METH and (b) the acquisition and maintenance of conditioned place preference (CPP) by METH. The latter is a paradigm for the assessment of the rewarding properties of abused substances. The administration of the high dose of METH resulted in significant depletion of dopamine (DA) and its metabolites and dopamine transporter (DAT) binding sites in the striatum. The dopaminergic markers were below control levels until the 95th day after METH administration. METH-pretreated mice were sensitized to the psychomotor-stimulating effect of METH (1 mg/kg) as determined on Days 3 and 74 after the initial exposure to the neurotoxic dose of METH. However, the acquisition of CPP by METH (0.5 mg/kg) was markedly reduced in the mice pretreated with the neurotoxic dose of METH compared with the control group. The CPP was maintained for 8 weeks in the control group but not in the METH group. A priming injection of METH (0.5 mg/kg) caused marked reinstatement of place preference in the control group; this response was maintained for three additional weeks. However, the priming injection of METH resulted in diminished place preference in the METH group and the conditioned response dissipated within 3 weeks. These findings suggest that METH-induced striatal dopaminergic neurotoxicity is associated with two opposing and long-lasting behavioral outcomes: (a) sensitization to the psychomotor-stimulating effect of the drug and (b) desensitization to the rewarding properties of the drug. These consequences may be relevant to the psychopathology of METH abuse.

Animals↗

PubMed1997

Effects of haloperidol and cocaine pretreatments on brain distribution and kinetics of [11C]methamphetamine in methamphetamine sensitized dog: application of PET to drug pharmacokinetic study.

Repeated administration of methamphetamine (MAP) causes behavioral sensitization in animals. We previously reported that the maximum accumulation level of [11C]MAP in the MAP-sensitized dog brain was 1.4 times higher than that in the control. In behavioral studies, haloperidol (a dopamine D2 receptor antagonist) prevents MAP-induced behavioral sensitization, and cocaine (a dopamine reuptake blocker) has the cross-behavioral sensitization with MAP. In the present study, to elucidate the relation between the MAP-induced behavioral sensitization and the pharmacokinetics of MAP, we investigated the effects of haloperidol and cocaine pretreatments on brain regional distribution and kinetics of [11C]MAP using positron emission tomography (PET). A significant increase of [11C]MAP uptake into the sensitized dog brain was prevented by haloperidol and cocaine pretreatments. These pharmacokinetic changes were not due to the changes in the rate of MAP metabolism. These results suggest haloperidol and cocaine can change the cerebral pharmacokinetic profile of MAP in the behavioral-sensitized dog. The variations of MAP-accumulation may affect the development or expression of MAP-induced behavioral sensitization.

Animals↗

PubMed2001

Generation of anti-(+)methamphetamine antibodies is not impeded by (+)methamphetamine administration during active immunization of rats.

The goal of these studies was to determine if chronic (+)methamphetamine ((+)METH) administration affects the production of anti-(+)METH antibodies during active immunization of rats. Active immunization for the treatment of chronic drug abuse has been proposed for drugs such as cocaine and nicotine. However, studies have not adequately addressed whether continual drug use during treatment would affect the development of an immune response. For the current studies, male Sprague-Dawley rats were immunized with either keyhole limpet hemocyanin (KLH; control group) or a (+)METH hapten ((+)METH with a six carbon spacer group at the para position of the ring structure)-KLH conjugate. The (+)METH-KLH animals were further divided into two groups. One group was immunized with no subsequent administration of (+)METH, while the other group was immunized and repeatedly challenged (twice a week throughout the study) with an i.p. dose of 3 mg/kg (+)METH. The results showed that the two groups of (+)METH-KLH immunized rats developed and maintained anti-(+)METH antibody titers. The anti-(+)METH immune responses of the two groups were not statistically different (P < 0.05) as measured by serum titers and the relative antibody affinities. These data suggest that repeated administration of (+)METH does not affect the generation of an anti-(+)METH antibody response in actively immunized rats.

Animals↗

PubMed2003

Escalating dose methamphetamine pretreatment alters the behavioral and neurochemical profiles associated with exposure to a high-dose methamphetamine binge.

The neurotoxic effects of methamphetamine (METH) have been characterized primarily from the study of high-dose binge regimens in rodents. However, this drug administration paradigm does not include a potentially important feature of stimulant abuse in humans, that is, the gradual escalation of stimulant doses that frequently occurs prior to high-dose exposure. We have argued that pretreatment with escalating doses (EDs) might significantly alter the neurotoxic profile produced by a single high-dose binge. In the present study, we tested this hypothesis by pretreating rats with saline or gradually increasing doses of METH (0.1-4.0 mg/kg over 14 days), prior to an acute METH binge (4 x 6 mg/kg at 2 h intervals). These animals, whose behavior was continuously monitored throughout drug treatment, were then killed 3 days later for determination of caudate-putamen dopamine (DA) content, levels of [(3)H]WIN 35,428 binding to the DA transporter, and levels of [(3)H]dihydrotetrabenazine ([(3)H]DTBZ) binding to the vesicular monoamine transporter. ED pretreatment markedly attenuated the stereotypy response, as well as the hyperthermia and indices of sympathetic activation associated with the acute binge. In addition, ED pretreatment prevented the decline in [(3)H]WIN 35,428 binding, and significantly diminished the decrease in DA levels, but did not affect the decrease in [(3)H]DTBZ binding associated with the acute binge. We suggest that further study of the effects produced by a regimen which includes a gradual escalation of doses prior to high-dose METH binge exposure could more accurately identify the neurochemical and behavioral changes relevant to those that occur as a consequence of high-dose METH abuse in humans.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2002

Methamphetamine in Japan: the consequences of methamphetamine abuse as a function of route of administration.

AIMS: To determine differences in life backgrounds and clinical features between methamphetamine (MAP) smokers and injectors in Japan. SETTING: Out-patient clinic at a psychiatric centre. PARTICIPANTS: Among 451 MAP abusers undergoing initial assessments, 116 subjects whom the first author had directly interviewed and treated were studied. DESIGN AND PROCEDURES: In this study, life backgrounds, clinical features and psychiatric symptoms were compared between three subgroups: 42 (36.2%) in group S (smoking only); 57 (49.1%) in group I (injection only); and 17 (14.7%) in group SI (initially smoking, later injecting). FINDINGS: Group I more often had parental absence (P < 0.001), a family history of alcoholism (P < 0.05), limited education (P < 0.001), or a criminal record (P < 0.001) than patients in the other two groups. Group S had the most cannabis use (P < 0.01), while group I had the most volatile solvents use (P < 0.01). Group S experienced their first psychotic episode sooner after first MAP use (P < 0.01), but showed fewer auditory hallucinations at initial assessment than patients in other groups (P < 0.001). Group SI was intermediate between groups S and I in life background, clinical features and psychotic symptoms, while they had lost control of their drug use most frequently (P < 0.02). CONCLUSIONS: In Japan, MAP smokers have different life backgrounds from injectors. Smoking MAP does not appear to be a safer route as regards losing control of MAP use and inducing psychosis than injection.

Adolescent↗

PubMed1997

5-hydroxy-3-ethylamino-2-oxindole is not formed in rat brain following a neurotoxic dose of methamphetamine: evidence that methamphetamine does not induce the hydroxyl radical-mediated oxidation of serotonin.

Oxygen radicals have been implicated in the neurodegenerative and other neurobiological effects evoked by methamphetamine (MA) in the brain. It has been reported that shortly after a single large subcutaneous dose of MA to the rat, the serotonergic neurotoxin 5,6-dihydroxytryptamine (5,6-DHT) is formed in the cortex and hippocampus. This somewhat controversial finding suggests that MA potentiates formation of the hydroxyl radical (HO.) that oxidizes 5-hydroxytryptamine (5-HT) to 5,6-DHT, which, in turn, mediates the degeneration of serotonergic terminals. A major and more stable product of the in vitro HO.-mediated oxidation of 5-HT is 5-hydroxy-3-ethylamino-2-oxindole (5-HEO). In this investigation, a method based on HPLC with electrochemical detection (HPLC-EC) has been developed that permits measurement of very low levels of 5-HEO in rat brain tissue in the presence of biogenic amine neurotransmitters/metabolites. After intracerebroventricular administration into rat brain, 5-HEO is transformed into a single major, but unknown, metabolite that can be detected by HPLC-EC. One hour after administration of MA (100 mg/kg s.c.) to the rat, massive decrements of 5-HT were observed in all regions of the brain examined (cortex, hippocampus, medulla and pons, midbrain, and striatum). However, 5-HEO, its unidentified metabolite, or 5,6-DHT were not detected as in vivo metabolites of 5-HT. MA administration, in particular to rats pretreated with pargyline, resulted in the formation of low levels of N-acetyl-5-hydroxytryptamine (NAc-5-HT) in all brain regions examined. These results suggest that MA does not potentiate the HO.-mediated oxidation of 5-HT. Furthermore, the rapid MA-induced decrease of 5-HT might not only be related to oxidative deactivation of tryptophan hydroxylase, as demonstrated by other investigators, but also to the inhibition of tetrahydrobiopterin biosynthesis by NAc-5-HT. The massive decrements of 5-HT evoked by MA are accompanied by small or no corresponding increases in 5-hydroxyindole-3-acetic acid (5-HIAA) levels. This is due, in part, to the relatively rapid clearance of 5-HIAA from the brain and monoamine oxidase (MAO) inhibition by MA. However, the loss of 5-HT without corresponding increases in its metabolites point to other mechanisms that might deplete the neurotransmitter, such as oxidation by superoxide radical anion (O2.-), a reaction that in vitro does not generate 5-HEO or 5,6-DHT but rather another putative neurotoxin, tryptamine-4,5-dione. One hour after administration, MA evokes large depletions of norepinephrine (NE) throughout the brain but somewhat smaller decrements of dopamine (DA) that are restricted to the nigrostriatal pathway. Furthermore, MA evokes a major shift in the metabolism of both NE and DA from the pathway mediated by MAO to that mediated by catechol-O-methyltransferase. The profound and widespread effects of MA on the noradrenergic system, but more anatomically localized influence on the dopaminergic system, suggests that NE in addition to DA, or unusual metabolites of these neurotransmitters, might play roles in the neurodegenerative effects evoked by this drug.

Animals↗

PubMed2001

Inhibitors of Na(+)/H(+) and Na(+)/Ca(2+) exchange potentiate methamphetamine-induced dopamine neurotoxicity: possible role of ionic dysregulation in methamphetamine neurotoxicity.

Although the neurotoxic potential of methamphetamine (METH) is well established, underlying mechanisms have yet to be identified. In the present study, we sought to determine whether ionic dysregulation was a feature of METH neurotoxicity. In particular, we reasoned that if METH impairs the function of Na(+)/H(+) and/or Na(+)/Ca(2+) antiporters by compromising the inward Na(+) gradient [via prolonged DA transporter (DAT) activation and Na(+)/K(+) ATPase inhibition], then amiloride (AMIL) and other inhibitors of Na(+)/H(+) and/or Na(+)/Ca(2+) exchange would potentiate METH neurotoxicity. To test this hypothesis, mice were treated with METH alone or in combination with AMIL or one of its analogs; 1 week later, the animals were killed for studies of dopamine (DA) neuronal integrity. AMIL markedly potentiated the toxic effect of METH on DA neurons. Potentiation was not caused by increased core temperature, enhanced DAT activity or higher METH brain levels. The DAT inhibitor, WIN-35,428, protected completely against METH-induced DA neurotoxicity in AMIL pretreated animals, suggesting that the potentiating effects of AMIL require a METH/DAT interaction. Findings with METH and AMIL were extended to six other AMIL analogs (MIA, EIPA, DIMA, BENZ, BEP, DiCBNZ), another species (rats), and neuronal type (5-HT neurons). These results support the notion that ionic dysregulation may play a role in METH neurotoxicity.

Amiloride↗

PubMedDate not supplied

Simultaneous HPLC analysis of optical isomers of methamphetamine and its metabolites, and stereoselective metabolism of racemic methamphetamine in rat urine.

Simultaneous identification of optical isomers (D and L) of methamphetamine (MAMP), amphetamine (AMP), para(p)-hydroxy(OH)-MAMP, and para(p)-hydroxy(OH)-AMP in rat urine was attempted by high-performance liquid chromatography (HPLC). They were determined as benzoyl derivatives. After administration of D- or L-isomer (15 mg/kg), only D- or L-isomers of the above mentioned metabolites were found in rat urine. In rats administered racemic MAMP (15 mg/kg), each percent dose of L-isomers of MAMP or AMP excreted at four collection times up to 24 h was less than that of the D-isomer (L/D less than 1.00), but the doses of L-isomers of p-OH-MAMP and p-OH-AMP excreted were higher than those of D-isomers (L/D greater than 1.00). Simultaneous analysis within 36 minutes showed good peak resolution. The L/D ratio for each metabolite decreased with time. The total percent doses of D- or L-isomer excreted by 24 hours were about 50% of the administered dose, 23.70 +/- 1.45% for the D-isomer, 25.70 +/- 1.54% for the L-isomers. The total L/D ratio was 1.08 +/- 0.03. These results indicated that Wistar rats have no chiral isomerization enzyme of MAMP, and show stereoselective metabolism of DL-MAMP. In the optical isomer analysis of 11 MAMP powder samples and 28 human urine specimens obtained from Japanese abusers, only D-MAMP was detected in the powder, and D-MAMP and D-AMP were detected in urine, respectively. This suggested that humans have no chiral isomerization enzyme of D-MAMP.

Adolescent↗

PubMed2000

Interpretation and enantiomer analysis of methamphetamine abusers' urine and illegally brewed methamphetamine crystals.

This study deals with the high-performance liquid chromatographic identification of methamphetamine (MAMP) and amphetamine (AMP) enantiomers (d- and l-forms) in five illicit MAMP crystals and in urine specimens from 30 Japanese MAMP abusers. The analysis revealed that two of the types of crystals have a different optical purity ratio (l/d) and the other three have a single crystal of either the d- or l-enantiomer. The l/d ratios of two types of crystals were 0.04 and 49.4, and no racemic form (l/d = 1.00) was found. The urinary analysis showed that nonmetabolized MAMP and its demethylated metabolite, AMP, were present in urine specimens of all addicts. The stereoisomeric profiles in urine can be classified roughly into five groups according to the detected amount and the l/d ratio of MAMP and AMP enantiomers collected at one time point. In the first group, only d-MAMP and d-AMP were detected (in 16 cases). In the second group, only l-MAMP and l-AMP were detected (in one case). In the third group, the amount of the l-enantiomer detected, for both MAMP and AMP, was less than that of the d-enantiomer, and the l/d ratio was between 0.004 and 0.54 for MAMP and between 0.01 and 0.07 for AMP (in five cases). In the fourth group, the l-enantiomer of MAMP and AMP was found to be more abundant than the d-enantiomer, and the l/d ratio was between 2.63 and 30.11 for MAMP and between 1.23 and 31.30 for AMP (in four cases). In the fifth group, the amount of l-MAMP detected was greater than that of d-MAMP, and less l-AMP than d-AMP was detected. The l/d ratios were between 1.13 and 8.82 for MAMP and between 0.17 and 0.82 for AMP (in four cases). These results might be suitable for identification and the forensic toxicological investigation of AMP analogues.

Adolescent↗

PubMedDate not supplied

Dansyl chloride derivatization of methamphetamine: a method with advantages for screening and analysis of methamphetamine in urine.

The screening and quantitation of methamphetamine (MP) in urine using dansyl chloride (DNC) as the derivatization reagent were studied. Urinary MP derivatized with DNC could be detected by visual observation of the fluorescence in a solid-phase extraction column such as a Sep-Pak C18 cartridge to which the whole reaction solution was applied. The DNC-derivatized MP was eluted from the cartridge and then identified and quantitated by gas chromatography-mass spectrometry (GC-MS) and high-performance liquid chromatography (HPLC). In the GC-MS analysis with the MS detector in the electron-impact mode, DNC-derivatized MP and amphetamine (AP), exhibited diagnostic molecular ion peaks. The intensities of the molecular ions were 15% (DNC-MP) and 35% (DNC-AP) of the base peak (a fragment ion because of the loss of dimethylnaphthalene from M+), demonstrating that this method of derivatization has a major advantage for confirming APs by GC-MS. MP derivatized with DNC could be determined by HPLC with ultraviolet detection. Because a good correlation (r = 0.95) between the GC-MS and HPLC method for urinary MP was confirmed, both HPLC and GC-MS appear to be useful tools for determining urinary MP. The intensity of the cartridge fluorescence due to DNC-derivatized MP was approximately related to the urinary content of MP determined by HPLC or GC-MS, although a false positive in the visual fluorescence was observed in some urinary specimens from healthy volunteers. From these results, screening and confirmation/determination following DNC derivatization is proposed as a suitable method for the analysis of MP.

Amphetamine-Related Disorders↗

PubMed2006

High-performance liquid chromatographic-mass spectrometric determination of methamphetamine and amphetamine enantiomers, desmethylselegiline and selegiline, in hair samples of long-term methamphetamine abusers or selegiline users.

We devised a highly sensitive method for simultaneously determining methamphetamine (MA) and amphetamine (AP) enantiomers, desmethylselegiline (DMSG) and selegiline (SG), in human hair using a derivatization technique and high-performance liquid chromatography-electrospray ionization-mass spectrometry (HPLC-ESI-MS). MA and AP enantiomers and DMSG were effectively converted to trifluoroacetic acid (TFA) derivatives, and the sensitivity of MA and DMSG increased five times over compared with that of free bases. The TFA derivatives of each compound were stable within one week in a stock solution of methanol or for 24 h in the HPLC mobile phase (mixture of methanol and ammonium formate buffer). Each compound was well separated, and calibration curves were linear in the concentration range 0.04-40 ng/mg for MA enantiomers, SG and DMSG, and 0.2-40 ng/mg for AP enantiomers. The accuracy and precision of the method were evaluated, and relative standard deviations were within 7%. Our method was successfully applied to hair samples obtained from long-term MA abusers and SG users. (+)-MA and (+)-AP were detected from three MA abusers at concentrations of 0.79-20.85 and 0.04-3.30 ng/mg, respectively. On the other hand, (-)-MA, (-)-AP, DMSG, and SG were detected in three SG users at concentrations of 2.48-9.05, 0.72-3.10, 0.12-0.59, and 0-0.04 ng/mg, respectively. Based on our obtained data, discrimination of MA abusers from SG users was considered to be possible by comparing optical isomers of MA and AP, the existence of DMSG and/or SG, and the concentration ratio of AP to MA in hair samples.

Amphetamine↗

PubMed1996

Hypersensitivity of nucleus accumbens neurons to methamphetamine and dopamine following repeated administrations of methamphetamine.

Methamphetamine (MAP) abuse is known to induce reverse tolerance in humans. Electrophysiological studies were performed to elucidate time-related changes in dopamine (DA) receptor sensitivities to DA and MAP after withdrawal following repeated MAP administrations. MAP (5 mg/kg) or physiological saline (1 ml/kg) was injected i.p. to rats once daily for 5 days. Single neuronal activities of nucleus accumbens (Acc) of 5-day MAP-administrated rats were extracellularly recorded with a glass microelectrode attached along a seven-barreled micropipette under chloral hydrate anesthesia. Each barrel was respectively filled with DA, MAP, haloperidol, glutamate and NaCl. Drugs were microiontophoretically applied to the immediate vicinity of Acc neurons receiving inputs from the parafascicular nucleus (Pf) of thalamus. Spikes elicited by Pf stimulation- and glutamate-induced firing were inhibited by iontophoretic application of either DA or MAP at doses of 20-40 nA in the saline-treated rats: EC50 for DA and MAP were 23.8 and 23.2 nA, respectively. At 24-30 hr after the final MAP administration, however, the inhibitory effects of both DA and MAP on Pf stimulation- and glutamate-induced firing of Acc neurons were less pronounced than those in the saline-treated animals. Furthermore, spontaneous firing was enhanced during haloperidol application. On day 5 postadministration, the inhibition of Acc neurons by DA or MAP was significantly more marked than that of saline-treated animals. On day 10 postadministration, the inhibition of Acc neurons by DA or MAP was comparable to that in controls. These results indicate that repeated administrations with MAP induce hyposensitivity and hypersensitivity of Acc neurons to DA and MAP at 24-30 hr and on day 5 postadministration, respectively.

Action Potentials↗

PubMed2000

Studies of amphetamine or methamphetamine psychosis in Japan: relation of methamphetamine psychosis to schizophrenia.

There exist clinical characteristics of methamphetamine (MAP) psychosis in the Japanese population. MAP psychosis involves paranoid-hallucinatory states indistinguishable from paranoid schizophrenia, with residual volitional disturbances (e.g., loss of spontaneity and idleness). Paranoid-hallucinatory states persist after the pharmacological effects of MAP have worn off and readily reappear upon a reinjection of MAP. Individuals with a history of MAP psychosis further undergo spontaneous recurrence of their paranoid-hallucinatory states in response to stress. The development of MAP psychosis might therefore be related to persisting brain damage or changes in brain metabolism induced by repeated MAP use, and thus studies of the clinical course and neurological basis of MAP psychosis could provide insights into the pathophysiology of schizophrenia. Accordingly, psychiatrists have studied the clinical characteristics of MAP psychosis and examined the neurobiological basis of MAP-induced behavioral sensitization, using animals. MAP-induced behavioral sensitization might well be related to dopamine supersensitivity; however, the contribution of presynaptic autoreceptors remains controversial, and other hypotheses should be considered. Recently, the process that triggers spontaneous recurrence of MAP psychosis (flashbacks) and corresponding peripheral neurotransmitter functions has been studied. Stress sensitization associated with noradrenergic hyperactivity, involving increased dopamine release, appears to be crucial in the development of flashbacks. Overall, MAP-induced susceptibility to paranoid-hallucinatory states and to abnormal behavior (e.g., stereotyped behavior) in animals is examined as a model for predicting relapses of paranoid schizophrenia. Further extensive studies on the neurobiological and molecular mechanisms of this susceptibility are required.

Amphetamines↗

PubMed2002

Behavioral consequences of methamphetamine-induced neurotoxicity in mice: relevance to the psychopathology of methamphetamine addiction.

Methamphetamine (METH) is a major drug of abuse in the United States. A high dose of METH given to mice and rats causes long-lasting depletion of tyrosine hydroxylase activity, dopamine (DA), and DA-transporter (DAT) binding sites in the striatum. In human METH-abusers, a marked decrease of the DAT in the caudate putamen was observed. Despite intensive investigations of the mechanism associated with METH-induced neurotoxicity, the behavioral consequences of this phenomenon are not clear. We used the mouse model of METH-induced neurotoxicity to investigate the response of the animals to the psychomotor-stimulating effect of METH and the rewarding effect of the drug. Mice pre-exposed to a neurotoxic dose of METH developed a marked sensitization to the psychomotor-stimulating effect of METH, which lasted for more than two months. The rewarding effect of METH was determined by the conditioned place preference (CPP) paradigm. Mice pre-exposed to the neurotoxic dose of METH showed reduced sensitivity to the rewarding effect of METH compared with control animals. While CPP was maintained for three months in the control group, the conditioned response in the METH pre-exposed animals lasted only a few days. These findings indicate that METH neurotoxicity is associated with opposing and long-lasting behavioral outcomes: (a) sensitization to the psychomotor-stimulating effect of the drug and (b) desensitization to the rewarding properties of the drug. These consequences may be relevant to the psychopathology of METH abuse. Sensitization is pertinent to compulsive drug-seeking behavior that is accompanied by desensitization to the rewarding effect of METH.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2004

The altered disposition of methamphetamine in the model of methamphetamine-induced neurotoxicity.

Methamphetamine (METH) is a drug of abuse, causing neurotoxic effects in mammals. Many hypotheses have been proposed to explain the underlying mechanisms of METH-induced toxicity, based on neurochemical/neuroanatomical changes. However, the pharmacokinetic properties of METH in the METH-induced neurotoxic model have not yet been evaluated. Thus, we investigated plasma and tissue levels of METH in the METH-induced neurotoxic model. As a result, when METH is administered multiply (5 mg/kg 4 times at 2-h intervals) in male Wistar rats, plasma METH levels at the third and forth injections were significantly higher than those at the first. The tissue distributions of METH in the brain as well as in the kidney were significantly decreased in the third injections, suggesting the importance of decreased transport of METH into tissues. Alternatively, one week after the establishment of METH-induced neurotoxicity, plasma levels of METH were back to normal, although METH levels in brain microdialysates were significantly higher than those in normal animals. These results suggest that the altered pharmacokinetic properties of METH, due to the abnormal membrane transport/disposition of METH into both central and peripheral tissues, might partially affect the emergence of METH-induced neurotoxicity.

Animals↗