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PubMed1993

Long-lasting decrease in dopamine uptake sites following repeated administration of methamphetamine in the rat striatum.

We investigated the effects of repeated administration of methamphetamine on dopamine (DA) uptake sites in the rat striatum by using an increasing dose paradigm of methamphetamine (2.5 mg/kg on day 1; 5 on day 3; 7.5 on day 5 and 10 on day 7), each being given twice on the indicated day by s.c. injection. It has been established that this administration paradigm produces distinct sensitization in methamphetamine-induced behavior. A 36% reduction in specific [3H]DA uptake, and a 29% reduction in specific [3H]GBR12935 binding in the striatum were demonstrated in rats sacrificed 7 days after the last methamphetamine administration. A similar reduction in striatal [3H]GBR12935 binding sites was observed even 30 days after discontinuation of the drug. These data indicate that this treatment regimen of gradually escalating doses of methamphetamine induces a long-lasting decrease of DA uptake sites in rat striatum.

Animals↗

PubMed1983

Behavioral sensitization and relative hyperresponsiveness of striatal and limbic dopaminergic neurons after repeated methamphetamine treatment.

Rats were used in a study of the effects of repeated methamphetamine treatment on stereotyped behavior and striatal and limbic dopamine metabolism in response to challenge with the drug or other dopamine agonists. Repeated administration of d-methamphetamine (6 mg/kg per day for 3-14 days) produced long-term behavioral sensitization (augmented response to a challenge injection) not only to the compound (at 44-89 days after drug withdrawal) but also to apomorphine and nomifensine. Even a single injection of d-methamphetamine (6 mg/kg) enhanced the behavioral response to the drug. A challenge dose of d-methamphetamine (2 mg/kg) markedly increased dopamine turnover (lower dopamine and higher 3,4-dihydroxyphenylacetic acid levels, higher ratios of 3,4-dihydroxyphenylacetic acid over dopamine) in the striatum and mesolimbic area of the sensitized animals on day 15 of withdrawal from treatment repeated for 14 days with the drug (6 mg/kg per day). These findings demonstrate that behavioral sensitization induced by methamphetamine is accompanied by increased central dopaminergic transmission.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1992

Persistent supersensitivity of sigma receptors develops during repeated methamphetamine treatment.

Functional changes in sigma receptors were examined after behavioral sensitization induced by repeated methamphetamine treatment. Rats received either saline or 4 mg/kg methamphetamine for 14 days. (+)3-(3-hydroxyphenyl)-N-(1-propyl)piperidine ((+)-3-PPP), a sigma receptor agonist, was given as challenge after various periods of abstinence. (+)-3-PPP at doses greater than 6 mg/kg stimulated several forms of behavior in naive rats. (+)-3-PPP at 12 and 24 mg/kg produced more frequent rearing and more intense stereotyped sniffing and repetitive head movements in rats previously sensitized with methamphetamine than in saline-pretreated rats. The augmented response to (+)-3-PPP in methamphetamine-treated rats was maintained for at least one month. The augmented response to (+)-3-PPP was reversed by the combined administration of 100 mg/kg (+/-)-sulpiride, a D2 dopamine receptor antagonist, and 30 mg/kg BMY 14802, a sigma receptor antagonist. These results suggest that repeated methamphetamine treatment induces persistent supersensitivity in sigma receptors and that it may subsequently activate the dopamine system.

Animals↗

PubMed1992

Multidimensional behavioral analyses show dynorphin A-(1-13) modulation of methamphetamine-induced behaviors in mice.

The effects of intracerebroventricular (i.c.v.) injection of dynorphin A-(1-13) on methamphetamine-induced behavioral alterations in mice were determined by using multidimensional behavioral analyses. Methamphetamine (0.3, 1.0 and 3.0 mg/kg s.c.) produced a marked increase in linear locomotion, circling, rearing and/or grooming behaviors. The behavioral effects of methamphetamine (1.0 mg/kg s.c.) were almost completely antagonized by pretreatment with the dopamine D2 receptor antagonist, S(-)-sulpiride (3.0 and/or 10.0 mg/kg i.p.), but not with the dopamine D1 receptor antagonist, SCH 23390 (0.01 or 0.03 mg/kg i.p.). Although dynorphin A-(1-13) (3.0 or 12.5 micrograms i.c.v.) alone did not produce any significant effects on behavior, the methamphetamine (1.0 mg/kg s.c.)-induced increase in circling ipsilateral to the injection side was markedly enhanced by dynorphin A-(1-13) (12.5 micrograms i.c.v.). In contrast, the peptide (12.5 micrograms i.c.v.) inhibited the methamphetamine (1.0 mg/kg s.c.)-induced increase in rearing, whilst the increase in grooming remained unchanged. The effects of dynorphin A-(1-13) (12.5 micrograms i.c.v.) were fully reversed by the opioid antagonist, Mr 2266 (5.6 mg/kg s.c.). These results suggest that the unilateral administration (i.c.v.) of dynorphin A-(1-13) inhibits the activity of dopamine-elicited neurotransmission, resulting in an increase in ipsilateral circling and in a decrease in rearing.

Animals↗

PubMed1984

Effect of methamphetamine on the locomotor activity in the 6-OHDA dorsal hippocampus lesioned rat.

The present studies were carried out to examine a possible role of hippocampal dopamine in the hyperactivity induced by methamphetamine. For this purpose, 6-hydroxydopamine (6-OHDA) lesion of the dorsal hippocampus (D-HPC) was made in desmethylimipramine pretreated rats in order to specifically destroy dopamine neurons. D-HPC lesions produced a large (96%) and selective depletion of content of dopamine in the D-HPC. This lesion did not change spontaneous locomotion and rearing behavior. The 6-OHDA lesioned rat produced a blockade of the increase in locomotor activity induced by 1.0 and 2.0 mg/kg of methamphetamine. In contrast, the 6-OHDA lesion of the D-HPC failed to influence the methamphetamine-induced rearing activity. These results indicate that dopamine neurons in the D-HPC may have some role in methamphetamine-induced locomotion, but not in methamphetamine-induced rearing.

Animals↗

PubMed1991

Clinical effects of methamphetamine vapor inhalation.

Despite the increasing popularity of crystalline methamphetamine ("ice") vapor inhalation, no investigations have reported drug plasma concentrations and effects. Under controlled laboratory conditions, six subjects were studied. Plasma concentrations of methamphetamine were determined, and subjective and cardiovascular effects were measured. Methamphetamine appeared in plasma rapidly, increased slowly over the next four hours and then progressively declined. The dose of methamphetamine administered produced modest ratings of subjective drug effects, and moderate changes in cardiovascular parameters. Both subjective and cardiovascular effects rapidly decreased despite the presence of sustained concentrations of methamphetamine in plasma.

Administration, Inhalation↗

PubMed1982

Effects of chronic methamphetamine administration on tryptophan hydroxylase activity, [3H]serotonin synaptosomal uptake, and serotonin metabolism in rat brain following systemic tryptophan loading.

Chronic administration of methamphetamine (20 mg/kg, i.p., every 12 hr for 6 days) produced significant decreases in the Vmax of brainstem (-32.8%) and forebrain (-31.5%) tryptophan hydroxylase when measured 12 hr after the final injection. Serotonin (5-HT), 5-hydroxyindoleacetic acid (5-HIAA), and [3H]5-HT synaptosomal uptake were decreased by a similar magnitude following chronic drug treatment. Administration of fluoxetine prior to each methamphetamine injection prevented these neurochemical changes. Neither acute nor chronic methamphetamine treatment produced any significant changes in the Km of tryptophan hydroxylase for either substrate or cofactor. Systemic tryptophan loading (50 mg/kg, i.p.) one hour prior to sacrifice in chronic methamphetamine treated rats restored brain 5-HT and 5-HIAA levels to normal. These data suggest that chronic methamphetamine treatment decreases central serotonergic neurotransmission by reducing the activity of the rate-limiting enzyme in 5-HT biosynthesis, possibly by disrupting serotonergic nerve terminals.

Animals↗

PubMed1991

Age-related toxicity in prefrontal cortex and caudate-putamen complex of gerbils (Meriones unguiculatus) after a single dose of methamphetamine.

Single, intermediate to large doses (6-60 mg/kg) of methamphetamine were applied to study the acute neurotoxic effects in developing male gerbils (up to 24 months). A sensitive silver-staining method was used to analyze the toxicity of methamphetamine by light and electron-microscopy. It was shown that treatment with the drug degraded synaptic components, as well as a small population of neurones in the caudate-putamen complex accompanied by accumulation of lysosomes in fibers and axon terminals. In juveniles, methamphetamine in doses of 25-60 mg/kg, resulted in accumulation of lysosomes, selectively in the prefrontal cortex. In young adults, only about half of these doses were sufficient to produce consistent and/or additional effects in the caudate-putamen complex. When the gerbils grew older than 8 months, treatment with drug led to accumulation of lysosomes, exclusively in the caudate-putamen, with acute doses ranging from 6 to 12 mg/kg. Acute neurotoxicity with methamphetamine has thus been induced by doses, which hitherto have been claimed to produce behavioural sensitization. Since dopamine (DA) seems the most likely transmitter to be affected, age-related differences in methamphetamine-induced neurotoxicity are discussed in relation to the background of developing DA-response systems, which are still changing in pattern during ageing.

Aging↗

PubMed1989

Methamphetamine induced locomotor rhythm entrains to restricted daily feeding in SCN lesioned rats.

Rats were lesioned in the SCN and treated with methamphetamine dissolved in drinking water. A robust rhythm appeared in spontaneous locomotor activity which was not affected by blinding. Periodic food restriction (RF) of a 24 hr period was imposed on SCN lesioned rats with free-access to food for 4 or 6 hr per day, while water was given ad lib. The locomotor rhythm induced by methamphetamine treatment was phase-set by RF immediately in most cases but with transients in some. The phase-angle difference (psi) between food presentation and the activity onset became more negative by increasing the dose of methamphetamine. Because there was a positive correlation between methamphetamine dose and the period of locomotor rhythm, the change in psi was most likely due to lengthening of the period. After the termination of the RF schedule, the locomotor rhythm started to free-run from the prior phase set by RF. These results indicate that the methamphetamine dependent locomotor rhythm entrains to RF.

Animals↗

PubMed1994

Effects of methamphetamine and methylphenidate on single and paired rat open-field behaviors.

The present study used a video analysis system to investigate the effects of indirect dopamine agonists, methamphetamine and methylphenidate, on single and paired rat open-field behaviors. Experimental rats were injected with saline, methamphetamine, or methylphenidate (0.008, 0.04, 0.2, 1.0, 5.0 mg/kg, IP) and put into an open field for 30 min singly or paired with another rat. The rats' movements were plotted on XY coordinates by a video analysis system every 0.5 s and analyzed by distance and time factors. When paired, the experimental rats moved more than when single, and the total move distance increased according to dose of methamphetamine or methylphenidate. Further analysis showed that under methamphetamine, fleeing distances increased significantly but chasing distances were not affected; under methylphenidate, fleeing distances also increased, but chasing distances decreased significantly. Although two rats in an open field often stand in contact with each other, both methamphetamine and methylphenidate in doses exceeding 1.0 mg/kg tended to keep the two rats separate. These phenomena indicate that the two indirect dopamine agonists induce less interaction and decrease social behavior.

Animals↗

PubMed1979

The effects and interactions of scopolamine, physostigmine and methamphetamine on human memory.

Seventy college age subjects learned and recalled a series of word lists prior to being injected with methamphetamine (0.2 mg/kg or 0.3 mg/kg), scopolamine (8 microgram/kg), or a placebo. Following the injection subjects were tested for their free recall and recognition of the words and they completed a short-term digit recall task. Subjects who had previously received scopolamine were next injected with either methamphetamine (0.2 mg/kg or 0.3 mg/kg), physostigmine (32 microgram/kg), or placebo, while other subjects received a placebo injection. The above memory procedure was then repeated with a second series of word lists. In addition, subjective feelings were measured with a questionnaire. Scopolamine and methamphetamine did not affect recall of information learned prior to injection. Scopolamine did, however, impair performance in both the digit recall task and in the second series of memory tests. Physostigmine and methamphetamine alleviated most of the memory deficits and sedation produced by scopolamine. Methamphetamine alone produced subjective arousal and a small improvement in recall of words learned after injection and a large increase in incorrect responding.

Adolescent↗

PubMed1993

Changes in the incidence and duration of electroconvulsions after acute or subchronic treatment with methamphetamine in mice.

The effects of acute or subchronic treatment with methamphetamine on the incidence, intensity, and duration of electroconvulsion were investigated in mice. The convulsion was induced by electrical stimulation (100 Hz, 60 mA, 0.1-s duration) through electrodes located at each ear of mice, then analyzed by the vibration monitoring apparatus. Acute methamphetamine (3 mg/kg) reduced the incidence of the electroconvulsion in mice; however, the duration of each phase of the convulsion was prolonged by acute methamphetamine. Repeated administration of methamphetamine prolonged the duration of clonic phase of the convulsion and enhanced the acute methamphetamine-induced reduction in the incidence of electroconvulsion. These data indicate that the incidence of electroconvulsion is regulated by different mechanisms underlying the duration and intensity of the convulsion.

Animals↗

PubMed1987

Neurotoxic effects of methamphetamine assessed in three-dimensional reaggregate tissue cultures.

Three-dimensional, rotation-mediated, reaggregate tissue cultures formed from dissociated fetal rostral mesencephalic tegmental (RMT) and corpus striatal (CS) or frontal cortical (FCx) cells were used to study methamphetamine neurotoxicity. Analysis of dopamine (DA), serotonin (5-HT) and gamma-aminobutyric acid (GABA) levels using HPLC techniques revealed decreases in RMT-CS and RMT-FCx reaggregate DA and 5-HT levels after treatment between 14 and 21 days in culture with methamphetamine in concentrations ranging from 10(-6)M to 10(-3)M. Dopamine cell numbers in RMT-CS and RMT-FCx reaggregates were estimated after visualization by histofluorescent techniques. Methamphetamine treatment caused decreases in DA cell numbers which paralleled the decreases in endogenous DA levels. Estimates of the accumulation of exogenous DA by RMT-CS reaggregates treated with methamphetamine showed that the amount of accumulation per cell remained fairly constant despite marked reductions in total DA cell numbers. This suggests that the reductions in endogenous DA levels following methamphetamine were secondary to loss of entire DA neurons rather than of a portion of the terminal axonal fields in the surviving neurons. Reaggregate tissue cultures are a useful tool in the study of potential neurotoxic effects of new or untested psychotherapeutic agents.

Animals↗

PubMed1996

Effects of acute methamphetamine administration on spacing in paired rats: investigation with an automated video-analysis method.

1. Effects of acute methamphetamine administration on spacing and locomotor activity were investigated in paired rats using a computer-assisted automated video-analysis method. 2. Both 0.1 and 1 mg/kg of methamphetamine significantly increased the spacing in comparison with saline. This alteration in behavioral interaction by methamphetamine may serve as one of the animal models of social withdrawal. 3. A significant increase in locomotor activity was found after 1 mg/kg of methamphetamine. 0.1 mg/kg dosage was accompanied by a locomotor change of a lesser degree and shorter duration. 4. The difference with respect to the dose dependency and the time course indicates that the changes in these two behavioral indices by methamphetamine may have different underlying mechanisms.

Animals↗

PubMed1992

MK-801, a non-competitive antagonist of NMDA receptor, prevents methamphetamine-induced decrease of striatal dopamine uptake sites in the rat striatum.

We investigated the effects of MK-801, a non-competitive antagonist of NMDA receptor, on methamphetamine-induced decrease in dopamine (DA) uptake sites in the rat striatum. Repeated administrations of an escalating dose of methamphetamine (2.5, 5, 7.5, 10 mg/kg s.c. x2, every other day for a week) produced decreased DA uptake sites assayed by binding with [3H]GBR 12935 in the striatum. Co-administration of MK-801 and methamphetamine significantly prevented the methamphetamine-induced decrease in striatal [3H]GBR 12935 binding. Administration of MK-801 alone did not affect [3H]GBR 12935 binding. These results suggest that some neurochemical effects of methamphetamine may be mediated via mechanism involving excitatory amino acids.

Animals↗

PubMed1987

Autoradiographic analysis of muscarinic cholinergic and serotonergic receptor alterations following methamphetamine treatment.

Autoradiographic examination of the response of muscarinic cholinergic (M1 and M2) receptors to multiple doses of methamphetamine has been performed in several regions of the rat brain. Both muscarinic receptor subtypes were identified with [3H]-N-methylscopolamine, while M1 receptors were specifically labeled with [3H]-pirenzepine. No change in muscarinic receptors labeled with [3H]-pirenzepine was found in any of the brain regions examined following methamphetamine treatment; however, [3H]-N-methylscopolamine binding was significantly reduced (24-40%). These results indicate that M1 receptors remained unchanged after the drug treatment, while M2 receptors were reduced in many areas of the rat central nervous system following multiple high doses of methamphetamine. Five doses of methamphetamine (6-hour interval between doses) were required to elicit the receptor changes in all brain regions analyzed. Within 7 days after drug treatment, the receptor number returned to control values in the affected brain areas. Additionally, the response of serotonin (5-HT1 and 5-HT2) receptors to methamphetamine was examined and found to be reduced in a few brain areas analyzed. The receptor changes were accompanied by METH-induced decreases in tyrosine hydroxylase and tryptophan hydroxylase activities.

Animals↗

PubMed1990

Immunoassay for methamphetamine with a new antibody.

p- and o-Aminomethamphetamine were synthesized as haptens to be coupled with carrier protein at the benzene ring of methamphetamine. Immunogens were prepared by the glutaraldehyde method or the MBS (N-(m-maleimidobenzoyloxy)succinimide) type cross-linking reagent method. In particular, immunization with p-aminomethamphetamine-bovine serum albumin (BSA) conjugate prepared by the glutaraldehyde method gave an anti-methamphetamine antiserum having a low cross-reactivity with methylephedrine. With the antiserum, three kinds of immunoassays for methamphetamine were established. An enzyme immunoassay (EIA) and an enzyme-linked immunosorbent assay (ELISA) were developed with alkaline phosphatase (ALP) as a label enzyme. The amount of antibody bound ALP conjugate was determined by its activity in dephosphorylating p-nitrophenyl phosphate in EIA and nicotinamide adenine dinucleotide phosphate (NADP+) in ELISA. The range of methamphetamine measurable by ELISA was 0.025-0.5 ng/well and its sensitivity was superior to that of EIA (0.3-300 ng/tube). A latex agglutination inhibition reaction test (LAIRT) was also developed for the mass screening method of urine samples. The sensitivity of this method for methamphetamine was 0.1 micrograms/ml urine.

Alkaline Phosphatase↗

PubMed1996

Enantiomeric composition of amphetamine and methamphetamine derived from the precursor compound famprofazone.

Fourteen different metabolic precursors of amphetamine or methamphetamine have previously been identified. Many of these drugs are available only by prescription and several are only available in some parts of the world and not in others. One of these drugs, famprofazone, is available over-the-counter which complicates the interpretation of methamphetamine urine drug testing results. To assist in the interpretation of typical laboratory results, a study was conducted to determine the enantiomeric composition of the methamphetamine and amphetamine produced from the metabolism of famprofazone. Fifty mg of famprofazone was administered to a volunteer followed by collection of urine for the next 6 days. The resulting quantity, enantiomeric composition and percent conversion from famprofazone to the product amphetamine and methamphetamine was determined. The results showed the amphetamine and methamphetamine to include both the d- and l-enantiomers. Percent conversion and peak concentrations were similar to those reported in previous studies.

Amphetamines↗