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Test for oral and postingestional factors mediating differential acceptability of morphine, methamphetamine, and chlordiazepoxide drinking solutions.

The relative degrees to which aversive oral (presumably gustatory) and postingestional variables attenuate the voluntary drinking of morphine, methamphetamine, and chlordiazepoxide solutions by rats were assessed by comparing immediate acceptability with subsequent acceptability. Results indicated that morphine solutions (0.01--0.05%) are avoided primarily because of unpalatability, while methamphetamine (0.005--0.02%) and chlordiazepoxide solutions (0.02--0.08%) are avoided primarily because of aversive postingestional effects.

Administration, Oral↗

Swimming capacity of mice after prolonged treatment with psychostimulants. II. Effect of methamphetamine on swimming performance and availability of metabolic substrates.

Swimming endurance and availability of metabolic substrates (blood glucose and nonesterified fatty acids [NEFA], liver and muscle glycogen, body fat) were studied in mice treated with 10 microgram/g methamphetamine/day for 6 weeks. At the end of the 6-week treatment, motor coordination of the methamphetamine-treated animals was much better than that of controls, and swimming capacity tended to increase. While swimming, mice treated with methamphetamine mobilized more glycogen from the hepatic stores and utilized glucose more effectively. Their NEFA levels in blood were higher than those of controls. There was no difference in the muscular glycogen content.

Animals↗

Inhibitory effect of a selective kappa receptor agonist, U-50, 488H, on methamphetamine-elicited ipsilateral circling behavior in rats with unilateral nigral lesions.

The present study was designed to investigate the effect of U-50, 488H, a highly selective kappa opioid agonist, on ipsilateral and contralateral circling behavior induced by methamphetamine and by apomorphine, respectively. U-50, 488H (3.2-10 mg/kg IP) by itself failed to induce either ipsilateral or contralateral circling in rats with unilateral nigral lesions produced by an injection of 6-hydroxydopamine. U-50, 488H produced a significant dose-dependent inhibition of methamphetamine (1.0 mg/kg SC)-elicited ipsilateral circling. However, it had no effect on contralateral circling induced by apomorphine (0.5 mg/kg SC). The present results indicate that U-50, 488H presynaptically inhibits the release of dopamine in the rat striatum.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

Behavioral sensitization to methamphetamine in the rat: an ontogenic study.

The behavioral effect of repeated methamphetamine (MAP) treatment was observed in young rat to establish the ontogenetic period crucial to methamphetamine sensitization. Animals were treated with MAP (2 mg/kg, SC) once daily for 5 days (Group 1: postnatal days 2-6, G-2: 7-11, G-3: 12-16, G-4: 17-21, G-5: 22-26, G-6: 27-31). Control animals were similarly treated with an equal volume of saline. On the 35th postnatal day, all rats were challenged with MAP (2 mg/kg, IP). Behavioral sensitization to MAP was not found in G-1, G-2, G-3 or G-4, although responsiveness to MAP was observed in rats after the 2nd postnatal day. The animals in G-5 and G-6 showed hypersensitivity to MAP in locomotor activity and stereotyped behavior. These findings indicate that the period crucial to behavioral sensitization to MAP corresponds to the period of presynaptic dopamine autoreceptor formation in the rat brain.

Aging↗

Acute neuropathological changes in the caudate nucleus caused by MPTP and methamphetamine: immunohistochemical studies.

Three days after the administration of MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) or methamphetamine to mice, there is degeneration and disappearance of punctate tyrosine hydroxylase-containing synaptic endings in the caudate nucleus. The neuropil is occupied with longer, varicose, branching fibres, which appear to be preterminal fibres. An intense gliosis occurs. The sparsely-occurring glial cells, with profuse lightly-stained (by glial fibrillary acidic protein) processes which are primarily located near blood vessels, become transformed into more heavily-stained star-shaped cells with fewer but thicker processes. These cells are distributed throughout the caudate. Despite apparent differences in the mechanism by which MPTP and methamphetamine cause dopamine depletion, the neuropathological changes in the caudate induced by these substances are identical.

Animals↗

Ontogeny of PFC-related behaviours is sensitive to a single non-invasive dose of methamphetamine in neonatal gerbils (Meriones unguiculatus).

A single dose of methamphetamine (50 mg/kg; i.p.) was administered to neonatal male gerbils (Meriones unguiculatus) aged 14 days, and adult prefrontal cortex (PFC)-related behaviours were analysed and compared with saline-treated controls at the age of postnatal day 90. For that purpose, animals were tested for open-field activities and y-maze delayed alternation. This solitary and non-invasive drug challenge, which has recently been found to initiate serious restraint in maturation of the mesoprefrontal dopamine (DA)-system (Dawirs et al., 1994), induces a significant delayed alternation impairment as well as significant increases in open-field motor activity and emotionality. Since an undisturbed development of the prefrontal DA-innervation seems to be a precondition for the maturation of normal PFC-related behaviours, a single early methamphetamine impact may be a suitable animal model for further investigation of structural and functional aspects of non-invasively induced behavioural deficits in rodents. The present results are discussed with regard to the assumption that hypofunctional mesoprefrontal DA-systems might be basic to schizophrenic behaviours in man.

Animals↗

Toxicological detection of selegiline and its metabolites in urine using fluorescence polarization immunoassay (FPIA) and gas chromatography-mass spectrometry (GC-MS) and differentiation by enantioselective GC-MS of the intake of selegiline from abuse of methamphetamine or amphetamine.

Selegiline (R(-)-N-methyl-N-(1-phenyl-2-propyl)-2-propinylamine), a selective MAO-B inhibitor used as an antiparkinsonian, is excreted in urine as N-desmethyl selegiline (norselegiline), R(-)-methamphetamine (R(-)-MA), R(-)-amphetamine (R(-)-AM) and their conjugated p-hydroxy derivatives. We found that the fluorescence polarization immunoassays (FPIA) TDx amphetamine/methamphetamine II (AM/MA II) and TDx amphetamine class (AM class) lead to positive results for up to 2 days after a single oral dose of 10 mg selegiline (detection limit: 0.1 mg/l, each). Every urine specimen from long term selegiline patients (10 mg/day) showed positive TDx results during the selegiline regimen. Positive TDx results were confirmed using gas chromatography-mass spectrometry (GC-MS). Selegiline metabolites, particularly MA, could be detected in urine for up to 7 days after intake of a single oral dose of 10 mg selegiline (detection limit: 0.01 mg/l for MA and AM). Norselegiline, the only specific selegiline metabolite, was only detectable for about 12 h. Moreover, norselegiline was not detected in all urine samples from long term selegiline patients (10 mg/day). Since differentiation of selegiline intake from MA/AM abuse by detecting norselegiline was not possible in most cases, an enantioselective GC-MS procedure was developed. It allowed differentiation of the enantiomers of the selegiline metabolites and thereby separation of selegiline intake (only R(-)-enantiomers) from methamphetamine and/or amphetamine abuse (racemates or S(+)-enantiomers). After derivatization with S(-)-N-trifluoroacetyl-prolyl chloride (TPC), the two enantiomers of MA and AM were each separated as diastereomers employing the routinely used achiral GC capillary.(ABSTRACT TRUNCATED AT 250 WORDS)

Amphetamine↗

Postnatal maturation of prefrontal pyramidal neurones is sensitive to a single early dose of methamphetamine in gerbils (Meriones unguiculatus).

The effect of a single methamphetamine application on postnatal maturation of the prefrontal cortex was studied using pyramidal cell morphology and spine density as parameters of systemic plasticity. Male gerbils were injected a single dose of methamphetamine (METH, 50mg/kg, i.p.) on postnatal day 14. On postnatal day 90, prefrontal cortices of METH-treated animals and saline-treated controls were processed for Golgi-staining. Dendritic arbours of layer III and V pyramidal neurones were measured to describe pyramidal cell morphology, and segmental spine counts were carried out. The results showed that a single postnatal METH-challenge significantly alters morphological differentiation of pyramidal cells towards adulthood. Cells from METH-treated animals showed a higher total dendritic length based on longer segments between subsequent dendritic branchings, with only the apical stem dendrite being shorter in METH-treated than in control subjects. The branching rate was slightly but not significantly increased in METH-treated animals. Nevertheless, spine density was significantly increased on all types of dendrites, with apical dendrites of both layers III and V showing the highest drug-induced progression of about 50% compared to control values. The present results are discussed with regard to probable clues they may provide for investigating neurobiological principles of psychotic behaviour in an animal model.

Animals↗

Methamphetamine-induced behavioral sensitization in mice: alterations in mu-opioid receptor.

We had previously demonstrated that opioid receptors contribute to the induction and expression of behavioral sensitization induced by repeated daily injection with 2.5 mg/kg of methamphetamine for 7 days. Using the same regimen, the present study investigated the alterations in mu-opioid receptor during the induction (on days 2, 5, and 8) and expression (on days 11 and 21) periods of behavioral sensitization. Radioligand binding revealed that the maximal binding of mu-opioid receptor was not changed on days 2 and 5, but down-regulated on day 8. After cessation of drug treatment, the maximal binding of mu-opioid receptor gradually and time-dependently returned to normal level on day 11 and up-regulated on day 21. In contrast, no changes in delta- and kappa-opioid receptors were detectable on any given day examined. The potency of DAMGO for [(35)S]-GTPgammaS coupling was enhanced on days 2, 5, 11, and 21. Moreover, 1 muM of naltrexone or beta-chlornaltrexamine significantly suppressed the basal [(35)S]-GTPgammaS coupling on days 2, 11, and 21. These findings indicate enhanced responsiveness and elevated constitutive activity of mu-opioid receptor. In summary, our data clearly demonstrate that alterations in mu-opioid receptor are involved in and may contribute to the sensitization to locomotor stimulating effect of methamphetamine.

Analgesics, Opioid↗

Sexual and injection risk among women who inject methamphetamine in San Francisco.

Methamphetamine (MA) use is on the rise in the United States, with many cities reporting increases of 100% or more in MA-related Emergency Department (ED) mentions. Women are keeping pace with this trend: in 2003, 40% of ED mentions and 45% of MA-related treatment admissions were female. Although there have been extensive examinations of MA use and HIV/STI risk among gay men in recent years, literature regarding female MA users is scarce. This paper examines female methamphetamine injectors in San Francisco, CA, from 2003-2005. We assessed sexual and injection related risk behaviors, comparing female MA injectors to female injectors of other drugs. We also examined whether MA use was independently associated with specific sexual and injection risk behaviors. We found that female MA injectors were significantly more likely than non-MA injectors to report unprotected anal intercourse, multiple sexual partners, receptive syringe sharing and sharing of syringes with more than one person in the past six months. In multivariate analysis, MA use among female injectors was significantly associated with anal sex, more than five sexual partners, receptive syringe sharing, and more than one syringe-sharing partner in the past six months. Deeper exploration of the relationship between MA use and sexual risk among women would benefit HIV/STI prevention efforts. In addition, existing interventions for drug-injecting women may need to be adapted to better meet the risks of female MA injectors.

Adult↗

Methamphetamine intoxication. A speedy new treatment.

This communication describes the use of droperidol in methamphetamine poisoning. Droperidol antagonizes the central stimulatory effects of amphetamines producing a person who is indifferent to environmental stimuli, calm and cooperative. Coupled with an acid diuresis, causing a fivefold increase in the urinary concentration of methamphetamine and recovery of 66% of the ingested drug, a seriously intoxicated patient showed rapid improvement.

Adult↗

Presynaptic modulation of the release of dopamine from striatal synaptosomes: differences in the effects of high K+ stimulation, methamphetamine and nicotinic drugs.

We examined the effects of nicotinic drugs on the metabolites of [3H]dopamine (DA) released from rat striatal synaptosomes in comparison with the effects of high K+ and methamphetamine stimulation. The pattern of outflow of [3H]DA and its metabolites induced by nicotine stimulants, acetylcholine (ACh), nicotine and lobeline, was different from that induced by high K+ and methamphetamine.

Animals↗

Long-term effects of chronic methamphetamine administration in rhesus monkeys.

Biochemical and neuropathological effects of exposure to a high dose regimen of methamphetamine were evaluated in rhesus monkeys approximately 4 years after the last drug injection. Concentrations of dopamine and serotonin in caudate were below control levels as were concentrations of serotonin in several other brain regions. These changes were more severe in a monkey that was exposed twice to the drug regimen. A decrease in caudate synaptosomal uptake of both neurotransmitters as well as neuropathological changes were evident in that monkey. Although it is possible that partial recovery occurred, these results strongly suggest that methamphetamine-induced neurotoxicity may be permanent.

Animals↗

Striatal subregions are differentially vulnerable to the neurotoxic effects of methamphetamine.

Methamphetamine (m-AMPH) or saline was repeatedly administered to rats. One week later, the caudate-putamen of the m-AMPH-treated rats revealed a decrease in both [3H]mazindol-labeled dopamine uptake sites and tissue dopamine content. Moreover, the resulting pattern of decline in these measures was regionally heterogeneous. The ventral caudate-putamen displayed the greatest decrease in both [3H]mazindol binding and dopamine content while the neighboring nucleus accumbens and the dorsal caudate-putamen remained relatively intact. These results indicate a regional difference in the susceptibility of striatal dopaminergic terminals to the neurotoxic effects of methamphetamine.

Animals↗

Neuronal induction of 72-kDa heat shock protein following methamphetamine-induced hyperthermia in the mouse hippocampus.

By means of an immunohistochemical technique, we examined the neuronal induction of 72-kDa heat shock protein (HSP72) in response to methamphetamine-induced hyperthermia in the mouse hippocampus. Strong HSP72 immunoreactivity (ir) was found in the neurons of hippocampus proper, particularly in the CA1/2 and medical CA3 subfields, at 10 h after drug injection. By 18 h, those neurons still revealed HSP72-ir, while neurons of the dentate gyrus also appeared positive for HSP72. At this stage, intense HSP72-ir was first detected in non-neuronal cells, i.e. glial and vascular endothelial cells. At 24 h, no apparent HSP72-ir was found in the hippocampal neurons, while only non-neuronal cells still revealed immunoreactivity for HSP72. In addition, no morphological evidence of cell degeneration or loss was noted in the CA1 sector or other hippocampal regions at 5 days after hyperthermic insult. In conclusion, (1) methamphetamine-induced hyperthermia per se is a stressful stimulant causing neuronal induction of HSP72 in the hippocampus neurons, particularly of CA1/2 and medial CA3 sectors, but does not prove fatal to the cells; (2) there is a cell type-specific difference in response to hyperthermic insult by inducing HSP72 and the timing of the induction response in the hippocampal formation; and (3) the animals that underwent drug-induced hyperthermia may be useful as an experimental model for the study of the protective mechanism of heat shock proteins against subsequent harmful stimuli.

Animals↗

Methamphetamine stimulates the release of neuropeptide Y and noradrenaline from the paraventricular nucleus in rats.

Effects of methamphetamine (MAP) on the extracellular neuropeptide Y (NPY) and noradrenaline (NA) levels were examined in the vicinity of the paraventricular nucleus (PVN) of freely moving rats by means of push-pull perfusion. The NA and NPY levels increased significantly in 30-60 min and reached the maximum level in 90-120 min after intraperitoneal administration of MAP. The effects were dose-dependent. The maximum levels were 1.6-fold of the pretreatment level for NPY and 7-fold for NA, respectively, when 5.0 mg/kg b.w. of methamphetamine was administered. It is concluded that MAP stimulates the releases of paraventricular NPY and NA, but the effect is more strong for NA than for NPY.

Animals↗

Blockade of tachykinin NK1 receptors by CP-96345 enhances dopamine release and the striatal dopamine effects of methamphetamine in rats.

The nonpeptide, tachykinin NK1 receptor antagonist, CP-96345, permits the study of the physiological role of extrapyramidal substance P systems. Using microdialysis, we observed that locally applied CP-96345 (200 nM) caused a significant increase in dopamine release in the striatum as well as substantially enhancing striatal dopamine release caused by a low dose of methamphetamine (0.5 mg/kg s.c.). In addition, multiple systemic administrations of CP-96345 almost doubled the dopamine-mediated responses of the striatal neurotensin and dynorphin systems to high doses of methamphetamine (10 mg/kg/dose s.c.). Our findings suggest that the physiological role of substance P released in the striatum is to decrease the activity of the nigrostriatal dopamine pathway.

Animals↗

Indication of methamphetamine-induced reactive synaptogenesis in the prefrontal cortex of gerbils (Meriones unguiculatus).

A single dose of methamphetamine (25 mg/kg i.p.) was administered to young adult gerbils (Meriones unguiculatus) aged 90 days and the number of spices was determined along 40-microns segments of basal, lateral and apical dendrites of pyramidal cells in layers III and V of the prefrontal cortex, after 1.5, 7, 20 and 30 days. The density of spines rapidly increased by more than 80% within 7 days after drug challenge, and subsequently returned to the original normal values within about 2 weeks. Thirty days after drug administration the density of dendritic spines was slightly, but significantly, less than control values (about 5%). The density of spines was likewise affected in layer III and V neurones, irrespective of the spatial domain of their dendritic ramifications. Since several lines of investigation indicate that methamphetamine can cause the destruction of dopaminergic nerve terminals in the mammalian forebrain, the present results are discussed against the background of current concepts about reactive synaptic reorganization and adaptive remodelling of neural circuits in the central nervous system.

Animals↗