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PubMed1991

L-DOPA potentiation of the serotonergic deficits due to a single administration of 3,4-methylenedioxymethamphetamine, p-chloroamphetamine or methamphetamine to rats.

The role of dopamine in the serotonergic neurotoxicity of 3,4-methylenedioxymethamphetamine, p-chloroamphetamine, methamphetamine, N-ethyl-3,4-methylenedioxyamphetamine and fenfluramine was assessed by determining the long-term effect of their coadministration with the dopamine precursor, L-DOPA (L-2,4-dihydroxyphenylalanine). L-DOPA administration potentiated the regional deficits in brain concentrations of serotonin measured one week after a single high dose of 3,4-methylenedioxymethamphetamine, p-chloroamphetamine or methamphetamine but did not alter the neurochemical response to N-ethyl-3,4-methylenedioxyamphetamine nor to fenfluramine. Consistent with this, in vitro release studies found the latter two agents to be the weakest of the five at increasing [3H]dopamine efflux from preloaded rat striatal slices. As an estimate of in vivo release, the effect of each agent on striatal dopamine concentrations was determined. Only those agents showing a synergism with L-DOPA in the long-term studies also produced changes in striatal dopamine consistent with an increase in transmitter release and synthesis. These results provide additional support for the hypothesis that dopamine release plays a role in the neurotoxicity of methylenedioxymethamphetamine, p-chloroamphetamine and methamphetamine. The lack of effect of L-DOPA on the neurotoxicity of fenfluramine as well as the modest effects of fenfluramine on dopamine release indicate this drug may produce its long-term effects on the serotonergic system through a unique mechanism not involving dopamine.

3,4-Methylenedioxyamphetamine↗

PubMed1992

Attenuation of the inhibitory effect of dynorphin on dopamine release in the rat nucleus accumbens by repeated treatment with methamphetamine.

Dynorphin (1-100 nM) dose dependently inhibited both spontaneous and electrically evoked endogenous dopamine (DA) release from slices of the nucleus accumbens of untreated rats. When this inhibitory effect was compared, it was significantly reduced in rats pretreated (for 9 days) with methamphetamine (6 mg/kg per day i.p.) relative to rats treated with saline. These findings indicate that dynorphin inhibits DA release from the nucleus accumbens, and that treatment with methamphetamine reduces the modulatory action of dynorphin on DA release. It is possible that repeated administration of methamphetamine leads to attenuation of the inhibition of DA release from the nucleus accumbens via presynaptic dynorphin-sensitive receptors.

Animals↗

PubMed1993

Repeated methamphetamine-treatment alters brain sigma receptors.

The present study was undertaken to examine whether repeated exposure of rats to the psychostimulant drug, methamphetamine, induces changes in sigma receptor binding. A significant up-regulation (130-145% of control Bmax) of sigma receptors, labeled with [3H](+)pentazocine, was observed in the substantia nigra, frontal cortex and cerebellum of rats treated with methamphetamine (4.0 mg/kg per day; 10 days). These findings suggest that methamphetamine-induced psychosis may be associated with the up-regulation of sigma receptors in critical brain regions.

Animals↗

PubMed1995

Norepinephrine loss exacerbates methamphetamine-induced striatal dopamine depletion in mice.

Evidence is accumulating that norepinephrine depletion enhances the neurotoxic effect of the parkinsonism inducing neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In this study we investigated whether norepinephrine loss potentiates methamphetamine-induced striatal dopamine depletion. Injection of C57BL/6N mice with methamphetamine (2 x 5 mg/kg i.p., at 2-h intervals) produced only a partial (50%) striatal dopamine depletion 7 days after drug administration. Pretreatment with the selective noradrenergic neurotoxin N-(-2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4; 50 mg/kg i.p.) enhanced methamphetamine-induced striatal dopamine depletion by 86%, without decreasing striatal dopamine levels when injected alone. Our results extend previous findings obtained with the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine in DSP-4-pretreated mice.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed1996

Effect of haloperidol on the behavioral stimulation by N-cyanomethylmethamphetamine, a main product of smoking methamphetamine mixed with tobacco.

N-Cyanomethylmethamphetamine is a main product of smoking methamphetamine mixed with tobacco. The aim of this experiment was to evaluate the effects of haloperidol on behavioral stimulation by N-cyanomethylmethamphetamine (3 mg/kg s.c.) in terms of ambulation in mice. Repeated administration of N-cyanomethylmethamphetamine, carried out 5 x at 3-day intervals, induced a sensitization to its ambulation-increasing effect. Haloperidol (0.01, 0.03, 0.1 and 0.3 mg/kg s.c.) significantly inhibited not only the acute stimulant effect of N-cyanomethylmethamphetamine but also the induction of sensitization. The dose-effect curves for the inhibitory effects of haloperidol on the N-cyanomethylmethamphetamine-induced ambulatory stimulation were almost the same between the drug-native and N-cyanomethylmethamphetamine-sensitized mice. Moreover, such behavioral characteristics of N-cyanomethylmethamphetamine; the behavioral stimulant effect, the induction of sensitization following repeated administration, and the inhibition of its effects by haloperidol, were qualitatively the same as those of methamphetamine (2 mg/kg s.c.). These results suggest that N-cyanomethylmethamphetamine possesses methamphetamine-like central stimulant effect and that D2 dopaminergic mechanisms are involved in the effect of N-cyanomethylmethamphetamine.

Amphetamines↗

PubMed1996

Pharmacological characterization of BNMPA (alpha-benzyl-N-methylphenethylamine), an impurity of illicit methamphetamine synthesis.

alpha-Benzyl-N-methylphenethylamine (BNMPA), an impurity of illicit methamphetamine synthesis, has previously been reported to produce convulsions in mice without affecting spontaneous locomotor activity or altering methamphetamine-induced increases in spontaneous activity. In this study the in vitro effects of BNMPA on a variety of neuronal receptor types was determined to better characterize the pharmacological actions of this novel compound. BNMPA and N-demethyl-BNMPA fully displaced the dopamine transporter selective ligand [3H]CFT (2-beta-carbomethoxy-3-beta-(4-fluorophenyl)tropane) from rat striatal membranes with Ki values (mean +/- S.E.M) of 6.05 microM +/- 0.15 and 8.73 microM +/- 1.66, respectively. BNMPA also inhibited [3H]dopamine uptake into striatal synaptosomes with an IC50 value of 5.1 +/- 1.4 microM. The basal efflux of [3H]dopamine from striatal slices was slightly enhanced by BNMPA only at concentrations > or = 100 microM. BNMPA had no effect on [3H]norepinephrine efflux from hippocampal slices. BNMPA displaced tritiated paroxetine and prazosin binding from rat cortical membranes with Ki values of 14.5 microM and 11.7 microM respectively. In electrophysiological studies, BNMPA (100 microM) had no significant effects on either GABAA Cl- currents in cultured neurons or non-NMDA glutamate receptors expressed in oocytes. However, BNMPA significantly inhibited NMDA-stimulated currents in oocytes expressing the NR1/2A or NR1/2C receptor subunit combinations (IC50 values = 24.6 +/- 1.8 and 24.0 +/- 1.5 microM, respectively). This inhibition was rapid, reversible and voltage-dependent. These results indicate that BNMPA has multiple sites of action in the CNS that could be important in modulating a variety of behavioral effects upon exposure to this synthetic byproduct of illicit methamphetamine synthesis.

Analysis of Variance↗

PubMed1983

Methamphetamine mortality to emotional stimuli administered in the form of affective communication.

Methamphetamine induced mortality in physically stressed and non-physically stressed mice was investigated by employing a communication box in which shocked mice communicated their distress to unshocked mice in neighboring boxes. Intraperitoneal administration of methamphetamine 30 mg/kg caused greater mortality in both the shocked "sender" mice and the unshocked "responder" mice than in control when maintained at 27 +/- 1 degree C. Forty-eight hours after injection, the "sender", "responder" and control mice showed mortality of 80, 60 and 10%, respectively. This result indicates that the mortality of methamphetamine may be potentiated not only by physical stress but also by non-physical stress.

Animal Communication↗

PubMed1985

Subchronic methamphetamine treatment selectively attenuates apomorphine-induced decrease in 3,4-dihydroxyphenylacetic acid level in mesolimbic dopaminergic regions.

To investigate mechanisms of behavioral enhancement produced by repeated doses of amphetamines, the effects of apomorphine on 3,4-dihydroxyphenylacetic acid (DOPAC) and dopamine (DA) levels were examined in various brain regions of the rat on the 4th day of withdrawal after repeated administration of saline or methamphetamine (3 mg/kg, s.c.) twice daily for 14 days. Apomorphine (0.1 and 1.0 mg/kg, i.p.) produced a dose-dependent decrease in DOPAC levels and no effect on DA levels in the olfactory tubercle, nucleus accumbens, striatum, frontal and cingulate cortices of saline-treated animals. A decrease in DOPAC levels produced by a low dose of apomorphine was attenuated selectively in the olfactory tubercle and nucleus accumbens of methamphetamine-treated animals. A high dose of apomorphine produced a significant decrease in DOPAC levels in both regions. No such attenuation was obtained in the striatum and the frontal and cingulate cortices. These results suggest that subchronic methamphetamine may induce development of hyposensitivity of presynaptic DA receptors in the mesolimbic regions, which contribute to the behavioral enhancement produced by the drug.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1996

Formalin- and carrageenan-induced inflammation attenuates place preferences produced by morphine, methamphetamine and cocaine.

Morphine-, methamphetamine- and cocaine-induced place preferences under inflammation produced by unilateral injections of 2.5% formalin (50 microliters) and 1% carrageenan (100 microliters) into the hind paw were examined in rats. Formalin and carrageenan reduced the paw pressure threshold, and this hyperalgesia lasted for 9 and 13 days, respectively. Morphine-, cocaine- and methamphetamine-induced place preferences were significantly attenuated in inflamed groups as compared with the respective noninflamed groups. However, indomethacin failed to produce a place preference in either group. Furthermore, the morphine-induced place preference in the inflamed group gradually recovered to the respective control level as the inflammation healed. These results suggest that the rewarding effects of morphine, cocaine and methamphetamine are attenuated in the presence of inflammatory nociception.

Animals↗

PubMed1983

Fluoxetine increases long-lasting neostriatal dopamine depletion after administration of d-methamphetamine and d-amphetamine.

Repeated administration of large doses of d-methamphetamine produce long-lasting depletion of brain dopamine (DA) and serotonin (5-HT), as well as persistent decreases in the activity of their respective biosynthetic enzymes, tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH). The present results indicate that the inhibitor of 5-HT uptake fluoxetine, prevented the long-term depletion of 5-HT produced by large doses of methamphetamine (15 mg/kg X 5, 6 hr apart) in the neostriatum and hippocampus, while simultaneously augmenting the depletion of DA produced by this drug in the neostriatum. Fluoxetine also enhanced the prolonged neostriatal depletion of DA produced by a comparable regimen of d-amphetamine. In these doses (15 mg/kg X 5,6 hr apart), d-amphetamine did not produce long-lasting depletion of 5-HT in either the neostriatum or hippocampus. Larger depletion of DA after the amphetamines had been administered in the fluoxetine pretreated animal were associated with a transient increase in the brain levels of methamphetamine and amphetamine. This suggests that fluoxetine may inhibit the metabolism of amphetamines.

Animals↗

PubMed1983

Effects of apomorphine and methamphetamine on a quickly-learned conditioned-suppression response in rats.

Rats exhibited a marked suppression of motor activity when placed in the same chamber where they had been given electric shocks. Administration of apomorphine-HCl (0.1, 0.5 and 1.0 mg/kg, i.p.) attenuated the conditioned suppression, dose-dependently, but did not facilitate motor activity of control (i.e. non-shocked) rats. Methamphetamine-HCl (0.1, 0.5 and 1 mg/kg, i.p.) increased motor activity of both the shocked and non-shocked rats, in a dose-related manner. Haloperidol (0.3 and 1 mg/kg, i.p.), but not chlorpromazine-HCl (5 mg/kg, i.p.), enhanced the conditioned-suppression response. Atropine-sulfate (5 and 10 mg/kg, i.p.), p-chlorophenylalanine (300 mg/kg, i.p.) and alpha-methyl-p-tyrosine (100 mg/kg, i.p.) were slightly effective in reducing the conditioned-suppression response. Apomorphine- and methamphetamine-induced reduction of the conditioned-suppression response was inhibited by pretreatment with haloperidol. When catecholamine-synthesizing processes in rats were inhibited by pretreatment with alpha-methyl-p-tyrosine, or alpha-adrenergic receptor sites were blocked by pretreatment with phenoxybenzamine, the effect of methamphetamine, but not that of apomorphine, was reduced. Therefore, enhancement of dopaminergic neurotransmission may be responsible for attenuation of the conditioned-suppression response.

Animals↗

PubMed1986

Ascorbic acid reduces the dopamine depletion induced by methamphetamine and the 1-methyl-4-phenyl pyridinium ion.

The neurotoxic actions of methamphetamine and the 1-methyl-4-phenyl pyridinium ion (MPP+) have been ascribed, at least in part, to the generation of free radicals. This hypothesis was evaluated by attempting to reduce the toxic actions of these compounds by pretreatment with an antioxidant, ascorbic acid. The intrastriatal administration of methamphetamine caused a 37% depletion of dopamine. Treatment with 100 or 1000 mg/kg of ascorbic acid significantly reduced the methamphetamine-induced dopamine depletion (by 21 and 27%, respectively). The intrastriatal administration of MPP+ caused an 88% depletion of dopamine. Treatment with 100 or 1000 mg/kg of ascorbic acid significantly reduced the MPP+-induced dopamine depletion (by 22 and 45%, respectively). Thus, free radicals may mediate the toxic actions of these compounds.

1-Methyl-4-phenylpyridinium↗

PubMed1989

Methamphetamine-induced neuronal damage: a possible role for free radicals.

The hypothesis that methamphetamine-induced neuronal damage is mediated by the production of free radicals was evaluated by pretreating rats with either antioxidants or a superoxide dismutase (SOD) inhibitor. It was found that methamphetamine (dose range 6.25-25.0 mg/kg) caused long-lasting depletions of dopamine and serotonin in the striatum and that pretreatment with the antioxidants, ascorbic acid (10-100 mg/kg), ethanol (1 g/kg), mannitol (2 g/kg), or vitamin E (2 g/kg), attenuated these depletions, whereas pretreatment with the superoxide dismutase inhibitor diethyldithiocarbamate (200-400 mg/kg) exacerbated the depletions. The alteration of this effect by four different antioxidants, as well as an inhibitor of superoxidase dismutase, indicated that oxygen-free radicals may have a role in the methamphetamine-induced neurotoxicity.

Animals↗

PubMed1991

Single doses of methamphetamine cause changes in the density of dendritic spines in the prefrontal cortex of gerbils (Meriones unguiculatus).

Single doses of methamphetamine (25 mg/kg) were administered to adult gerbils. All detectable spines were counted along defined segments of basal, apical and lateral dendrites of Golgi-impregnated pyramidal cells in the medial prefrontal cortex (layers III and V) and the parietal cortex (layer V). These two areas were selected because previous investigations had shown methamphetamine-induced neurotoxicity in prefrontal cortex but not in parietal cortex. The frequencies of dendritic spines in methamphetamine-treated gerbils were found to be significantly increased in the prefrontal cortex, while no significant change was found in the parietal cortex.

Animals↗

PubMed1992

Entrainment of methamphetamine-induced locomotor activity rhythm to feeding cycles in SCN-lesioned rats.

Suprachiasmatic nuclei (SCN)-lesioned rats, showing a locomotor activity rhythm with a circadian period by chronic methamphetamine treatment, were subjected to the periodic food restriction (RF) of 4 h per every 27 h and 24 h. All rats were phase set by the feeding schedule of both 24-h and 27-h periods. Phase angle differences between the activity onset and food presentation were more positive under the RF with a period of 27 h than that of 24 h. Methamphetamine-induced locomotor rhythm showed a stable entrainment to RF of the 27-h period in all rats. Under the RF of the 24-h period, on the other hand, some rats showed circabidian rhythms, i.e., an activity band appeared at every second food presentation. After the termination of feeding schedule, the locomotor rhythm started to free-run from the phase set by the previous feeding schedule in all rats examined. Methamphetamine-induced locomotor rhythm was shown to be entrained by the RF with a predictable manner of an oscillation theory.

Animals↗

PubMed1989

Methylphenidate and pemoline do not cause depletion of rat brain monoamine markers similar to that observed with methamphetamine.

Methylphenidate (Ritalin) and pemoline (Cylert) are central nervous system stimulants which are widely prescribed for attention deficit and other psychiatric disorders. Several other related stimulants, including amphetamine and methamphetamine, have been shown to cause long lasting decreases in monoamine markers in rat brain, characteristic of axonal degeneration. To assess the neurotoxic potential of methylphenidate and pemoline, we compared the effects of multiple injections (sc, bid for up to 4 days) of methylphenidate (21 and 50 mg/kg) and pemoline (20 and 70 mg/kg) with methamphetamine (5 and 15 mg/kg) on rat brain norepinephrine, dopamine, and serotonin levels and transport sites. While decreases were observed in all brain monoamine markers measured in rats treated with methamphetamine, no changes were observed in animals treated with methylphenidate as compared to saline-treated controls. Pemoline failed to induce significant changes in the level of monoamine transport sites; however, a wide array of changes were observed in the levels of 5-hydroxyindoleacetic acid, dopamine, and norepinephrine in various brain areas after a 3-day treatment regimen with a high dose (70 mg/kg) of pemoline. The lack of changes in monoamine transport sites following the repeated administration of high doses of methylphenidate and pemoline suggests that these drugs do not affect axonal integrity. However, the pattern of changes observed in the levels of monoamines after pemoline treatment may have relevance to the self-injurious behavior seen in these animals.

Animals↗

PubMed1990

Effects of 24-hr fasting on methamphetamine- and apomorphine-induced locomotor activities, and on monoamine metabolism in mouse corpus striatum and nucleus accumbens.

The effects of 24-hr fasting on the vertical (VMA) and horizontal (HMA) locomotor activities, on cage climbing activity and on brain monoamine-related substances, were examined using male ddY mice. Both the VMA and HMA increased with fasting, but not the cage climbing activity. Methamphetamine (2 mg/kg, SC) increased the VMA and HMA in both the feeding and fasting mice, whereas with apomorphine (0.1 mg/kg, SC) both decreased. Furthermore, pretreatment with haloperidol (0.025 mg/kg, SC) showed no influence on the methamphetamine-induced VMA increase in both the feeding and fasting mice. However, pretreatment with haloperidol inhibited the methamphetamine-induced HMA increase in both the feeding and fasting mice and showed a higher level of HMA in fasting mice than in feeding mice. When measuring brain monoamine-related substances, the DA, NE, 5-HT, and 5-HIAA levels in the corpus striatum increased, whereas the 3-MT levels decreased. The monoamine levels in the nucleus accumbens of fasting mice were the same as those in feeding mice, except for a decrease of the 3-MT level. These results suggest that the locomotor activity in fasting mice may be increased by a change in the sensitivity of dopaminergic neurons in the corpus striatum.

Animals↗

PubMed1990

Methamphetamine- and apomorphine-induced changes in spontaneous motor activity using a new system to detect and analyze motor activity in mice.

A new system was devised to detect animal spontaneous motor activity in more detail, and methamphetamine- and apomorphine-induced changes in spontaneous motor activity were analyzed using this system. The system consists of a doughnut-shaped cage with 36 units of detectors. Scanning of each detector unit was three-dimensionally carried out, and then scanning data were fed into a personal computer. These steps were completed within 0.1 sec and repeated. Spontaneous motor activity was analyzed as changes in parameters, such as total activity, locomotor activity, vertical activity (the number of rearings and the rearing time), motion time, and average speed. Regarding dependence on the dosages of methamphetamine and apomorphine, the time courses of changes in total activity and locomotor activity markedly differed from those for changes in vertical activity. Changes in the numbers of rearings and rearing time induced by 2 mg/kg methamphetamine peaked 40-80 min after administration, whereas those in other parameters did so 15-25 min after. Three mg/kg apomorphine-induced changes in total activity and locomotor activity showed two peaks 10-15 and 40-50 min after administration, respectively. At the same dosage, apomorphine markedly increased rearing time with slight but not significant effects on the number of rearings. These effects peaked 20-30 min after administration. These results indicate this system to be quite useful to detect and analyze drug-induced changes in spontaneous motor activity.

Animals↗