Action Of Methamphetamine Research Articles

Reinforcing and discriminative stimulus effects of RTI 111, a 3-phenyltropane analog, in rhesus monkeys: interaction with methamphetamine.

The neuronal actions of methamphetamine (MA) include an increase in extracellular levels of monoamines, presumably via reverse transport involving the monoamine transporters. This action is thought to play an important role in the effects of MA. Therefore, in the present experiment, it was hypothesized that a monoamine uptake blocker would block behavioral effects of MA related to its abuse. RTI 111, a newly synthesized 3-phenyltropane analog with high affinity for the dopamine, norepinephrine, and serotonin transporters, was evaluated alone and in combination with MA for its ability to block the reinforcing and discriminative stimulus effects of MA in rhesus monkeys. RTI 111 (0.0003-0.03 mg/kg, i.v.) was made available to four rhesus monkeys for self-administration under a fixed-ratio 25 (FR 25) schedule of reinforcement. RTI 111 (0.01-0.1 mg/kg, i.m.) was also administered as a pretreatment (15 min prior) to four monkeys self-administering MA (0.0-0.3 mg/kg per injection, i.v.) on a progressive-ratio schedule of reinforcement. MA (0.01-1.0 mg/kg, i.m.), RTI 111 (0.001-0.1 mg/kg, i.m.), or the combination of MA and RTI 111 were administered to four monkeys trained to discriminate (+)-amphetamine (AMPH; 1.0 or 1.7 mg/kg, intragastric) from saline. When RTI 111 was made available for self-administration under an FR 25 schedule it functioned as a positive reinforcer in all four monkeys tested. When RTI 111 was given as a pretreatment to monkeys self-administering MA under a progressive-ratio schedule, the MA dose-response function shifted to the left and down. When RTI 111 or MA were given to monkeys trained to discriminate AMPH from saline, full AMPH-like responding was observed for both drugs. Given in combination, RTI 111 shifted the MA dose-response function to the left. These data suggest that RTI 111 is behaviorally similar to traditional psychomotor stimulants that act at the DA transporter and that it increases, rather than blocks, the behavioral potency of MA.

Molecular Footprints of Neurotoxic Amphetamine Action

Methamphetamine (METH) and 3,4-methylenedioxymethamphetamine (MDMA or Ecstasy) are amphetamine analogs with high abuse potential. These drugs also cause damage to dopamine and serotonin nerve terminals in vivo. The mechanisms by which these drugs cause neurotoxicity are not known, but a great deal of attention has been focused on reactive oxygen species (ROS) and reactive nitrogen species (RNS) as mediators of this toxicity. ROS and RNS have very short biological half-lives in vivo, and it is virtually impossible to measure them in brain directly. However, ROS and RNS are also characterized by their extreme reactivity with proteins and nucleotides. Tryptophan hydroxylase (TPH) and tyrosine hydroxylase (TH), the initial and rate limiting enzymes in the synthesis of serotonin and dopamine, respectively, are identified targets for the actions of METH and MDMA. Using recombinant forms of these proteins, we have found that nitric oxide, catechol-quinones, and peroxynitrite, all of which are potentially produced by the neurotoxic amphetamines, covalently modify both TPH and TH. The ROS and RNS cause reductions in catalytic function of these enzymes in a manner that is consistent with the effects of METH and MDMNA in vivo. Protein-bound ROS or RNS may serve as molecular footprints of neurotoxic amphetamine action.

Noradrenergic modulation of the discriminative-stimulus effects of methamphetamine in rats.

Neurochemical and clinical studies indicate involvement of noradrenergic (NE) neurotransmitter system in the actions of methamphetamine. The present study investigated NE involvement in the discriminative-stimulus effects of methamphetamine. In Sprague-Dawley rats trained to discriminate 1.0 mg/kg methamphetamine, IP, from saline under a fixed-ratio schedule of food presentation, effects of various NE agonists, antagonists and uptake inhibitors were tested. Desipramine (3.0-18.0 mg/kg) and nisoxetine (5.6-30.0 mg/kg), two selective NE-uptake inhibitors, did not significantly generalize to methamphetamine when administered alone, but 5.6 mg/kg desipramine and 10.0 mg/kg nisoxetine significantly shifted the methamphetamine dose-response curve to the left. The beta NE agonist, isoproterenol (0.56-3.0 mg/kg), and antagonist, propranolol (1.0-18.0 mg/kg), neither generalized to methamphetamine when given alone nor altered the discriminative-stimulus effects of methamphetamine when administered in combination. The alpha- NE agonist methoxamine (1.0-5.6 mg/kg) failed to generalize to the methamphetamine training stimulus. When given in combination with methamphetamine, the alpha-1 NE antagonist, prazosin (1.0 mg/kg), shifted the methamphetamine dose-response curve somewhat to the right and partially blocked the discriminative-stimulus effects of the 1.0 mg/kg training dose of methamphetamine, but these changes were not significant or dose-related, with further increases in prazosin dose (1.8-10.0 mg/kg) either producing similar or smaller changes. The alpha-2 NE agonist, clonidine, partially generalized to methamphetamine at doses of 0.1-0.18 mg/kg and increased drug-appropriate responding at lower doses of methamphetamine, but it partially blocked the discriminative-stimulus effects of higher 0.56-1.0 mg/kg doses of methamphetamine over the same dose range. The alpha-2 NE antagonist, yohimbine, also partially generalized to methamphetamine and blocked the discriminative-stimulus effects of the 1.0 mg/kg training dose of methamphetamine at doses of 5.6-10.0 mg/kg. A lower 3.0 mg/kg dose of yohimbine increased methamphetamine-appropriate responding when given together with low 0.1-0.3 mg/kg doses of methamphetamine. The present data suggest that the NE system plays a modulatory role in the discriminative-stimulus effects of methamphetamine. These effects appear to be mediated through NE uptake sites and alpha-2 receptors, with limited involvement of alpha- receptors and beta receptors.

Does nicotine modify the psychotoxic effect of methamphetamine? Assessment in terms of locomotor sensitization in mice.

In this study, effects of nicotine on locomotor sensitization to methamphetamine in mice were investigated to assess whether nicotine modified induction and expression of psychotoxic action of methamphetamine. Although nicotine (0.03-1 mg/kg s.c.) had no effect at first administration, 5-time nicotine administrations at 3-day intervals progressively developed a significant locomotor stimulant effect, and caused an enhanced sensitivity (cross-sensitization) to methamphetamine (2 mg/kg s.c.). Five-time administrations of methamphetamine (2 mg/kg) at 3-day intervals produced not only a locomotor sensitization to methamphetamine itself, but also a cross-sensitization to nicotine (0.1-1 mg/kg). Nicotine (0.03-1 mg/kg) did not affect the locomotor stimulant effect of methamphetamine (2 mg/kg) in the drug-naive mice. However, nicotine acted dose-dependently to reduce the progressive enhancement of the locomotor stimulant effect of methamphetamine during 5-time repeated administrations. Mice treated with coadministration of methamphetamine with nicotine (1 mg/kg) showed less sensitization to methamphetamine than mice treated with methamphetamine alone. In addition, nicotine (1 mg/kg) inhibited the locomotor stimulant effect of methamphetamine in mice sensitized to methamphetamine. These results suggest that methamphetamine and nicotine produce a symmetrical cross-sensitization, although nicotine may act to inhibit the induction and expression of locomotor sensitization to methamphetamine in mice.

Effects of 2-deoxy-D-glucose on methamphetamine-induced dopamine and serotonin neurotoxicity.

The mechanisms underlying the neurotoxic actions of methamphetamine (METH) and related substituted amphetamines are unknown. Previous studies with 2-deoxyglucose (2-DG) have suggested that METH-induced neurotoxicity may involve exhaustion of intracellular energy stores. However, because 2-DG also produces hypothermic effects, and because METH's neurotoxic actions are highly susceptible to thermoregulatory influence, previous findings with 2-DG are difficult to interpret. The present studies were undertaken to further examine the influence of 2-DG's glucoprivic and thermic effects in the context of METH-induced dopamine (DA) and serotonin (5-HT) neurotoxicity. 2-DG protected against METH-induced DA neurotoxicity in both rats and mice. In both species, 2-DG, alone or in combination with METH, produced hypothermic effects. METH's toxic effects on brain 5-HT neurons were either unaffected or exacerbated by 2-DG, depending on species, brain region, and dose of METH tested. These results indicate that different mechanisms may underlie METH-induced DA and 5-HT neurotoxicity, and suggest that, as compared with 5-HT neurons, DA neurons are more susceptible to temperature influence, whereas 5-HT neurons are more vulnerable than DA neurons to metabolic compromise. Additional studies are needed to further assess the role of energy stores in the neurotoxic effects of METH and related drugs.

Fetal responses to maternal and fetal methamphetamine administration in sheep

OBJECTIVES: The current study was designed to test the hypothesis that maternally administered methamphetamine decreasesfetal Pao 2 by reducing uterine blood flow and to determine the cardiovascular and blood gas responses to varying doses of methamphetamine given both to the fetus and the mother. STUDY DESIGN: Nine near-term pregnant sheep were surgically instrumented to measure maternal and fetal blood pressure and heart rate and uterine and umbilical blood flow. Fetal blood gases and pH were determined before and after each dose of methamphetamine. Methamphetamine was administered as intravenous bolus injections (30 to 35 minutes separating administration of each dose) into the maternal femoral vein in increasing doses of 0.03, 0.1, 0.3, and 1.0 mg/kg and on a separate days to the fetus into the hind limb vein as doses of 0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg estimated fetal weight. RESULTS: Maternal methamphetamine administration produced a dose-related increase in maternal and fetal blood pressure and uterine vascular resistance, whereas uterine blood flow decreased in a dose-related fashion. Umbilical blood flow tended to increase slightly, but this did not reach significance. Fetal Pao 2 decreased significantly, whereas fetal pH decreased only modestly. Direct fetal administration of methamphetamine produced dose-related increases in fetal blood pressure and umbilical blood flow and a significant decrease in fetal pH but no change in fetal Pao 2. CONCLUSIONS: The fetal Pao 2 decrease observed after maternal administration of methamphethamine appears to be a result of decreased uteroplacental perfusion, whereas the observed changes in fetal blood pressure and fetal pH appear to be a result of the direct action of methamphetamine on the fetus.

Introduction to the role of excitatory amino acids in the actions of abused drugs: a symposium presented at the 1993 annual meeting of the College on Problems of Drug Dependence

Recent evidence has demonstrated that N-methyl- d-aspartic acid (NMDA) and non-NMDA, excitatory amino acid (EAA) receptor antagonists block the motor stimulating, neurotoxic, and rewarding actions of cocaine and the amphetamines. The participants in this symposium discussed evidence that (i) the initiation of stimulant-induced behavioral sensitization involves NMDA receptor stimulation in the ventral tegmental area (VTA), (ii) competitive and non-competitve NMDA antagonists block the dopaminergic neurotoxic actions of methamphetamine, and (iii) NMDA receptor antagonists block cocaine and methamphetamine-induced increases in striatal neurotensin and dynorphin expression. Furthermore, a theoretical framework was proposed in which to interpret dopamine-glutamate interactions based on tonic and phasic dopamine release in the striatum under acute, chronic and withdrawal states of stimulant exposure.

Blockade by Ginseng Total Saponin of the Development of Methamphetamine Reverse Tolerance and Dopamine Receptor Supersensitivity in Mice

Repeated administration of methamphetamine (2 mg/kg) developed reverse tolerance to the ambulation-accelerating effect. Intraperitoneal administration of ginseng total saponin (GTS, 200 mg/kg of body weight) prior to and during chronic administration of methamphetamine inhibited the development of reverse tolerance. Dopamine receptor supersensitivity was also developed in reverse tolerant mice which had received the same methamphetamine. The development of dopamine receptor supersensitivity was evidenced by the enhanced hypothermic response to apomorphine (1 mg/kg) and the enhanced ambulatory activity of apomorphine (4 mg/kg). GTS also prevented the development of dopamine receptor supersensitivity induced by the chronic administration of methamphetamine. These results show that GTS may be useful for the prevention of and therapy for the adverse action of methamphetamine. It is concluded that the development of reverse tolerance to methamphetamine may be associated with the enhanced dopamine receptor supersensitivity since both phenomena were blocked by GTS.

Methamphetamine's action on brain-stimulation reward threshold and stereotypy.

Methamphetamine's action on brain-stimulation reward threshold and stereotypy.

Methamphetamine's action on brain-stimulation reward threshold and stereotypy.

Methamphetamine's action on brain-stimulation reward threshold and stereotypy.

Methamphetamine antagonistic property of (+)- and (−)-4-phenyltetrahydroisoquinoline in rat anococcygeus muscle

The antagonistic effects of (+)- and (−)-4-phenyl-1,2,3,4-tetrahydroisoquinoline (4PTIQ) on methamphetamine in the rat anococcygeus muscle were compared with those of cocaine and nomifensine. Methamphetamine contracted the anococcygeus muscle through the release of norepinephrine from noradrenergic nerve terminals. (+)-4PTIQ inhibited the methamphetamine-induced contractions more strongly than cocaine and nomifensine. (+)-4PTIQ had no potentiating effects on exogenous norepinephrine-induced contraction, which was considered to be an index of amine neuronal uptake blockade. On the other hand, (−)-4PTIQ, cocaine and nomifensine produced a significant leftward shift of the norepinephrine concentration-response curve, i.e. they showed a strong blocking effect on amine neuronal uptake. These results suggest that the inhibitory effects of (+)-4PTIQ on the action of methamphetamine are mediated by a mechanism other than inhibition of amine neuronal uptake.

Stimulatory Effects of HSR-803 on Ileal Motor Activity

The inhibitory actions of the selective dopamine D1-and D2-antagonists SCH 23390 and YM-09151-2, respectively, on the mouse's discrete shuttle avoidance were almost equipotent at doses ranging from 0.01-0.1 mg/kg. SCH 23390 reduced the stimulant action of methamphetamine (0.5 mg/kg), MK-801 (0.1 mg/kg) and ketamine (10 mg/kg) with a similar potency. YM-09151-2 also antagonized the actions of these drugs, with the following order of effectiveness: ketamine > MK-801 > methamphetamine. The present results indicate that methamphetamine, MK-801 and ketamine have different characteristics of CNS stimulant action through dopamine D2-receptors.

Role for protein synthesis in the neurotoxic effects of methamphetamine in mice and rats

The mechanism by which the amphetamines damage selectively nigrostriatal dopaminergic neurons in experimental animals remains uncertain. The observation that neuronal cell death during embryogenesis involves an activation of gene expression and new protein synthesis, coupled with recent reports indicating that the amphetamines are capable of inducing neuropeptide biosynthesis, offers a possible clue as to their ineurotoxic mechanism of action. Based on these considerations, we evaluated the effects of two different inhibitors of protein synthesis, cycloheximide and anisomycin, on the long-term, amine-depleting effects of methamphetamine (METH) in mice and rats. Both inhibitors were found to block the amine-depleting effects of METH in these species. In other experiments, cycloheximide did not affect the functional integrity of dopaminergic or glutamatergic neurons, transmitter systems previously implicated in the neurotoxic mechanism of action of METH. These findings raise the possibility that the neuronal-damaging effects of METH are mediated via a synthesis of ‘neurotoxic’ proteins.

Evaluation of the effects of inhibition of monoamine oxidase and senescence on methamphetamine-induced neuronal damage

The administration of high doses of methamphetamine causes long lasting damage to central dopaminergic and serotonergic neurons through a mechanism known to involve presynaptic, cytoplasmic stores of those transmitters and thought to be dependent upon a free radical reaction. The following studies were designed to determine if differential inhibition of the subtypes of monoamine oxidase would alter the magnitude of the methamphetamine induced neuronal damage. In addition, since monoamine oxidase type B increases with age, the effects of high dose administration of methamphetamine were evaluated in sensescent mice. It was observed that inhibition of monoamine oxidase type A, and to a lesser degree, type B, increased the magnitude of methamphetamine-induced neuronal damage and that aged mice were more sensitive to the toxic action of methamphetamine. These results are interpreted with respect to the use of monoamine oxidase inhibitors in the treatment of Parkinson's disease.

Effects of methamphetamine on central monoaminergic systems in normal and ascorbic acid-deficient guinea pigs

Repeated injections (s.c.) of methamphetamine (METH) were administered to normal and ascorbic acid-deficient (scorbutic) guinea pigs to assess a potential role for ascorbic acid in the METH-induced effects in central monoaminergic systems. The ascorbic acid-deficient condition differentially influenced the METH-induced responses of dopaminergic and serotonergic variables in the striatum: drug-induced changes in dopaminergic variables were identical in normal and scorbutic animals; METH-induced decreases in serotonergic variables [tryptophan hydroxylase activity, serotonin (5-HT) and 5-hydroxyindoleacetic acid concentrations], however, were prevented in scorbutic animals. The scorbutic condition did not alter significantly the distribution of METH in the brain, nor were striatal concentrations of dopamine (DA) or 5-HT affected. In vitro, ascorbic acid increased significantly DA-mediated [ 3H]5-HT release from striatal slices, thus suggesting a potential role for ascorbate in DA-mediated actions of METH on serotonergic systems. Although supplemental ascorbate failed to restore the METH-induced serotonergic effects in scorbutic guinea pigs, these data suggest that, in a normal animal, the effects of multiple injections of METH, on serotonergic systems, involve ascorbic acid.

Neurotoxic effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and methamphetamine in several strains of mice

We previously reported that C57 black mice were more sensitive than several other strains of mice to the neurotoxic actions of MPTP. We now report that a significantly higher amount of the 1-methyl-4-phenyl pyridinium species, a very toxic metabolite of MPTP, was found in the brains of C57 black mice than in the brains of CF-W or CD-1 mice, two strains of mice which are less sensitive to MPTP. In addition, we also found that there were strain differences in the response of mice to the neurotoxic actions of methamphetamine with CF-W mice being more sensitive to methamphetamine than C57 black mice.

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 methamphet-amine-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.

P-30) - Effect of Δ9-tetrahydrocannabinol (THC) on the action of methamphetamine (MAP)

P-30) - Effect of Δ9-tetrahydrocannabinol (THC) on the action of methamphetamine (MAP)

Influence of aggregation on the action of methamphetamine in locomotor activity.

Influence of aggregation on the action of methamphetamine in locomotor activity.

EFFECTS OF RUBIDIUM ON BEHAVIORAL RESPONSES TO METHAMPHETAMINE AND TETRABENAZINE

AbstractDifferent groups of mice were injected subcutaneously every other day with rubidium chloride at three doses (0.41(50), 1.23(150) and 3.69(450) meq/kg (mg/kg)) or with saline as a control for a period of 2-3 weeks. Rubidium administered acutely did not affect spontaneous locomotor activities, while it tended to increase the activities when administered repeatedly though the increase was not statistically significant. The methamphetamine-induced hyperlocomotor activities were potentiated in the rubidium groups as compared with those in the saline group, this effect of rubidium being increased with prolongation of repeated administrations. Monotonie decreases in ambulation after tetrabenazine were not significantly affected in the rubidium-treated animals though the decreases were sometimes preceded by slight increases and recovery from the decrement tended to be more rapid. After tetrabenazine in the rubidium-treated groups, incidences of catalepsy were increased and jumping behavior and Straub tail responses occurred in a few cases. The results suggest that rubidium potentiates the excitatory action of methamphetamine on spontaneous locomotor activities, as contrasted with inhibitory influence of lithium.