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PubMed2005

Etiology of xerostomia and dental caries among methamphetamine abusers.

This study reviews the peripheral effects of methamphetamine on the salivary acini, the pathogenesis of methamphetamine-induced xerostomia, and its anecdotal relationship to dental caries. Methamphetamine is a sympathomimetic central stimulant which is abused for its euphoric effects. Its pharmacological action is exerted indirectly by sustaining high levels of catecholamines in the synaptic cleft and directly by binding to the postsynaptic adrenergic receptors. Methamphetamine abusers report subjective perception of xerostomia, which cannot be explained by the direct peripheral action of methamphetamine on the secretory acini. The drug may cause a decrease in salivary flow rate by centrally inhibiting salivatory nuclei via stimulation of alpha-2 receptors in the brain. Drug mediated dehydration state may influence the perception of dry mouth in abusers. The decreased salivary flow rate, either due to a central inhibitory action of methamphetamine or generalised dehydration, likely contributes to the increased occurrence of dental caries. Five cases of methamphetamine abuse are presented, three of whom experienced rampant dental caries. A direct association between methamphetamine abuse and the occurrence of rampant caries was not clear.

Adult↗

PubMed2006

Impact of cannabinoid receptor ligands on behavioural sensitization to antiaggressive methamphetamine effects in the model of mouse agonistic behaviour.

OBJECTIVES: Psychostimulants and cannabinoids can elicit so called behavioural sensitization after repeated administration, a gradually increased behavioural response to a drug. This phenomenon if conditioned by previous pre-treatment with different drug is termed cross-sensitization. The present study was focused on a possible sensitisation to antiaggressive effect of methamphetamine and cross-sensitization to this effect after repeated pre-treatment with cannabinoid CB1 and CB2 receptor ligands with different intrinsic activity (CB1 agonist methanandamide, CB2 agonist JWH 015, and CB1 antagonist AM 251). METHODS: Behavioural interactions of singly-housed mice with non-aggressive group-housed partners were video-taped and behavioural elements of agonistic behaviour of isolates were recorded in four categories: sociable, timid, aggressive and locomotor. RESULTS: Repeated administration of methamphetamine elicited a significant sensitization to its antiaggressive effects. Methanandamide pre-treatment provoked cross-sensitization to this methamphetamine effect, whereas pre-treatment with JWH 015 did not. Combined pre-treatment with methamphetamine+AM 251 suppressed the sensitization to antiaggressive effects of methamphetamine. CONCLUSIONS: Our findings have shown that it is possible to provoke sensitization not only to the stimulatory effects as stated widespread in the literature but also to inhibitory antiaggressive effects of methamphetamine. Furthermore, we confirmed our working hypothesis that it is possible to elicit either cross-sensitization to inhibitory effects of methamphetamine conditioned by repeated pre-treatment with cannabinoid CB1 receptor agonist methanandamide, or suppression of methamphetamine sensitizing influence by co-administration of CB1 receptor antagonist.

Agonistic Behavior↗

PubMed1989

Interaction between caffeine and methamphetamine by means of ambulatory activity in mice.

Effects of repeated administration of caffeine as well as interaction between caffeine and methamphetamine were investigated by means of ambulatory activity in mice. The single administration of caffeine increased the ambulatory activity at 10 and 30 mg/kg, sc, but scarcely increased at 3 mg/kg and at 100 mg/kg which is a subconvulsive dose. Methamphetamine 2 mg/kg, sc also increased the ambulatory activity. The combined administration of caffeine (1-100 mg/kg) and methamphetamine (2 mg/kg) showed a synergistic action as compared with the effects of the individual drugs. The repeated 5-times administration of caffeine (10, 30, and 100 mg/kg) at intervals of 3-4 days produced neither tolerance nor reverse tolerance to caffeine. The caffeine-experienced mice showed no marked change in the sensitivity to the ambulation-increasing effect of methamphetamine 2 mg/kg. In contrast, the repeated administration of methamphetamine 2 mg/kg induced not only reverse tolerance to methamphetamine itself but also cross reverse tolerance to caffeine (30 mg/kg). Furthermore, the methamphetamine-experienced mice also showed an increased activity after challenge administration of saline. The present results suggest that, although caffeine showed central stimulant effect, the characteristics are different from those of methamphetamine.

Animals↗

PubMed1995

Methamphetamine-induced toxicity in cultured adult rat cardiomyocytes.

In an attempt to differentiate the direct effects of methamphetamine from the indirect sympathomimetic effects on the myocardium, primary culture of adult rat myocytes were established under serum-free conditions, and they were exposed to methamphetamine (1 x 10(-5) and 1 x 10(-3) M) for 1 to 24 h in the presence and absence of 1 x 10(-6) M propranolol. Cardiotoxicity was evaluated by light and ultramicroscopy, release of cytoplasmic enzymes (Lactate dehydrogenase: LDH and Creatine phosphokinase: CPK) and change in membrane permeability (Trypan blue stain). After 24 h methamphetamine treatment, light microscopy exhibited cellular granulation and swelling, myocyte hypercontraction, broken cellular membrane and cellular destruction. After the same time, electron microscopy revealed swelling and irregular mitochondria with disrupted cristaes, clump of sarcomeres with nearly complete loss of organized contractile elements, injury of intracellular membrane system and dissolution of myofibrils. These injurious features were more severe with the 1 x 10(-3) M methamphetamine. Propranolol (1 x 10(-6) M), a beta-adrenergic antagonist, failed to protect the myocytes against methamphetamine-induced cell injury. Release of LDH from methamphetamine (1 x 10(-5) and 1 x 10(-3) M)-treated myocytes increased significantly only after 24 h, while significant CPK release was observed in 1 x 10(-3) M methamphetamine-treated myocytes at 4 h. These findings suggest that methamphetamine exerts direct toxic effects on adult rat myocytes rather than indirect ones via receptors, although further experiments on more concentrations of propranolol are required.

Animals↗

PubMed1998

Brain dopamine neurotoxicity in baboons treated with doses of methamphetamine comparable to those recreationally abused by humans: evidence from [11C]WIN-35,428 positron emission tomography studies and direct in vitro determinations.

The present study sought to determine whether doses of methamphetamine in the range of those used recreationally by humans produce brain dopamine (DA) neurotoxicity in baboons and to ascertain whether positron emission tomography (PET) imaging with the DA transporter (DAT) ligand [11C]WIN-35,428 ([11C]2beta-carbomethoxy-3beta-(4-fluorophenyl)-tropane) could be used to detect methamphetamine-induced DAT loss in living primates. Baboons were treated with saline (n = 3) or one of three doses of methamphetamine [0.5 mg/kg (n = 2); 1 mg/kg (n = 2); and 2 mg/kg (n = 3)], each of which was given intramuscularly four times at 2 hr intervals. PET studies were performed before and 2-3 weeks after methamphetamine treatment. After the final PET studies, animals were killed for direct neurochemical determination of brain DA axonal markers. PET-derived binding potential values, used to index striatal DAT density, were significantly decreased after methamphetamine, with larger decreases occurring after higher methamphetamine doses. Reductions in striatal DAT documented by PET were associated with decreases in DA, dihydroxyphenylacetic acid, and specific [3H]WIN-35,428 and [3H]DTBZ binding determined in vitro. Decreases in DAT detected with PET were highly correlated with decreases in specific [3H]WIN-35,428 binding determined in vitro in the caudate of the same animal (r = 0.77; p = 0.042). These results indicate that methamphetamine, at doses used by some humans, produces long-term reductions in brain DA axonal markers in baboons, and that it is possible to detect methamphetamine-induced DAT loss in living nonhuman primates by means of PET.

Animals↗

PubMed1998

Noradrenergic modulation of methamphetamine-induced striatal dopamine depletion.

Noradrenergic (NE) neurons belonging to the locus coeruleus (LC), much more than the A1 and A2 areas, are lost in Parkinson's disease (PD). In this study, we reproduced the selective pattern of NE loss involving axons arising from the LC using the selective neurotoxin N-(-2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) (50 mg/kg). In these experimental conditions, we investigated whether NE loss potentiates methamphetamine-induced striatal dopamine (DA) depletion in mice and rats. Administration of a moderate dose of methamphetamine to C57B1/6N mice or Sprague-Dawley rats produced only a partial striatal DA depletion 7 days after drug administration. Pre-treatment with DSP-4, in both animal species, significantly enhanced methamphetamine-induced striatal DA depletion. Administration of a lower dose of methamphetamine did not decrease striatal DA levels when injected alone, but produced a significant decrease in striatal DA when given to DSP-4-pretreated rodents. Moreover, we found that agents reducing the noradrenergic activity (i.e., the alpha-2 agonist clonidine) enhanced, whereas alpha-2 antagonists decreased, methamphetamine toxicity. Enhancement of methamphetamine toxicity did not occur if the noradrenergic lesion was produced 12 hr after methamphetamine administration. By contrast, exacerbation of methamphetamine toxicity in NE-depleted animals was accompanied by increased extracellular DA levels measured with brain dialysis and by a more severe acute DA depletion measured in striatal homogenates.

Adrenergic Agents↗

PubMed1999

Dopamine quinone formation and protein modification associated with the striatal neurotoxicity of methamphetamine: evidence against a role for extracellular dopamine.

Methamphetamine-induced toxicity has been shown to require striatal dopamine and to involve mechanisms associated with oxidative stress. Dopamine is a reactive molecule that can oxidize to form free radicals and reactive quinones. Although this has been suggested to contribute to the mechanism of toxicity, the oxidation of dopamine has never been directly measured after methamphetamine exposure. In this study we sought to determine whether methamphetamine-induced toxicity is associated with the oxidation of dopamine by measuring the binding of dopamine quinones to cysteinyl residues on protein. We observed that administration of neurotoxic doses of methamphetamine to rats resulted in a two- to threefold increase in protein cysteinyl-dopamine in the striatum 2, 4, and 8 hr after treatment. When methamphetamine was administered at an ambient temperature of 5 degreesC, no increase in dopamine oxidation products was observed, and toxicity was prevented. Furthermore, as shown by striatal microdialysis, animals treated with methamphetamine at 5 degreesC showed DA release identical to that of animals treated at room temperature. These data suggest that the toxicity of methamphetamine and the associated increase in dopamine oxidation are not exclusively the result of increases in extracellular dopamine. Because dopamine-induced modifications of protein structure and function may result in cellular toxicity, it is likely that dopamine oxidation contributes to methamphetamine-induced toxicity to dopamine terminals, adding support to the role of dopamine and the evidence of oxidative stress in this lesion model.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2002

Fetal exposure to methamphetamine in utero stimulates development of serotonergic neurons in three-dimensional reaggregate tissue culture.

Methamphetamine is a potent psychomotor stimulant with neurotoxic potential which is widely abused by females of childbearing age, raising serious public health concerns in terms of exposure of the fetus to the drug. The current study was conducted to determine the effect of maternal administration of methamphetamine on developing monoaminergic neurons using three-dimensional reaggregate tissue cultures prepared from fetal mesencephalic and striatal cells. In this culture system, the dopaminergic and serotonergic mesencephalic-striatal projections are reconstructed and develop with a time course similar to that observed in vivo. Pregnant C57Bl/6J mice were injected twice daily with 40 mg/kg methamphetamine or saline from gestational days 6-13. On gestational day 14, cells from methamphetamine and saline-exposed embryos were used to prepare reaggregate cultures. Levels of neurotransmitters and their metabolites in the reaggregates and culture medium were monitored at 14, 29, 43, and 64 days of culture. Reaggregates prepared from methamphetamine-exposed embryos showed a significant elevation in serotonin levels at all culture ages compared to reaggregates prepared from saline-treated embryos. Levels of 5-HIAA in reaggregates and culture medium were also elevated in 14- and 29-day-old cultures derived from drug-exposed embryos. The development of the dopaminergic nigrostriatal projection was resistant to repeated in utero exposure to methamphetamine. In contrast, exposure of the fetus to methamphetamine, during early to midgestation, produced a long-lasting stimulatory effect on serotonergic development in culture.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2004

Methamphetamine-induced loss of striatal dopamine innervation in BDNF heterozygote mice does not further reduce D3 receptor concentrations.

Depletion of dopamine (DA) reduces D(3) receptor number, but D(3) receptor expression is also regulated by brain-derived neurotrophic factor (BDNF). We took advantage of transgenic heterozygous BDNF mutant mice (+/-) to determine if reduced BDNF and loss of DA fibers produced by methamphetamine were additive in their impact on D(3) receptor number. We assessed selective markers of the dopaminergic system including caudate-putamen DA concentrations and quantitative autoradiographic measurement of tyrosine hydroxylase (TH) levels, DA transporter (DAT), and DA D(3) receptor binding between vehicle and methamphetamine-treated BDNF +/- and their wildtype (WT) littermate control mice. Caudate-putamen DA concentrations, TH and DAT levels were significantly reduced following methamphetamine treatment in both WT and BDNF +/- mice. The extent of methamphetamine-induced reduction in TH and DAT was greater for the WT than BDNF +/- mice and DAT levels were also decreased to a greater extent in nucleus accumbens of WT as compared to BDNF +/- mice. Lower D(3) receptor existed in caudate-putamen and nucleus accumbens in BDNF +/- mice and these differences were not affected by methamphetamine treatment. Taken together, these results not only substantiate the importance of BDNF in controlling D(3) receptor expression, but also indicate that a methamphetamine-induced depletion of DA fibers fails to produce an additive effect with lowered BDNF for control of D(3) receptor expression. In addition, the reduction of D(3) receptor expression is associated with a decreased neurotoxic response to methamphetamine in BDNF +/- mice.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1995

Protective effects of MK-801 on methamphetamine-induced depletion of dopaminergic and serotonergic terminals and striatal astrocytic response: an immunohistochemical study.

It has been shown previously that methamphetamine induces dopaminergic nerve terminal degeneration, serotonin depletion and striatal reactive astrogliosis, and that the noncompetitive N-methyl-D-aspartate (NMDA) antagonist MK-801 can block methamphetamine (MA)-induced depletion of dopamine and serotonin and reduction in activity of their synthetic enzymes. In this study, immunohistochemistry was used to evaluate the effect of MK-801 on methamphetamine-induced neuropathological alterations of dopaminergic and serotonergic terminals and striatal astrocytic responses. Adult male rats were treated with methamphetamine (4 injections of 10 mg/kg at 2 hour intervals) in conjunction with MK-801 which was administered 15 min before each methamphetamine administration at doses of 1 mg/kg or 2 mg/kg. Brains were examined three days following treatment. MK-801 administration prevented methamphetamine-induced depletion of 5-hydroxytryptophan (5-HT) terminals in the forebrain and depletion of tyrosine hydroxylase-positive dopaminergic terminals and astrocytic response in the neostriatum in most animals. These results support the concept that excitatory amino acids acting through an NMDA receptor are involved in methamphetamine-induced neuronal damage on dopaminergic and serotonergic terminal fields. A minor depletion of TH-positive terminals and astrogliosis in the neostriatum was seen in three of nine MA-MK-801-treated animals. This indicates that the protective effects of MK-801 on MA-induced dopaminergic terminal degeneration varies among animals with complete protection in most animals and partial protection in the others using the present doses and dosing regimen.

Animals↗

PubMed1989

Functional consequences following methamphetamine-induced neuronal damage.

The functional consequences following methamphetamine-induced neuronal damage were evaluated under several different conditions known to affect the magnitude of the lesion. It was found that methamphetamine (6.25 mg/kg administered SC, four times at 2-h intervals) caused long-lasting depletions of striatal dopamine and serotonin and that pretreatment with the antioxidant, ascorbic acid (100 mg/kg), attenuated these depletions, whereas pretreatment with the superoxide dismutase inhibitor diethyldithiocarbamate (200 mg/kg) exacerbated these depletions. The dopamine depletions resulting from the repeated administration of methamphetamine under these various conditions did not result in any alteration in the consumption of a sweetened-condensed milk solution under baseline conditions. However, when these lesioned animals were challenged with acutely administered methamphetamine, it was observed that there was an altered sensitivity to the milk intake decreasing effects of this compound. That is, the degree to which the acutely administered methamphetamine reduced the intake of sweetened-condensed milk was highly correlated with the magnitude of the methamphetamine-induced dopamine and serotonin depletions. These observations support the hypothesis that methamphetamine-induced neuronal damage is mediated by free radical formation and indicate that behavioral measures may be employed to assess neuronal damage.

Animals↗

PubMed2005

Prolonged exposure of rats to intravenous methamphetamine: behavioral and neurochemical characterization.

The translational value of preclinical models of methamphetamine abuse depends in large part on the degree to which the drug regimens used in animals produce methamphetamine exposure patterns similar to those experienced by human methamphetamine abusers. To approximate one common form of methamphetamine abuse, we studied the effects of a schedule of intravenous methamphetamine administration in rats which included 2 weeks of progressively more frequent drug injections (0.125 mg/kg/injection) followed by 40 maintenance days during which animals received 40 daily injections (at 15-min intervals), with the dose gradually increasing (0.125-0.25 mg/kg per injection) every 5-10 days. This treatment produced an emerging behavioral profile characterized by gradually more continuous periods of activation consisting of progressively more intense, focused stereotypy interrupted by episodic bursts of locomotion. We also assessed markers of dopamine neurotransmission (dopamine transporter, vesicular monoamine transporter, and dopamine D1 and D2 receptors) at 15 min and (including dopamine levels) at 6 and 30 days following cessation of methamphetamine treatment. All dopamine components measured in caudate-putamen were significantly reduced at 15 min and 6 days after the final methamphetamine injection. Dopamine D1 and D2 receptors fully recovered after 30 days of drug abstinence, whereas dopamine and the dopamine transporter exhibited significant but incomplete recovery by this time point. In contrast, only the vesicular monoamine transporter exhibited no evidence of recovery over the 30-day withdrawal period. These data are discussed in terms of damage to dopamine terminals and compensatory adjustments in mechanisms maintaining functional dopaminergic transmission.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2000

Estrogen and progesterone distinctively modulate methamphetamine-induced dopamine and serotonin depletions in C57BL/6J mice.

Intra-striatal infusion of a high dose (100 microg/3 microl) of methamphetamine produced long-lasting depletions of striatal dopamine and serotonin in both male and female mice. Male mice exhibited a greater depletion of striatal dopamine and serotonin than female mice. A similar trend of sexual differences was observed when 4 cumulative doses of methamphetamine were administered systemically. Thus, the sexual differences in methamphetamine-induced neurotoxicity in the striatum are probably not due to their differences in peripheral metabolism of methamphetamine. Moreover, ovariectomized (OVX) mice supplemented with 3 daily doses of estradiol benzoate (EB) at high or physiological levels, 3 daily doses of progesterone (P), and 2 doses of EB followed by 1 dose of P all demonstrated higher striatal dopamine levels following methamphetamine treatment as compared to vehicle-supplemented controls. The OVX mice pretreated with 3 daily doses of P exhibited the highest striatal serotonin levels after methamphetamine administration of all groups. In conclusion, sexual differences observed in methamphetamine-induced striatal neurotoxicity may be modulated by ovarian hormones.

Animals↗

PubMed2006

Associations between methamphetamine use and HIV among men who have sex with men: a model for guiding public policy.

Among men who have sex with men (MSM) in Los Angeles County, methamphetamine use is associated with high rates of HIV prevalence and sexual risk behaviors. In four separate samples of MSM who differed in the range of their intensity of methamphetamine use, from levels of recreational use to chronic use to those for MSM seeking drug abuse treatment, the association between methamphetamine use and HIV infection increased as the intensity of use increased. The lowest HIV prevalence rate (23%) was observed among MSM contacted through street outreach who mentioned recent methamphetamine use, followed by MSM who used at least once a month for six months (42%), followed by MSM seeking intensive outpatient treatment (61%). The highest rate (86%) was observed among MSM seeking residential treatment for methamphetamine dependence. The interleaving nature of these epidemics calls for comprehensive strategies that address methamphetamine use and concomitant sexual behaviors that increase risk of HIV transmission in this group already at high risk. These and other data suggest that MSM who infrequently use methamphetamine may respond to lower intensity/lower cost prevention and early intervention programs while those who use the drug at dependence levels may benefit from high intensity treatment to achieve goals of reduced drug use and HIV-risk sexual behaviors.

Amphetamine-Related Disorders↗

PubMed2005

The methamphetamine epidemic: implications for HIV prevention and treatment.

Methamphetamine and related amphetamine compounds are among the most commonly used illicit drugs, with over 35 million users worldwide. In the United States, admissions for methamphetamine treatment have increased dramatically over the past 10 years. Methamphetamine use is prevalent among persons with HIV infection and persons at risk for HIV, particularly among men who have sex with men. In addition to being associated with increased sexual risk behavior, methamphetamine causes significant medical morbidity, including neurologic deficits, cardiovascular compromise, dental decay, and skin infections, all of which may be worsened in the presence of HIV/AIDS. Methamphetamine use may also result in decreased medication adherence, particularly during "binging" episodes. Behavioral counseling remains the standard of treatment for methamphetamine dependence, although the effectiveness of most counseling interventions has not been rigorously tested. Pharmacologic and structural interventions may prove valuable additional interventions to reduce methamphetamine use.

Amphetamine-Related Disorders↗

PubMed1992

Acute and persistent effects of methamphetamine on developing monoaminergic neurons in reaggregate tissue culture.

Three-dimensional, rotation-mediated reaggregate tissue cultures composed of rostral mesencephalic cells and corpus striatal cells were used to examine the short-term and persistent effects of methamphetamine on developing monoamine-containing neurons. Reaggregates were exposed to drug for one week. Reductions in reaggregate endogenous dopamine and serotonin levels occurred following treatment with methamphetamine during days 15-22 of culture over the concentration range 10(-7) to 10(-4) M. The highest methamphetamine concentration reduced dopamine and serotonin levels to 29 and 33%, respectively, of control values. Monoamine levels were reduced from control values after 3 days of exposure to 10(-4) M methamphetamine. No further reduction resulted from 4 additional days of drug treatment. In order to determine whether monoaminergic neurons would recover from the drug-induced deficit, reaggregates were exposed to 10(-4) M methamphetamine for 7 days and then grown in drug-free media for an additional 20 days. During the 20 day recovery period, monoamine levels in the control group increased with time in culture. After an initial rapid increase (recovery days 0-9), the level of monoamines in the recovery group remained at a constant proportion to the level in the control group suggesting that the monoaminergic neurons return to a rate of development similar to that seen in untreated cultures. However, this rate was not sufficient to overcome the reduction in monoamine levels produced by 7 days of methamphetamine treatment. The results indicate that the effects of methamphetamine on developing monoaminergic neurons are marked and persistent.

Animals↗

PubMed1980

Blockade of methamphetamine-induced depression of tyrosine hydroxylase by GABA transaminase inhibitors.

Tyrosine hydroxylase (TH) levels in the rat neostriatum are decreased by chronic treatment with methamphetamine. GABAergic neurons could potentially interact with the nigrostriatal dopaminergic neurons in either the neostriatum or the substantia nigra; therefore, the GABA transaminase inhibitors, amino-oxyacetic acid, gamma-acetylenic GABA and ethanolamine-O-sulfate, were evaluated for possible influences on the methamphetamine-induced decrease in TH. TH was measured by the procedure of Nagatsu et al. (1964). Methamphetamine (10 mg/kg, s.c.) was given every 6 h for 24 h. Thirty-six h after initiation of the methamphetamine treatment, neostriatal TH activity was approximately 70% of control. Concurrent administration of amino-oxyacetic acid (20 mg/kg, i.p.) or gamma-acetylenic GABA (15 mg/kg, i.p.) with methamphetamine completely blocked the TH depression. Dose-response curves were constructed for amino-oxyacetic acid and gamma-acetylenic GABA. A single intraventricular injection of ethanolamine-O-sulfate (400 micrograms/rat), 2-6 h before initiating the methamphetamine regimen, also completely blocked the TH depression. These data suggest that the striatonigral or other GABAergic systems are involved in the regulation of the functional state of the nigrostriatal dopaminergic neurons, and that enhanced GABAergic function will antagonize the effects of high doses of methamphetamine.

4-Aminobutyrate Transaminase↗

PubMed1985

Role of the dopamine uptake carrier in the neurochemical response to methamphetamine: effects of amfonelic acid.

Repeated administration of large doses of methamphetamine depresses both neostriatal tyrosine hydroxylase and tryptophan hydroxylase activity. Neostriatal concentrations of dopamine, serotonin and their acidic metabolites are similarly reduced by methamphetamine. Coadministration of the dopamine uptake inhibitor, amfonelic acid, selectively prevented the methamphetamine-induced decrease in tyrosine hydroxylase activity while not altering the depression of tryptophan hydroxylase activity. In vitro, amfonelic acid blocked methamphetamine-induced [3H]dopamine release from neostriatal slices but had no effect on [3H]serotonin release. In experiments conducted with [3H]amphetamine and amfonelic acid, no evidence was found for carrier-mediated transport of amphetamine. The results demonstrate a role for the dopamine uptake carrier in the neurochemical effects of high doses of methamphetamine. Furthermore, the ability of amfonelic acid to antagonize the neurochemical effects of methamphetamine appears to be due to an inhibition of carrier-mediated dopamine efflux rather than carrier-mediated uptake of methamphetamine.

3,4-Dihydroxyphenylacetic Acid↗