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PubMed2000

Multiple modes of hepatitis A virus transmission among methamphetamine users.

Methamphetamine users are at increased risk of hepatitis A, but modes of transmission are unclear. The authors conducted a case-control study among methamphetamine users during an outbreak in Iowa in 1997. Twenty-eight reported, laboratory-confirmed, hepatitis A cases did not differ from 18 susceptible controls with respect to age, sex, or number of doses used. When compared with controls in multivariate analysis, case-patients were more likely to have injected methamphetamine (odds ratio (OR) = 5.5, 95% confidence interval (CI): 1.1, 27), to have used methamphetamine with another case-patient (OR = 6.2, 95% CI: 0.95, 41), and to have used brown methamphetamine (OR = 5.5, 95% CI: 0.51, 59). Receptive needle sharing was reported by 10 of the 20 case-patients who injected. Methamphetamine use with another case-patient was also associated with hepatitis A in an analysis restricted to noninjectors (OR = 17, 95% CI: 1.0, 630). During this outbreak, hepatitis A may have been transmitted from person to person among methamphetamine users through the fecal-oral and the percutaneous routes. Methamphetamine users should be vaccinated against hepatitis A and should be given immune globulin if they used methamphetamine with a case-patient in the last 2 weeks. Persons who intend to continue using methamphetamine should be advised about safer practices.

Adolescent↗

PubMedDate not supplied

Improving ion mass ratio performance at low concentrations in methamphetamine GC-MS assay through internal standard selection.

In federally regulated drug testing, laboratories must identify and quantitate drugs and their breakdown products by gas chromatography-mass spectrometry (GC-MS) to a concentration that is at least 60% below the cutoff concentration for reconfirmation purposes. Use of methamphetamine-d5 as an internal standard in routine testing with derivatization by HFBA was found to contribute m/z 91 and 118 ions to the same ions from the nondeuterated methamphetamine in the specimen. This resulted in poor chromatography and occasionally caused the 91/254 and 118/254 ion mass ratios to exceed the +20% acceptance limit established in the calibration process at low concentrations. The analogues methamphetamine-d8 and -d11 were evaluated for contributions to the nondeuterated methamphetamine ion fragments. Methamphetamine-d8 produced m/z 91 and 118 ions, but in less abundance than methamphetamine-d5. Methamphetamine-d11 was found to produce little or no detectable m/z 91 or 118. Replacing methamphetamine-d5 with methamphetamine-d11 eliminates this problem and allows the assay to consistently produce ion mass ratios and acceptable chromatography sufficient for identifying and quantitating methamphetamine at 60% below the 500-ng/mL cutoff concentration.

Gas Chromatography-Mass Spectrometry↗

PubMed2005

Sustained reductions in drug use and depression symptoms from treatment for drug abuse in methamphetamine-dependent gay and bisexual men.

Methamphetamine abusers often complain of feelings of depression that can complicate accurately diagnosing these individuals during treatments for methamphetamine abuse. This article presents an examination of temporal associations between documented methamphetamine use and reported ratings of depression among 162 gay and bisexual male methamphetamine abusers who participated in a 16-week randomized clinical trial of four behavioral therapies for methamphetamine abuse. Methamphetamine use was measured using thrice-weekly urine samples analyzed for drug metabolite. Self-reported depressive symptoms were collected weekly using the Beck Depression Inventory (BDI). At treatment entry, 73.2% of participants rated their depressive symptoms as mild or higher in severity (BDI>or=10), with 28.5% reporting BDI scores in the moderate to severe range (BDI>or=19). All participants reported significant decreases in depressive symptoms from baseline through the end of treatment, regardless of treatment condition, HIV status, or mood disorder diagnosis. A mixed regression model showed methamphetamine use for up to 5 days prior to the BDI score strongly predicted depressive symptoms (F1, 968=18.6, P<.0001), while BDI scores had no significant association with subsequent methamphetamine use. Findings show that behavioral methamphetamine abuse treatment yields reductions in methamphetamine use and concomitant depressive symptom ratings that are sustained to 1 year after treatment entry.

Adolescent↗

PubMed2003

Effects of prenatal methamphetamine exposure on fetal growth and drug withdrawal symptoms in infants born at term.

To determine fetal growth and the incidence of withdrawal symptoms in term infants exposed to methamphetamine in utero, we retrospectively identified neonates whose mothers used methamphetamine during pregnancy and matched them to unexposed newborns. Exclusion criteria included multiple and preterm gestations. Although there were no differences in infant growth parameters between the methamphetamine-exposed and methamphetamine-unexposed neonates, methamphetamine exposure throughout gestation was associated with decreased growth relative to infants exposed only for the first two trimesters. In addition, there were significantly more small for gestational age infants in the methamphetamine group compared with the unexposed group. Methamphetamine-exposed infants whose mothers smoked had significantly decreased growth relative to infants exposed to methamphetamine alone. Withdrawal symptoms (as determined by a previously reported scoring system) requiring pharmacologic intervention were observed in 4% of methamphetamine-exposed infants. These preliminary findings indicate that methamphetamine use is associated with growth restriction in infants born at term.

Amphetamine-Related Disorders↗

PubMed2004

Urinary pharmacokinetics of methamphetamine and its metabolite, amphetamine following controlled oral administration to humans.

Methamphetamine is widely abused for its euphoric effects. Our objectives were to characterize the urinary pharmacokinetics of methamphetamine and amphetamine after controlled methamphetamine administration to humans and to improve the interpretation of urine drug test results. Participants (n = 8) received 4 daily 10-mg (low) oral doses of sustained-release (d)-methamphetamine hydrochloride within 7 days. After 4 weeks, 5 participants received 4 daily 20-mg (high) oral doses. All urine specimens were collected during the study. Methamphetamine and amphetamine were measured by GC-MS/PCI. Maximum excretion rates ranged from 403 to 4919 microg/h for methamphetamine and 59 to 735 microg/h for amphetamine with no relationship between dose and excretion rate. The mean molar percentage of dose in the urine as total methamphetamine and amphetamine were 57.5 +/- 21.7% (low dose) and 40.9 +/- 8.5% (high dose). Mean urinary terminal elimination half-lives across doses were 23.6 +/- 6.6 hours for methamphetamine and 20.7 +/- 7.3 hours for amphetamine. Methamphetamine renal clearance across doses was 175 +/- 102 mL/min. The mean amphetamine/methamphetamine percentage ratio based on the area under the urinary excretion-time curve increased over time from 13.4 +/- 6.5% to 35.7 +/- 26.6%. Slow urinary excretion results in drug accumulation and increases in detection time windows. Our findings also support the presence of an active renal excretion mechanism for methamphetamine.

Administration, Oral↗

PubMed2005

GABAergic modulation of the discriminative stimulus effects of methamphetamine.

To assess whether gamma-aminobutyric acid (GABA) modulation of dopamine is important in mediation of the discriminative stimulus effects of methamphetamine, the GABA compounds chlordiazepoxide (benzodiazepine site agonist), pentobarbital (barbiturate site agonist), bicuculline and pentylenetetrazol (GABA(A) receptor antagonists) were tested in Sprague-Dawley rats trained to discriminate methamphetamine (1 mg/kg, i.p.) from saline. Each of the compounds produced modest amounts of methamphetamine-appropriate responding (20-35%) when tested alone. When tested in combination with methamphetamine, the antagonists (bicuculline and pentylenetetrazol) failed to shift the methamphetamine dose-effect curve. In contrast, chlordiazepoxide (25 mg/kg, i.p.) reduced methamphetamine-appropriate responding at each dose of methamphetamine tested, and pentobarbital (10 mg/kg, i.p.) dose-dependently decreased the discriminative stimulus effects of 1 mg/kg methamphetamine. In conclusion, GABA(A) antagonists and positive modulators likely do not produce methamphetamine-like stimulus effects. However, activation of GABA(A) receptors can interfere with the discriminative stimulus effects of methamphetamine.

Animals↗

PubMed2005

Attenuated microglial activation mediates tolerance to the neurotoxic effects of methamphetamine.

Methamphetamine causes persistent damage to dopamine nerve endings of the striatum. Repeated, intermittent treatment of mice with low doses of methamphetamine leads to the development of tolerance to its neurotoxic effects. The mechanisms underlying tolerance are not understood but clearly involve more than alterations in drug bioavailability or reductions in the hyperthermia caused by methamphetamine. Microglia have been implicated recently as mediators of methamphetamine-induced neurotoxicity. The purpose of the present studies was to determine if a tolerance regimen of methamphetamine would attenuate the microglial response to a neurotoxic challenge. Mice treated with a low-dose methamphetamine tolerance regimen showed minor reductions in striatal dopamine content and low levels of microglial activation. When the tolerance regimen preceded a neurotoxic challenge of methamphetamine, the depletion of dopamine normally seen was significantly attenuated. The microglial activation that occurs after a toxic methamphetamine challenge was blunted likewise. Despite the induction of tolerance against drug-induced toxicity and microglial activation, a neurotoxic challenge with methamphetamine still caused hyperthermia. These results suggest that tolerance to methamphetamine neurotoxicity is associated with attenuated microglial activation and they further dissociate its neurotoxicity from drug-induced hyperthermia.

Animals↗

PubMed1996

Characteristics of behavioural stimulant effect of N-cyanomethylmethamphetamine, a main product of smoking methamphetamine mixed with tobacco: evaluation by ambulatory activity in mice.

N-cyanomethylmethamphetamine is main product of smoking methamphetamine HCl (CAS code value: 537-46-2, molar mass: 185.70 g/mol) mixed with tobacco, and has a central stimulant action. The aims of this study were to assess in terms of ambulation in mice whether repeated administration of N-cyanomethylmethamphetamine HCl (molar mass: 211.70 g/mol) induced sensitization to its central stimulant effect, and whether there were cross-sensitization from N-cyanomethylmethamphetamine HCl to methamphetamine HCl, and from methamphetamine HCl to N-cyanomethylmethamphetamine HCl. N-cyanomethylmethamphetamine HCl 14.2 and 47.2 mumol/kg subcutaneously dose-dependently accelerated ambulation of mice. Five administrations at 3 day intervals caused sensitization, the activity counts in the fifth administration being approximately 2.6 and 1.6 times, higher respectively, than those in the first administration. Furthermore, the mice repeatedly given 14.2 and 47.2 mumol/kg N-cyanomethylmethamphetamine HCl exhibited cross-sensitization to methamphetamine HCl (10.8 mumol/kg subcutaneously). Whereas 1.4 and 4.7 mumol/kg N-cyanomethylmethamphetamine HCl did not induce significant acceleration of the ambulation throughout the 5 repeated administrations, nor cross-sensitization to methamphetamine HCl. On the other hand, the 5 repeated administrations of methamphetamine HCl (10.8 mumol/kg) also caused sensitization to its ambulation-increasing effect, and the activity count in the fifth administration attained approximately 2.0 times higher than that in the first administration. The mice given methamphetamine HCl demonstrated cross-sensitization to 1.42-14.2 mumol/kg N-cyanomethylmethamphetamine HCl. Haloperidol (CAS code value: 52-86-8, molar mass: 375.88 g/mol; 0.027-0.80 mumol/kg subcutaneously) dose-dependently reduced the ambulation-increasing effects of N-cyanomethylmethamphetamine HCl and methamphetamine HCl in the drug-naive, and N-cyanomethylmethamphetamine HCl- and methamphetamine HCl-sensitized mice. These dose-effect relationships were similar between groups. The present results suggest that N-cyanomethylmethamphetamine HCl has a behavioural stimulant effect almost similar to that of methamphetamine HCl.

Amphetamines↗

PubMed2001

Comparison of cocaine- and methamphetamine-evoked dopamine and glutamate overflow in somatodendritic and terminal field regions of the rat brain during acute, chronic, and early withdrawal conditions.

Methamphetamine and cocaine are among the most commonly abused psychostimulants. Repeated injections of psychostimulants produce behavioral sensitization or augmented locomotion in rats. Behavioral sensitization to methamphetamine and cocaine is long lasting and persists after cessation of drug treatment. Because dopamine and glutamate are major neurotransmitters of the neostriatum, we evaluated the profile of cocaine- or methamphetamine-evoked dopamine and glutamate overflow in the caudate putamen, nucleus accumbens, ventral tegmental area, and substantia nigra compacta of the rat brain. We also compared acute exposure to these drugs with chronic treatment and early withdrawal. Acute injection of methamphetamine (1 mg/kg of body weight) or cocaine (10 mg/kg) resulted in elevated levels of extracellular dopamine in all brain regions measured, although the magnitude of increase varied between brain regions. Overall, methamphetamine caused more dopamine to accumulate in the extracellular space than did cocaine when administered to animals during early withdrawal (7 days of daily injections and challenge on day 11). For example, a challenge injection of methamphetamine produced a greater elevation of extracellular dopamine in the caudate putamen when compared to acute (naïve) exposure. By contrast, a challenge injection of cocaine resulted in dopamine levels in the caudate putamen that were lower than those observed for acute exposure. In the ventral tegmental area and the substantia nigra compacta, a challenge injection of methamphetamine or cocaine resulted in extracellular dopamine levels that were lower than those for acute exposure. Thus, it appears that behavioral sensitization to cocaine can be sustained during early withdrawal in the absence of augmented drug-evoked dopamine overflow. Acute injection of methamphetamine or cocaine did not change extracellular levels of glutamate in the neostriatum. Cocaine challenge (early withdrawal) increased glutamate overflow in the caudate putamen and the nucleus accumbens. In contrast, methamphetamine challenge increased glutamate overflow in the caudate putamen, but it decreased glutamate in the nucleus accumbens. In the ventral tegmental area and the substantia nigra compacta, acute methamphetamine exposure decreased glutamate overflow, but acute cocaine exposure increased it. Although amphetamines and cocaine induce similar behavioral responses, the results presented here demonstrate that at the neurochemical level (neurotransmitter release) they sometimes evoke opposite effects depending on the brain region studied and the duration of drug treatment. Moreover, the sensitized augmentation of locomotor activity observed by us and others in response to a challenge injection of cocaine is not dependent on elevation of the extracellular concentration of dopamine in the neostriatum. We are currently investigating the hypothesis that cocaine activates peptidergic systems of the neostriatum and that these systems modulate the synaptic release of dopamine in response to psychostimulants.

Animals↗

PubMed1989

Enhancement of dopamine actions on rat nucleus accumbens neurones in vitro after methamphetamine pre-treatment.

1. Intracellular recordings were made from the nucleus accumbens neurons in brain slices from rats previously treated with saline or methamphetamine. 2. In neurones from both methamphetamine- and saline (control)-treated rats, dopamine (0.1 mM) produced three types of responses: a biphasic response consisting of an initial hyperpolarization followed by a depolarization, a monophasic hyperpolarization and a simple depolarization. 3. Haloperidol (1 microM) reversibly suppressed both responses to dopamine; (-)-sulpiride (1 microM) selectively abolished the depolarization and prolonged the hyperpolarization. Forskolin (10 microM) and dibutyryl adenosine 3',5'-cyclic monophosphate (1 mM) mimicked the hyperpolarization. Both of the latter two substances were more effective in neurones from methamphetamine-treated rats than in neurones from control rats. 4. In slices from methamphetamine-treated rats, the dose-response curve for the dopamine hyperpolarization was shifted to the left of that seen in neurones from control rats by a factor of approximately 100. The dose-response curve for the dopamine depolarization was shifted to the right about 10-fold in neurones from rats treated with methamphetamine. 5. In slices from control rats, dopamine (less than or equal to 0.1 mM) and methamphetamine (less than or equal to 1 microM) had no effect on the EPSPs evoked by focal electrical stimulation of the periaccumbens regions: dopamine (greater than or equal to 10 nM) and methamphetamine (1 microM) markedly depressed the EPSPs in slices from methamphetamine-treated rats. Depolarizations evoked by application of exogenous glutamate were unaffected by dopamine (less than 5 microM). 6. In slices from methamphetamine-treated rats, dopamine (greater than or equal to 10 nM), forskolin (greater than or equal to 1 microM) and dibutyryl adenosine 3',5'-cyclic monophosphate (1 mM) depressed Ca2+-dependent spikes as well as the EPSPs. Haloperidol (1 microM) completely reversed the depressions of the EPSPs and Ca2+-dependent spikes by dopamine, while (-)-sulpiride (1 microM) was only partially effective. 7. These results indicate that chronic methamphetamine administration leads to enhancement of the actions of dopamine at D1 receptors located on glutamate and/or aspartate nerve terminals and of the dopamine hyperpolarization of principal neurones, which is also mediated by D1 receptors.

Action Potentials↗

PubMed2005

Effects of methamphetamine dependence and HIV infection on cerebral morphology.

OBJECTIVE: The authors examined the separate and combined effects of methamphetamine dependence and HIV infection on brain morphology. METHOD: Morphometric measures obtained from magnetic resonance imaging of methamphetamine-dependent and/or HIV-positive participants and their appropriate age- and education-matched comparison groups were analyzed. Main effects of age, HIV infection, methamphetamine dependence, and the interactions of these factors were examined in analyses of cerebral gray matter structure volumes. RESULTS: Independent of the effect of age, HIV infection was associated with reduced volumes of cortical, limbic, and striatal structures. There was also some evidence of an interaction between age and HIV infection such that older HIV-positive participants suffered disproportionate loss. Methamphetamine dependence was surprisingly associated with basal ganglia and parietal cortex volume increases, and in one of these structures-the nucleus accumbens-there appeared to be a larger effect in younger methamphetamine abusers. Neurocognitive impairment was associated with decreased cortical volumes in HIV-positive participants but with increased cortical volumes in methamphetamine-dependent participants. CONCLUSIONS: These results suggest significant brain structure alterations associated with both HIV infection and methamphetamine dependence. The regional patterns of the changes associated with these factors were distinct but overlapping, and the effects on brain volumes were opposing. Although the results of the present study provide little information about the specific mechanisms leading to the unexpected methamphetamine effects, they may be related to glial activation or neuritic growth, both of which have been associated with methamphetamine exposure in animal studies. These results have implications for the interpretation of brain morphological findings in methamphetamine-dependent, HIV-positive individuals, a group whose numbers are unfortunately increasing.

Adult↗

PubMed2000

Evidence for long-term neurotoxicity associated with methamphetamine abuse: A 1H MRS study.

OBJECTIVE: To determine whether proton MRS (1H MRS) can detect long-term metabolite abnormalities in abstinent methamphetamine users. BACKGROUND: Methamphetamine is toxic to dopaminergic and serotonergic neurons in rodents; however, little data are available on the toxic effects of methamphetamine on the human brain. METHODS: 1H MRS was performed in 26 abstinent methamphetamine abusers with a history of methamphetamine dependence (median total cumulative lifetime exposure, 3,640 g; median recency of last methamphetamine use, 4.25 months) and 24 healthy subjects without a history of drug abuse. Cerebral metabolite concentrations on 1H MRS were measured in the frontal cortex, frontal white matter, and basal ganglia. RESULTS: The concentration of N-acetylaspartate ([NA]), a neuronal marker, was reduced significantly (-5 to -6%) in the basal ganglia and frontal white matter of methamphetamine users compared with control subjects. The frontal white matter [NA] correlated inversely with the logarithm of the lifetime methamphetamine use. The methamphetamine users also showed significantly reduced total creatine in the basal ganglia (-8%), and increased choline-containing compounds ([CHO], +13%) and myo-inositol ([MI], +11%) in the frontal grey matter. CONCLUSIONS: The reduced [NA] on 1H MRS provides evidence for long-term neuronal damage in abstinent methamphetamine users.

Adult↗

PubMed1999

N-oxygenation of amphetamine and methamphetamine by the human flavin-containing monooxygenase (form 3): role in bioactivation and detoxication.

(+)- And (-)-amphetamine and methamphetamine were N-oxygenated by the cDNA expressed adult human flavin-containing monooxygenase form 3 (FMO3), their corresponding hydroxylamines. Two major polymorphic forms of human FMO3 were studied, and the results suggested preferential N-oxygenation by only one of the two enzymes. Chemically synthesized (+/-)-amphetamine hydroxylamine was also a substrate for the human FMO3 and it was converted to phenylpropanone oxime with a stereoselectivity ratio of trans/cis of 5:1. Human FMO3 also N-oxygenated methamphetamine to produce methamphetamine hydroxylamine. Methamphetamine hydroxylamine was also N-oxygenated by human FMO3, and the ultimate product observed was phenylpropanone. For amphetamine hydroxylamine, studies of the biochemical mechanism of product formation were consistent with the production of an N, N-dioxygenated intermediate that lead to phenylpropanone oxime. This was supported by the observation that alpha-deutero (+/-)-amphetamine hydroxylamine gave an inverse kinetic isotope effect on product formation in the presence of human FMO3. For methamphetamine, the data were consistent with a mechanism of human FMO3-mediated N,N-dioxygenation but the immediate product, a nitrone, rapidly hydrolyzed to phenylpropanone. The pharmacological activity of amphetamine hydroxylamine, phenylpropanone oxime, and methamphetamine hydroxylamine were examined for effects at the human dopamine, serotonin, and norepinephrine transporters. Amphetamine hydroxylamine and methamphetamine hydroxylamine were apparent substrates for the human biogenic amine transporters but phenylpropanone oxime was not. Presumably, phenylpropanone oxime or nitrone formation from amphetamine and methamphetamine, respectively, represents a detoxication process. Because of the potential toxic nature of amphetamine hydroxylamine and methamphetamine hydroxylamine metabolites and the polymorphic nature of N-oxygenation, human FMO3-mediated metabolism of amphetamine or methamphetamine may have clinical consequences.

Amphetamine↗

PubMed2001

Gender-dependent enhanced adult neurotoxic response to methamphetamine following fetal exposure to the drug.

Methamphetamine use by females of child-bearing age has become a major public health concern in terms of the long-term risk to the exposed fetus. We examined the possibility of enhanced adult neurotoxic potential of the drug in offspring that had been exposed to methamphetamine in utero during gestational days 7 to 18. While basal levels of monoamines were not affected by prenatal exposure to methamphetamine, we observed an enhanced neurotoxicity in adult male offspring following drug challenge with effects localized primarily to the dopaminergic nigrostriatal projection. This was evidenced by greater methamphetamine-induced reductions of dopaminergic markers in the striatum [dopamine (DA), dihydroxyphenylacetic acid, homovanillic acid (HVA), and 3-methoxytyramine (3-MT)] and ventral brainstem (DA) of prenatal methamphetamine-treated males compared with saline-treated animals. Some effects of prenatal methamphetamine exposure were observed in female offspring, but these were limited to striatal levels of 3-MT and HVA. Differential gender sensitivity to the neurotoxic effect of methamphetamine was shown to be correlated with hyperthermic response. Hyperthermic effects, however, do not account for the increased susceptibility of prenatal methamphetamine-treated males to drug-induced striatal DA neurotoxicity since methamphetamine challenge did not evoke a significantly greater hyperthermic response in these animals compared with prenatal saline-treated males. The findings raise the concern that male methamphetamine abusers may be at risk for an enhanced neurotoxic risk if they were exposed to the drug in utero.

Animals↗

PubMed1978

Enhancement of morphine analgesia and brain levels by methamphetamine in mice.

Methamphetamine and morphine were approximately equipotent in producing analgesia in mice using the tail-flick assay. The ED50 for morphine analgesia was significantly reduced when 3.2 mg/kg of methamphetamine was given 5 or 60 min before morphine. Methamphetamine pretreatment increased the peak effect but did not alter the duration of morphine analgesia. Enhancement of morphine analgesia was apparent when methamphetamine was given up to 60 min before morphine and it did not coincide with analgesia produced by methamphetamine alone. Brain levels of morphine were found to be significantly higher in methamphetamine- compared to saline-pretreated mice, at times when enhanced analgesia was observed. Further studies showed that morphine brain levels were increased by methamphetamine pretreatment in an apparent dose-dependent manner. The analgesia observed at several morphine brain levels was compared in order to determine whether enhanced analgesia resulted from increased morphine brain levels. Methamphetamine administration 5 or 60 min before morphine shifted the log morphine brain level-response curves for morphine analgesia to the left and the morphine brain level at a given percent analgesia was significantly lower in methamphetamine- than in saline-pretreated mice. In addition, methamphetamine pretreatment enhanced methadone analgesia but had no effect on methadone brain levels.

Analgesia↗

PubMed2002

Acute methamphetamine administration upregulates NGFI-B mRNA expression in the striatum: co-localization with c-Fos immunoreactivity.

In this study, the effects of acute methamphetamine administration on expression of the nuclear transcription factor NGFI-B mRNA and its co-localization with c-Fos immunoreactivity in the striatum were evaluated in animals receiving a single dose of methamphetamine (4 mg/kg) given at 2 or 6 h prior to perfusion. All animals received a daily saline injection for 6 days prior to methamphetamine treatment. We have found that, similar to c-fos activation, NGFI-B mRNA levels were significantly increased 2 h after methamphetamine treatment and returned to basal levels 6 h later. Induction of NGFI-B mRNA levels by methamphetamine was highest in central striatum as compared to the dorsomedial distribution pattern observed in control animals. After acute methamphetamine treatment, the distribution pattern of NGFI-B mRNA upregulation was very similar to that of methamphetamine induced c-Fos immunoreactivity. However, co-localization studies with c-Fos immunoreactivity showed that not all NGFI-B-positive cells contained c-Fos after methamphetamine treatment. Forty-five percent of all NGFI-B mRNA expressing neurons contained c-Fos immunoreactivity in the dorsomedial striatum as compared to 60% in central and 35% in ventrolateral striatum. This study provides a detailed description of the differential spatial and temporal modulation of NGFI-B and c-Fos expression in the striatum by acute methamphetamine treatment over time.

Animals↗

PubMed1993

Prenatal methamphetamine attenuates serotonin mediated renin secretion in male and female rat progeny: evidence for selective long-term dysfunction of serotonin pathways in brain.

In adult rats, methamphetamine produces biochemical alterations in brain serotonin (5-HT) neurons. Since 5-HT is critical to the development of fetal 5-HT neurons and target tissues, we hypothesized that in utero exposure to methamphetamine could result in long-term alterations in postnatal 5-HT systems. Pregnant Sprague-Dawley rats, administered either saline or (+/-)methamphetamine (5 mg/kg, s.c., b.i.d.) from gestational day 13 to 20, were divided into three treatment groups: Saline-injected/Ad Lib Fed (VEH); Saline-injected/Pair Fed (PF); and methamphetamine injected (METH). Prenatal methamphetamine exposure did not alter litter size, gender number, or progeny birth weights. Functional alterations in serotonergic systems were determined in postnatal day (PD) 70 male progeny and in PD 30 female progeny by measuring changes in 5-HT mediated increases in plasma hormones following a single injection of the 5-HT releaser p-chloroamphetamine (PCA; 8 mg/kg). Prenatal methamphetamine produced long-term marked (-30 to -62%) attenuation of plasma renin responses to PCA in male and female progeny. In contrast, no alterations were observed in the ACTH, corticosterone, or prolactin responses to PCA in male and female progeny. Prenatal methamphetamine did not alter basal levels of any hormones measured regardless of gender. No significant differences were observed in the density of cortical or hypothalamic 5-HT uptake sites, or in the density of cortical 5-HT1 or 5-HT2 receptors in male progeny. The lack of significant differences in cortical 5-HT uptake sites observed between PF and METH treated dams 2 days post-parturition indicates that methamphetamine was not neurotoxic to the pregnant dams. These data, which demonstrate longterm postnatal deficits in 5-HT mediated renin secretion, suggest selective functional alterations of brain 5-HT systems in male and female progeny exposed in utero to methamphetamine.

Analysis of Variance↗

PubMed1985

Role of the serotonin uptake carrier in the neurochemical response to methamphetamine: effects of citalopram and chlorimipramine.

The role of the serotonin uptake carrier in the methamphetamine-induced depression of serotonin synthesis was examined. In vivo, coadministration of citalopram or chlorimipramine with methamphetamine blocked the irreversible depression of tryptophan hydroxylase activity observed in the neostriatum and cerebral cortex after repeated administration of high doses of methamphetamine. The methamphetamine-induced reduction of neostriatal serotonin and 5-hydroxyindoleacetic acid was also attenuated by the two uptake inhibitors. In contrast, neither drug antagonized the depression of neostriatal tyrosine hydroxylase activity observed after methamphetamine administration. Citalopram also blocked the reversible inhibition of tryptophan hydroxylase activity observed after the acute administration of methamphetamine. In vitro, citalopram significantly inhibited methamphetamine-induced [3H]serotonin release from neostriatal slices. The results demonstrate that inhibitors of the serotonin uptake carrier can antagonize both the in vivo and in vitro effects of methamphetamine on serotonergic neurons. Furthermore, the methamphetamine-induced depression of serotonin synthesis is dependent upon a functional serotonin uptake system.

3,4-Dihydroxyphenylacetic Acid↗