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PubMed2006

Effects of terguride, ropinirole, and acetyl-L-carnitine on methamphetamine withdrawal in the rat.

Withdrawal from psychostimulants, including methamphetamine, induces a depressive state associated with lethargy, dysphoria, hyperphagia and psychomotor retardation. Previous work with repeated administration of amphetamine in rats has shown that amphetamine withdrawal produces decreased motivation to work for a non-drug reward, and this withdrawal is reversed by administration of a dopamine partial agonist. The purpose of the present study was to examine decreased motivation to work for a non-drug reward during methamphetamine withdrawal and explore the effects of a dopamine agonist, dopamine partial agonist, and indirect monoamine agonist on methamphetamine withdrawal. During withdrawal from repeated methamphetamine administration, rats showed reduced responding for a sweet solution in a progressive-ratio schedule of reinforcement, and this effect was significantly more pronounced than previously observed with amphetamine. Repeated systemic treatment with the dopamine partial agonist terguride (0.2 and 0.4 mg/kg, i.p., twice daily), the full dopamine agonist ropinirole (1 mg/kg, i.p., twice daily), and acetyl-L-carnitine (60 and 100 mg/kg, i.p.), a compound with a potential antidepressant effect, during methamphetamine withdrawal restored responding for the sweet solution, suggesting that these drugs may represent potential therapeutic strategies for the treatment of methamphetamine addiction during the withdrawal phase.

Acetylcarnitine↗

PubMed2004

Nerve growth factor protects R2 cells against neurotoxicity induced by methamphetamine.

It is well known that methamphetamine is a neurotoxic drug of abuse to cause cell death both in vitro and in vivo. In this study, the protective effect of nerve growth factor on methamphetamine-induced neurotoxicity was examined in R2 cells. Treatment of R2 cells with methamphetamine for 48 h induced apoptotic-like death as determined by cell viability assay, DNA fragmentation on agarose gel and flow cytometric analysis. Co-treatment of R2 cells with nerve growth factor (10-1000 U/ml) in the presence of methamphetamine increased cell viability, decreased the intensity of methamphetamine-induced DNA fragmentation and reduced the number of apoptotic cells with flow cytometry. These results indicate that nerve growth factor may be useful for the treatment of methamphetamine users.

Animals↗

PubMed1998

Lithium inhibits the reverse tolerance and the c-Fos expression induced by methamphetamine in mice.

To elucidate the mechanism of psychostimulant-induced reverse tolerance, the effects of lithium on ambulatory activity and cerebral c-Fos protein expression were investigated in mice injected with methamphetamine (2 mg/kg, s.c., 1-5 times). The ambulatory activity enhanced by either acute or chronic methamphetamine injection was delayed or diminished by LiCl pretreatment (170 mg/kg, s.c., 1 h before methamphetamine). The c-Fos expression in the dorsal lateral geniculate nucleus and in the striatum was significantly increased by acute but not chronic injection of methamphetamine, and the increases were significantly suppressed by LiCl pretreatment. Although how the Li-sensitive c-Fos expressions in the dorsolateral geniculate nucleus and striatum are related to methamphetamine-induced behavioral excitation is unclear, these results suggest that lithium at least functionally interferes with the formation of the state of reverse tolerance to methamphetamine in the mouse.

Animals↗

PubMed1998

Methamphetamine induces fos expression in the striatum and the substantia nigra pars reticulata in a rat model of Parkinson's disease.

In rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion in the nigrostriatal pathway, methamphetamine (3 mg/kg, i.p.) induced Fos-like immunoreactivity (FLI) not only in the striatum on the intact side but also in the substantia nigra pars reticulata (SNr) on the lesioned side. The methamphetamine-induced hyperexpression of FLI in the SNr on the lesioned side was suppressed by pretreatment with either dopamine D1 receptor antagonist SCH-23390 (0.5 mg/kg, i.p.), D2 receptor antagonist raclopride (2 mg/kg, i.p.) or N-methyl-d-aspartate receptor antagonist MK-801 (1 mg/kg, i.p.), which was concomitant with inhibition of the methamphetamine-induced rotational behavior of each antagonist. However, the hyperexpression of FLI in the SNr was not suppressed by intrastriatal grafts of fetal ventral mesencephalon which could suppress the methamphetamine-induced rotation completely. These results indicate that opposite hemispheric asymmetries in FLI are induced by methamphetamine in the striatum and the SNr in the 6-OHDA rats. It is suggested that the FLIs in the two discrete sites are activated independently by different mechanisms, and furthermore, different neuronal pathways are involved in the methamphetamine-induced rotation and Fos expression in the SNr of 6-OHDA rats.

Animals↗

PubMed2002

Carnosine prevents methamphetamine-induced gliosis but not dopamine terminal loss in rats.

The neuroprotective effect of carnosine, an endogenous antioxidant, was examined against methamphetamine-induced neurotoxicity in rats. Carnosine pretreatment had no effect on dopamine terminal loss induced by methamphetamine (assessed by [3H]1-(2-[diphenylmethoxy]ethyl)-4-[3-phenylpropyl]piperazine([3H]GBR 12935) binding) but prevented microgliosis (increase in [3H]1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinolinecarboxamide ([3H]PK 11195) binding) in striatum. The 27-kDa heat-shock protein (HSP27) expression was used as indicator of astroglial stress. Methamphetamine treatment induced the expression of HSP27 in striatum and hippocampus, which was inhibited by carnosine, indicating a protective effect. Carnosine had no effect on methamphetamine-induced hyperthermia. Thus, carnosine prevents the microgliosis in striatum (where we did not detect loss of serotonergic terminals by [3H]paroxetine binding) and the expression of HSP27 in all the areas, but fails to prevent methamphetamine-induced loss of dopamine reuptake sites. Therefore, carnosine inhibits only some of the consequences of methamphetamine neurotoxicity, where reactive oxygen species play an important role.

Animals↗

PubMed1997

Methamphetamine-induced decrease in tryptophan hydroxylase activity: role of 5-hydroxytryptaminergic transporters.

Methamphetamine-induced 5-hydroxytryptaminergic neuronal damage purportedly involves transport of newly released dopamine from extracellular spaces into 5-hydroxytryptaminergic terminals. This hypothesis is based primarily on findings that dopamine is required for, whereas 5-hydroxytryptamine (5-HT) uptake inhibitors prevent, methamphetamine-induced deficits in 5-hydroxytryptaminergic neuronal function. This hypothesis is not, however, supported by findings presented in this study that 5-hydroxytryptaminergic neuronal damage, induced by p-chloroamphetamine, does not decrease [3H]dopamine uptake into rat brain synaptosomes prepared from 5-HT-transporter-containing tissue. Moreover, despite having greater affinity for the 5-HT transporter, citalopram has an IC50 for [1H]dopamine transport into these synaptosomal preparations that is considerably greater than that of fluoxetine. These data suggest that 5-HT transporters may not effect dopamine uptake and thereby methamphetamine-induced 5-hydroxytryptaminergic neuronal damage. Other possible mechanisms related to 5-HT uptake inhibitor attenuation of methamphetamine-induced deficits were investigated. Fluoxetine pretreatment prevented the methamphetamine-induced decrease in tryptophan hydroxylase activity: this effect cannot be attributed to altered body temperatures or brain concentrations of methamphetamine which suggests that neither, per se, is sufficient to impair 5-hydroxytryptaminergic neuronal function.

Animals↗

PubMed1998

The effect of methamphetamine on the release of acetylcholine in the rat striatum.

We examined the effect of methamphetamine on the release of acetylcholine in the striatum of freely moving rats, using an in vivo microdialysis method. The basal level of acetylcholine was 3.67+/-0.47 pmol/30 microl per 15 min in the presence of neostigmine (10 microM). Tetrodotoxin (1 microM), a selective blocker of voltage-dependent Na+ channels, markedly inhibited the release of acetylcholine in the striatal perfusates. Apomorphine (1.0 mg/kg, i.p.), a dopamine receptor agonist, also significantly attenuated acetylcholine release. Methamphetamine (0.1 and 0.5 mg/kg, i.p.) did not immediately affect acetylcholine release in the striatum, but a dose of 1.0 mg/kg (i.p.) induced an increase of acetylcholine release in the striatum at 15-60 min. Striatal infusion of methamphetamine (5 and 10 microM) did not influence acetylcholine release. The increase following intraperitoneal administration of methamphetamine was slightly diminished by haloperidol (0.5 mg/kg). After microinjection of the neurotoxin, 6-hydroxydopamine (6 microg/3 microl), in the substantia nigra 7 days before, the increase of acetylcholine induced by the administration of methamphetamine (1.0 mg/kg) was slightly attenuated, whereas the administration of reserpine (2 mg/kg, i.p.) 24 h before, combined with alpha-methyl-p-tyrosine (300 mg/kg, i.p.) 2.5 h before, completely blocked the increase in release of acetylcholine. These findings suggest that methamphetamine exerts an excitatory influence on striatal acetylcholine release in freely moving rats, and that this excitatory effect involves the dopaminergic system and the catecholaminergic system.

Acetylcholine↗

PubMed1999

Striatal dopamine depletion and behavioural sensitization induced by methamphetamine and 3-nitropropionic acid.

The neurotoxic effects of methamphetamine (4 x 5 mg/kg i.p. at 2-h intervals) and 3-nitropropionic acid (20 mg/kg i.p. on days 1-4 and 6-9, saline on day 5), administered alone or in combination (3-nitropropionic acid as above and methamphetamine on day 5), were investigated in rats 1 week after the last injection. Neither methamphetamine nor 3-nitropropionic acid on their own altered brain dopamine levels, but in combination, they selectively lowered dopamine in the terminal regions of the corpus striatum and nucleus accumbens. Methamphetamine depleted 5-hydroxytryptamine (5-HT) in the striatum, while 3-nitropropionic acid depleted 5-HT in the accumbens and substantia nigra, but a combination of the two toxins failed to lower 5-HT in any of these brain regions. Measurements of aromatic L-amino acid decarboxylase activity disclosed no change in the capacity to decarboxylate L-3,4-dihydroxyphenylalanine in any region with any of the treatments, but a lowered capacity to decarboxylate 5-hydroxytryptophan in the nigra after all three treatments. Methamphetamine evoked characteristic hyperactivity and stereotypy in the animals, whereas 3-nitropropionic gave rise to early hypermotility followed by hypoactivity. At 1 week after treatment with 3-nitropropionic/methamphetamine, rats exhibited normal spontaneous motor behaviour, a poor response to dopamine D(1) receptor stimulation and an exaggerated response to dopamine D(2) receptor agonists. These results show that combined systemic treatment with methamphetamine and 3-nitropropionic acid partially depletes dopamine in the basal ganglia, rendering the animals supersensitive to dopamine D(2) receptor activation without altering their spontaneous locomotion.

Animals↗

PubMed2000

Roles of adenosine A(1) and A(2A) receptors in the expression and development of methamphetamine-induced sensitization.

We studied the effects of adenosine A(1) and A(2A) receptor agonists on the expression and development of methamphetamine-induced sensitization in rats. When animals were treated with the adenosine A(1) receptor agonist, N(6)-cyclohexyladenosine (CHA), along with methamphetamine every 3 days with a total of five administrations, the augmentation of hyperlocomotion by methamphetamine re-administration after 7-day withdrawal (methamphetamine challenge administration) was not inhibited. However, when the adenosine A(2A) receptor agonist, 2-p-(2-carboxyethyl) phenethyl-amino-5'-N-ethylcarboxy-amide adenosine (CGS21680), was administered according to the same schedule, the augmentation was significantly inhibited. On the other hand, when CHA or CGS21680 was administered 30 min before methamphetamine challenge, both drugs dose-dependently inhibited the augmentation of hyperlocomotion. These results suggested that both adenosine A(1) and A(2A) receptors play important roles in the expression of methamphetamine-induced sensitization, and that adenosine A(2A) receptors do so in the development of this sensitization.

Adenosine↗

PubMed2000

Determination of amphetamine and methamphetamine in serum via headspace derivatization solid-phase microextraction-gas chromatography-mass spectrometry.

This study evaluates solid-phase microextraction (SPME) coupled with gas chromatography-mass spectrometry (GC-MS) to determine trace levels of amphetamine and methamphetamine in serum. Headspace post-derivatization in a laboratory-made design with heptafluorobutyric anhydride vapor following SPME was compared with that without derivatization SPME. The SPME experimental procedures to extract amphetamine and methamphetamine in serum were optimized with a relatively non-polar poly(dimethylsiloxane) coated fiber at pH 9.5, extraction time for 40 min and desorption at 260 degrees C for 2 min. Experimental results indicate that the concentration of the serum matrix diluted to a quarter of original (1:3) ratio by using one volume of buffer solution of boric acid mixed with sodium hydroxide and two volumes of water improves the extraction efficiency. Headspace derivatization following SPME was performed by using 6 microl 20% (v/v) heptafluorobutyric anhydride ethyl acetate solution at an oil bath temperature of 270 degrees C for 10 s. The precision was below 7% for analysis for without derivatization and below 17% for headspace derivatization. Detection limits were obtained at the ng/l level, one order better obtained in headspace derivatization than those achieved without derivatization. The feasibility of applying the methods to determine amphetamine and methamphetamine in real samples was examined by analyzing serum samples from methamphetamine abused suspects. Concentrations of the amphetamine and methamphetamine ranged from 6.0 microg/l (amphetamine) to 77 microg/l (methamphetamine) in serum.

Amphetamines↗

PubMed1987

Perinatal cocaine and methamphetamine exposure: maternal and neonatal correlates.

Maternal and neonatal growth, behavior, and physiologic organization were evaluated in 104 mother-infant pairs with positive results of urine toxicology screens. ANOVA comparison of cocaine, methamphetamine, and cocaine plus methamphetamine groups revealed no significant differences in perinatal variables. The Finnegan withdrawal scoring scheme demonstrated that all three groups of infants had altered neonatal behavioral patterns, characterized by abnormal sleep patterns, poor feeding, tremors, and hypertonia. Infants exposed to cocaine or methamphetamine or both were combined and compared with both narcotic-exposed and drug-free mother-infant pairs matched for known maternal risk factors. All drug-exposed groups had significantly higher rates of prematurity and intrauterine growth retardation and smaller head circumferences than did the drug-free comparison group. A significantly higher rate of placental hemorrhage occurred in the cocaine plus methamphetamine group. Stepwise multiple regression analysis assessed the independent contribution of maternal factors; cocaine or methamphetamine was adversely, negatively associated with gestational age, birth weight, length, and occipitofrontal circumference. The increased rate of prematurity, intrauterine growth retardation, and perinatal complications associated with perinatal exposure to cocaine or methamphetamine was greater than that predicted by coexisting risk factors and was consistent with the pharmacologic properties of these drugs.

Apgar Score↗

PubMed2001

Methamphetamine neurotoxicity: necrotic and apoptotic mechanisms and relevance to human abuse and treatment.

Research into methamphetamine-induced neurotoxicity has experienced a resurgence in recent years. This is due to (1) greater understanding of the mechanisms underlying methamphetamine neurotoxicity, (2) its usefulness as a model for Parkinson's disease and (3) an increased abuse of the substance, especially in the American Mid-West and Japan. It is suggested that the commonly used experimental one-day methamphetamine dosing regimen better models the acute overdose pathologies seen in humans, whereas chronic models are needed to accurately model human long-term abuse. Further, we suggest that these two dosing regimens will result in quite different neurochemical, neuropathological and behavioral outcomes. The relative importance of the dopamine transporter and vesicular monoamine transporter knockout is discussed and insights into oxidative mechanisms are described from observations of nNOS knockout and SOD overexpression. This review not only describes the neuropathologies associated with methamphetamine in rodents, non-human primates and human abusers, but also focuses on the more recent literature associated with reactive oxygen and nitrogen species and their contribution to neuronal death via necrosis and/or apoptosis. The effect of methamphetamine on the mitochondrial membrane potential and electron transport chain and subsequent apoptotic cascades are also emphasized. Finally, we describe potential treatments for methamphetamine abusers with reference to the time after withdrawal. We suggest that potential treatments can be divided into three categories; (1) the prevention of neurotoxicity if recidivism occurs, (2) amelioration of apoptotic cascades that may occur even in the withdrawal period and (3) treatment of the atypical depression associated with withdrawal.

Amphetamine-Related Disorders↗

PubMed2000

Involvement of sigma 1 receptors in methamphetamine-induced behavioral sensitization in rats.

MS-377 is a novel selective sigma(1) ligand, currently being developed for the treatment of schizophrenia. In the present study, we examined the effects of MS-377 on behavioral sensitization induced by subchronic treatment with methamphetamine. MS-377 was administered at doses of 1.875-15 mg/kg (p.o.), to rats, and methamphetamine was administered at doses of 2 mg/kg (i.p.), 60 min later once daily for 10 days. Repeated administration of methamphetamine caused enhanced stereotypy, and behavioral sensitization was developed. MS-377 did not affect the acute effects of methamphetamine. However, co-administration of MS-377 attenuated the development of methamphetamine-induced behavioral sensitization in a dose-dependent manner. These results suggested that sigma(1) receptors play an important role in the developmental period of behavioral sensitization induced by methamphetamine in rats.

Administration, Oral↗

PubMed2003

Implication of brain-derived neurotrophic factor in the release of dopamine and dopamine-related behaviors induced by methamphetamine.

It is widely recognized that methamphetamine enhances the release of dopamine at dopaminergic neuron terminals of the mesolimbic system, which induces dopamine-related behaviors. Brain-derived neurotrophic factor (BDNF), a neurotrophin, binds to and activates its specific receptor tyrosine kinase, TrkB. BDNF has been shown to influence the release of dopamine in the mesolimbic dopamine system. The present study was designed to investigate roles of BDNF and TrkB in the expression of methamphetamine-induced dopamine release in the nucleus accumbens and dopamine-related behaviors induced by methamphetamine in rats. Methamphetamine (1 mg/kg, s.c.) produced a substantial increase in the extracellular levels of dopamine and induced a progressive augmentation of dopamine-related behaviors such as rearing and sniffing. In contrast, both the stimulation of dopamine release and induction of dopamine-related behaviors by methamphetamine were significantly suppressed by pretreatment with intra-nucleus accumbens injection of either BDNF (2.0 microl/rat, 1:1000, 1:300 and 1:100) or TrkB (2.0 microl/rat, 1:1000 and 1:100) antibody. Furthermore, the basal level of dopamine in the nucleus accumbens was not affected by treatment with both BDNF and TrkB antibodies. These findings provide further evidence that BDNF/TrkB pathway is implicated in the methamphetamine-induced release of dopamine and the induction of dopamine-related behaviors.

Amphetamine-Related Disorders↗

PubMed1997

MK-801 inhibits methamphetamine-induced conditioned place preference and behavioral sensitization to apomorphine in mice.

Intraperitoneal administration of MK-801 (0.1 mg/ kg), an N-methyl-D-aspartate (NMDA) receptor antagonist, before and during methamphetamine treatment inhibited methamphetamine-induced conditioned place preference (CPP) in mice. Behavioral sensitization to a dopamine (DA) receptor agonist apomorphine that developed in methamphetamine-induced CPP mice was also inhibited by MK-801. Furthermore, MK-801 inhibited apomorphine-induced postsynaptic dopaminergic action, cage-climbing behavior. Therefore, the present studies suggest that methamphetamine-induced behaviors, such as CPP and behavioral sensitization, may be closely related to the dopaminergic activation mediated via the NMDA receptor. The behavioral sensitization to apomorphine may be a possible underlying mechanism of methamphetamine-induced CPP, because behavioral sensitization developed in methamphetamine-induced CPP mice, as well as apomorphine-induced climbing behavior in mice, were inhibited by MK-801.

Animals↗

PubMed2001

Craving predicts use during treatment for methamphetamine dependence: a prospective, repeated-measures, within-subject analysis.

Clinical lore dictates that craving drives the compulsive use of drugs and alcohol - the core feature of substance dependence. Yet limited research has yielded mixed results, suggesting that craving is neither necessary nor sufficient for continued use or relapse to addictive substances. To investigate the role of craving in compulsive methamphetamine use, 31 men and women in treatment for methamphetamine dependence were asked to indicate, once each week for 12 weeks, the severity of craving that they had experienced during the previous 24 h, using a 100-mm visual analog scale. In a prospective, repeated-measures, within-subject analysis, craving intensity significantly predicted methamphetamine use in the week immediately following each craving report. Craving remained a highly significant predictor in multivariate models controlling for pharmacological intervention, and for methamphetamine use during the prior week. Craving scores that preceded use were 2.7 times higher than scores that preceded abstinence. Risk of subsequent use was 2.5 times greater for scores in the upper half of the scale relative to scores in the lower half. The results obtained demonstrate that, while craving alone may be neither necessary nor sufficient to explain substance addiction, when measured prospectively in a carefully-designed study craving emerges as a salient predictive factor in continued methamphetamine use for patients in treatment for methamphetamine dependence.

Adult↗

PubMed2000

Methamphetamine-related fatalities in forensic autopsy during 5 years in the southern half of Osaka city and surrounding areas.

To outline the recent features of methamphetamine-related fatalities from the medico-legal point of view, a retrospective investigation of forensic autopsy cases involving methamphetamine during a 5-year period (1994-1998) in the southern half of Osaka city and surrounding areas (about 1.57 million population) was undertaken. Among 646 autopsy cases, methamphetamine was detected in 15 victims (nine males, six females; 16-71 years of age; most frequently in males in their thirties). Primary scenes of fatal events were concentrated in the middle of the city. About half of them were transferred from emergency medical centers (survival time, up to 30 h). The cause and manner of death were: methamphetamine poisoning (n=4), homicide (n=4), accidental falls and aspiration from drug abuse (n=4), fire death (n=1), myocardial infarction (n=1), and cerebral hemorrhage (n=1) under drug influence. Usually injection scars and fresh puncture sites were found. Blood methamphetamine concentrations were 2.29-17.05 micromol/dl in the fatal poisoning, 0. 44-3.80 micromol/dl in deaths from other extrinsic causes (trauma), and 1.35-2.17 micromol/dl in cardio- and cerebrovascular strokes. Common complications were cardiomyopathy, cerebral perivasculitis and liver cirrhosis/interstitial hepatitis. Fatal and nonfatal methamphetamine poisonings are separately dealt with by the administrative medical examiner's office and in emergency medical centers. Tightly cooperative approaches of clinical and medico-legal experts are required for the effective social and medical management of drug abuse.

Adolescent↗

PubMed2002

A case of fatal hemorrhage in the cerebral ventricles following intravenous use of methamphetamine.

We describe a case of massive hemorrhage in the cerebral ventricles, probably caused by methamphetamine abuse. A 44-year-old male was found dead in a prone position in a hotel room. Old and new injection marks were observed in his right cubital fossa. Petechiae were observed on the conjunctiva of his right eye, laryngeal mucosa, epicardium and under the capsule of the liver (to a slight or moderate degree). The brain, weighing 1.67 kg, was heavily edematous; the lateral and fourth ventricles were filled with hematomas. Subarachnoid, intracerebral hemorrhages were not observed. Cerebral vascular abnormalities were not evident. There were no remarkable changes in other organs, other than congestion. Gas chromatographic-mass spectrometric analysis of the urine disclosed the presence of methamphetamine and amphetamine. The concentration of methamphetamine within the femoral venous blood and intraventricular hematoma was 0.347 microg/ml and 0.189 microg/g, respectively. Amphetamine was not detected in either sample. Urine contained 3.15 microg/ml methamphetamine and 0.063 microg/ml amphetamine. These results indicate that intraventricular hemorrhage might have occurred shortly after intravenous self-administration of methamphetamine. Cerebral arterial spasm and hypertension resulting from the administration of methamphetamine might have resulted in intraventricular hemorrhage.

Acetic Anhydrides↗