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PubMed2006

Cocaine-but not methamphetamine-associated memory requires de novo protein synthesis.

Context-induced drug craving and continuous drug use manifest the critical roles of specific memory episodes associated with the drug use experiences. Drug-induced conditioned place preference (CPP) in C57BL/6J mouse model, in this regard, is an appropriate behavioral paradigm to study such drug use-associated memories. Requirement of protein synthesis in various forms of long-term memory formation and storage has been phylogenetically demonstrated. This study was undertaken to study the requirement of protein synthesis in the learning and memory aspect of the conditioned place preference induced by cocaine and methamphetamine, two abused drugs of choice in local area. Since pCREB has been documented as a candidate substrate for mediating the drug-induced neuroadaptation, the pCREB level in hippocampus, nucleus accumbens, and prefrontal cortex was examined for its potential participation in the formation of CPP caused by these psychostimulants. We found that cocaine (2.5 and 5.0 mg/kg/dose)-induced CPP was abolished by the pretreatment of anisomycin (50 mg/kg/dose), a protein synthesis inhibitor, whereas methamphetamine (0.5 or 1.0 mg/kg/dose)-induced CPP was not affected by the anisomycin pretreatment. Likewise, cocaine-induced CPP was mitigated by another protein synthesis inhibitor, cycloheximide (15 mg/kg/injection) pretreatment, whereas methamphetamine-induced CPP remained intact by such pretreatment. Moreover, anisomycin treatment 2h after each drug-place pairing disrupted the cocaine-induced CPP, whereas the same treatment did not affect methamphetamine-induced CPP. An increase of accumbal pCREB level was found to associate with the learning phase of cocaine, but not with the learning phase of methamphetamine. We further found that intraaccumbal CREB antisense oligodeoxynucleotide infusion diminished cocaine-induced CPP, whereas did not affect the methamphetamine-induced CPP. Taken together, these data suggest that protein synthesis and accumbal CREB phosphorylation are essential for the learning and consolidation of the cocaine-induced CPP, whereas methamphetamine-induced CPP may be unrelated to the synthesis of new proteins.

Animals↗

PubMed2006

Differences in extinction responding and reinstatement of methamphetamine-seeking behavior between Fischer 344 and Lewis rats.

Fischer 344 (F344) and Lewis (LEW) rats differ in a number of self-administration behaviors. Whether or not these strains differ in methamphetamine-primed reinstatement of extinguished responding is unknown. F344 and LEW rats were trained to self-administer intravenous (i.v.) methamphetamine (0.06 mg/kg) during daily 2-h limited access sessions for 14 days. Following methamphetamine self-administration, subjects underwent a minimum of 6 extinction sessions where responding on the previously active lever resulted in no programmed consequences. Following extinction sessions, we evaluated strain and dose dependency of methamphetamine-primed (0.06, 0.12, or 0.24 mg/kg/i.v.) reinstatement of responding. All subjects received each dose once. Dosing order was determined by utilizing a within-subjects Latin square design. We found partial strain differences in daily methamphetamine self-administration. In addition, F344 rats responded significantly more during the first extinction session compared LEW rats. Last, the LEW rats demonstrated a heightened propensity to reinstate responding following methamphetamine priming injections compared to F344 rats. Our results suggest that genetic background influences differences in methamphetamine-seeking behaviors in rats.

Animals↗

PubMed1997

N-methylation dissociates methamphetamine's neurotoxic and behavioral pharmacologic effects.

The present studies further examined the effect of N-methylation on the behavioral and neurotoxic effects of methamphetamine. Drug discrimination studies employing a training dose of 1 mg/kg of methamphetamine were used to confirm and extend previous behavioral studies indicating that N-methylation reduced the behavioral activity of methamphetamine 5- to 10-fold. In subsequent neurotoxicity studies, rats received doses of methamphetamine (10 mg/kg, s.c., every 6 h x 5) or its N-methylated derivative, N,N-dimethylamphetamine (100 mg/kg, s.c., every 6 h x 5) that, based on the results of the behavioral studies, would be expected to produce behaviorally equivalent effects. Saline-treated rats served as controls. Two weeks after treatment, the status of brain dopamine (DA) and serotonin (5-HT) neurons was assessed by measuring DA and 5-HT axon terminal markers. As anticipated, methamphetamine produced neurochemical deficits indicative of DA and 5-HT axon terminal damage. By contrast, despite the fact that it was given at a dose behaviorally equivalent to methamphetamine, N-N-dimethylamphetamine failed to produce signs of DA or 5-HT neurotoxicity. These results indicate that N-methylation dissociates methamphetamine's neurotoxic and behavioral pharmacologic effects, and suggest that it may be possible to separate the neurotoxic and pharmacologic effects of other substituted amphetamine derivatives with potentially useful clinical activity (e.g. fenfluramine and methylenedioxymethamphetamine).

3,4-Dihydroxyphenylacetic Acid↗

PubMed2000

Methamphetamine decreases mouse striatal dopamine transporter activity: roles of hyperthermia and dopamine.

Multiple methamphetamine administrations rapidly decrease rat striatal dopamine transporter activity. To determine the species specificity of this phenomenon, the present studies examined effects of this stimulant on the dopamine transporter in mice. As in rats, multiple methamphetamine injections rapidly reduced striatal dopamine transporter activity; a decrease that was partially reversed 24 h later. Moreover, methamphetamine decreased binding of the dopamine transporter ligand, WIN35428, but to a lesser degree than the change in dopamine transporter function. These decreases did not appear to result from residual methamphetamine introduced by the original drug treatment. As in rats, hyperthermia contributed to this phenomenon. Unlike in rats, a role for dopamine was not observed in mice as dopamine depletion, resulting from alpha-methyl-p-tyrosine pretreatment, did not prevent this decrease. In addition, unlike in rats, pretreatment with either a dopamine D1 or D2 receptor antagonist (SCH23390 or eticlopride, respectively) did not attenuate the methamphetamine-induced reduction in dopamine uptake. These findings demonstrate both similarities and differences in the acute effects of methamphetamine on dopamine transporter function in mice and rats, and suggest the mouse as an additional model for assessing the acute effects of methamphetamine on the dopamine transporter.

Animals↗

PubMed2002

Tolerance to the neurotoxic effects of methamphetamine in young rats.

The present study examined whether exposure to methamphetamine during adolescence (as determined in post-natal day 40 rats) might alter its effects when used in young adulthood (as assessed in post-natal day 90 rats). Results confirm that high-dose methamphetamine administration (4x10 mg/kg/injection, s.c., 2-h intervals) decreases striatal dopamine uptake and transporter ligand binding in post-natal day 90 rats; effects that were blocked if animals received six biweekly methamphetamine pretreatments (15 mg/kg; s.c.) beginning at post-natal day 40. This neuroprotection was not likely due to pharmacokinetic tolerance, since brain methamphetamine concentrations did not differ 1 h after the high-dose methamphetamine regimen among treated rats regardless of pretreatment. The methamphetamine biweekly pretreatment attenuated the hyperthermia caused by the neurotoxic methamphetamine regimen; a phenomenon that may have contributed to the neuroprotection.

Age Factors↗

PubMed2002

The effect of 7-nitroindazole on the acquisition and expression of D-methamphetamine-induced place preference in rats.

The present study investigated the role of nitric oxide (NO) in the rewarding effects of D-methamphetamine using 7-nitroindazole, a potent inhibitor of neuronal nitric oxide synthase (nNOS), as determined by the conditioned place preference paradigm. Male Sprague-Dawley rats treated with D-methamphetamine (1 mg/kg) or saline every other day for 8 days (four drug and four saline sessions) developed marked place preference for the drug-paired side. The administration of 7-nitroindazole (12.5-50 mg/kg) 30 min prior to the exposure to D-methamphetamine dose-dependently attenuated the acquisition of D-methamphetamine-induced conditioned place preference. In addition, when it was acutely administered 30 min prior to the testing session of an already established D-methamphetamine-induced conditioned place preference, 7-nitroindazole (12.5-50 mg/kg) attenuated the expression of this conditioned response in a dose-dependent manner, while 7-nitroindazole (25 and 50 mg/kg) alone showed no place preference effects. These findings indicate that nitric oxide (NO) is involved in the rewarding properties of methamphetamine and suggest that selective nNOS inhibitors maybe useful in the management of methamphetamine abuse.

Animals↗

PubMed1998

Effects of neurotoxic doses of methamphetamine on potassium and amphetamine evoked overflow of dopamine in the striatum of awake rats.

The effects of neurotoxic doses of methamphetamine on basal and evoked overflow of dopamine in the striatum were examined in awake rats using microdialysis. Male Fischer-344 rats were administered methamphetamine (5 mg/kg s.c.) or saline four times in 1 day at 2-h intervals. Microdialysis experiments were carried out 1 week later. Basal levels of dopamine, 3,4-dihydroxyphenylacetic acid, and homovanillic acid were reduced in the striatum of the methamphetamine-treated animals. Local application of excess potassium (100 mM) and amphetamine (100 microM), and intraperitoneal injection of amphetamine (1.5 mg/ kg), led to increased levels of extracellular dopamine in the striatum of both methamphetamine- and saline-treated rats. However, the increase was significantly less in the methamphetamine-treated animals. Tissue levels of dopamine and metabolites were reduced in the striata of rats treated with methamphetamine. These results indicate that treatment with neurotoxic doses of methamphetamine can lead to functional changes in dopamine release in the striatum of Fischer-344 rats.

Amphetamine↗

PubMed1999

High-dose methamphetamine treatment alters presynaptic GABA and glutamate immunoreactivity.

The goal of this study was to determine if high-dose methamphetamine treatment altered presynaptic immunoreactivity for the amino acid neurotransmitters GABA and glutamate within the basal ganglia. Methamphetamine (15 mg/kg every 6 h, four doses) treatment in rats resulted in severe hyperthermia and a long-lasting (four weeks) depletion of striatal dopamine content (>80%). Severe dopamine loss correlated with a decrease in the density of presynaptic immunolabeling for GABA one week post-drug, and an increase after four weeks. Although no changes were seen in presynaptic striatal glutamate immunoreactivity, there was a significant increase in the percentage of glutamate-immuno-positive terminals associated with perforated postsynaptic densities. Rats given the same dose of methamphetamine but prevented from becoming hyperthermic showed less severe dopamine depletions and a lack of ultrastructural or immunocytochemical changes. In addition, induction of hyperthermia in the absence of drug decreased immunolabeling within mitochondria, but had no effect on dopamine content, morphology or nerve terminal immunoreactivity. Altered presynaptic GABA immunolabeling and terminal size were found in both the striatum and globus pallidus, suggesting that dynamic changes occur in the striatopallidal pathway following methamphetamine-induced dopamine loss. In addition, ultrastructural changes in glutamate-positive synapses which have been correlated with increased synaptic activity were found. These results are similar to changes in GABA and glutamate synapses that follow nigrostriatal dopamine loss in 6-hydroxydopamine-lesioned animals and in Parkinson's disease, and provide the first direct evidence that methamphetamine-induced dopamine loss alters the GABAergic striatopallidal pathway. Exposure to either methamphetamine or prolonged hyperpyrexia decreased mitochondrial Immunoreactivity, indicating that hyperthermia may contribute to methamphetamine toxicity by affecting energy stores.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1997

Effects of postmethamphetamine treatment with restraint on ambulatory sensitization to methamphetamine in mice.

The administration of methamphetamine (2 mg/kg SC) to mice was followed by acceleration of ambulation (locomotion) for 3 h, with the peak effect at 1/2-1 h. When mice were allowed free ambulation for 3 h in an activity cage of 20 cm in diameter after methamphetamine administration, repeated administrations of methamphetamine, four times at 3-day intervals, caused ambulatory sensitization; the count at the fourth administration being approximately 2.3 times as high as that at the first administration. Furthermore, the mice that were allowed ambulation in the activity cage during postmethamphetamine period of either 0-1/2, 0-1, 0-2, or 1/2-1 h (during the other periods, the mice were put in jars of 6 cm in diameter to restrict ambulation) demonstrated ambulatory sensitization to methamphetamine, and these levels were as same as that in the mice given methamphetamine with free ambulation for 3 h. However, the free ambulation during postmethamphetamine periods of 0-1/4 h and 1-3 h failed to produce strong sensitization to methamphetamine. These results suggest that a free ambulation for at least 1/2 h during the postmethamphetamine period of 0-1 h is important for induction of ambulatory sensitization to methamphetamine in mice.

Animals↗

PubMed1999

Methamphetamine abuse and rhabdomyolysis in the ED: a 5-year study.

Patients with methamphetamine toxicity are presenting in greater numbers each year to emergency departments (ED) in the US. These patients are frequently agitated, violent, and often require physical and chemical restraint. The incidence and risk of rhabdomyolysis in this subpopulation is unknown. We conducted a 5-year retrospective review of all ED patients who received the final diagnosis of rhabdomyolysis. Patients with toxicology screens positive for methamphetamine were identified, and demographics, laboratory results, resource utilization, disposition, and outcome were compared to the remaining patients. Of the total 367 patients identified, 166 (43%) were toxicology positive for methamphetamine. Methamphetamine patients differed significantly from nonmethamphetamine patients with regard to demographics and hospital utilization. Methamphetamine patients had significantly higher mean initial creatine phosphokinase (CK), 12,439 U/L versus 5,678 U/L (P = 0.02), and lower mean peak CK, 16,827 U/L versus 19,426 U/L (P = 0.03). The development of acute renal failure was not significantly different between the 2 groups. There were 16 total deaths in the study population, 11 from concomitant infection/sepsis. An association between methamphetamine abuse and rhabdomyolysis may exist, and CK should be measured in the ED as a screen for potential muscle injury in this subpopulation. Patients with rhabdomyolysis with an unclear cause should be screened for methamphetamine or other illicit drugs.

Acute Kidney Injury↗

PubMed2002

Metabolite alterations in basal ganglia associated with methamphetamine-related psychiatric symptoms. A proton MRS study.

Following the chronic use of methamphetamine, some individuals experience psychosis and anxiety. One reason may be the persistence of metabolite abnormalities in the brain of currently abstinent former methamphetamine users. In this study, N-acetylaspartate (NAA), creatine plus phosphocreatine (Cr+PCr), and choline-containing compound (Cho) levels were measured in the left and right basal ganglia using proton magnetic resonance spectroscopy (MRS) in 13 abstinent methamphetamine users and 11 healthy comparison subjects with no history of illicit drug use. The methamphetamine users showed a significantly reduced Cr+PCr/Cho ratio in the bilateral basal ganglia compared with the healthy comparison subjects. Furthermore, the reduction in the Cr+PCr/Cho ratio was significantly correlated with the duration of methamphetamine use and with the severity of residual psychiatric symptoms. NAA/Cho ratios in the bilateral basal ganglia did not significantly differ between methamphetamine users and comparison subjects. These findings suggest that protracted use of methamphetamine may cause metabolite alterations in the basal ganglia. Furthermore, residual psychiatric symptoms may be attributable to the metabolite alterations in the basal ganglia.

Adult↗

PubMed2004

Association between quantitative EEG and neurocognition in methamphetamine-dependent volunteers.

OBJECTIVE: Exposure to methamphetamine is associated with long-lasting reductions in markers for dopaminergic neurons in preclinical models and in humans. These changes may be associated with alterations in brain electrical activity and in cognition. METHODS: The sample included 9 methamphetamine-dependent subjects and 10 non-drug-using volunteers. Methamphetamine-dependent subjects were hospitalized for 4 days to document abstinence; non-drug-using volunteers were studied as outpatients. EEGs were recorded in the eyes-closed resting state, and absolute EEG power in each frequency band (0.5-4 Hz, 4-8 Hz, 8-12 Hz, and 12-20 Hz) was measured using a fast Fourier transform. EEG power was log-transformed prior to analysis. Cognition was measured using computerized reaction time tasks. RESULTS: Within the methamphetamine-dependent group only, increased theta quantitative EEG (QEEG) power correlated significantly with reaction time on tasks that were more difficult or that were degraded by fatigue. Increased theta QEEG power also correlated with reduced accuracy on a working memory task. CONCLUSIONS: Increased QEEG power in the theta band is associated with worse performance on reaction time tasks in the methamphetamine-dependent sample but not in the non-drug-using volunteers. SIGNIFICANCE: Methamphetamine dependence is associated with pathological alterations in brain electrical activity and in cognitive performance. QEEG appears to provide a sensitive measure of methamphetamine-associated alterations in brain function.

Adult↗

PubMed2003

Relationship between methamphetamine-induced dopamine release, hyperthermia, self-injurious behaviour and long term dopamine depletion in BALB/c and C57BL/6 mice.

Differential sensitivity to neurotoxic effects of methamphetamine on striatal dopaminergic neurones between C57BL/6 and BALB/c mice has been established. In the present studies, the interaction of methamphetamine-induced dopamine release, self-injurious behaviour, the neural immune response, and the long-term (3 day) dopamine depletion were examined in these strains after administration of 8 mg/kg methamphetamine. BALB/c mice showed increased hyperthermia compared to the C57BL/6 strain, as well as induction of interleukin-1beta. Additionally, homovanillic acid (HVA) levels, as well as HVA/DA turnover ratios were elevated in the striatum and frontal cortex of BALB/c mice, both compared to untreated mice and to the C57BL/6 strain after a single injection of methamphetamine. Pretreatment with acetaminophen eliminated the methamphetamine-induced hyperthermia in BALB/c mice and reduced body temperature in C57BL/6 mice. However, acetaminophen pretreatment did not affect any parameters of dopaminergic toxicity in the striatum or frontal cortex of the BALB/c strain following repeated methamphetamine injections. Furthermore, acetaminophen pretreatment did not alter the incidence of self-injurious behaviour in BALB/c mice. Therefore, hyperthermia and methamphetamine-induced toxicity appear to be independent phenomena while self-injurious behaviour may provide a better predictor of toxicity, which, in turn, may be related to dopamine release.

Actins↗

PubMed2003

Altering cortisol level does not change the pleasurable effects of methamphetamine in humans.

Preclinical studies have linked corticosteroid secretion and levels with drug self-administration by animals. In a double-blind, cross-over study, subjective, physiological, and endocrine responses to intravenous doses of methamphetamine 0.5 mg/kg or placebo were assessed in eight methamphetamine-experienced subjects after three cortisol-modifying premedication conditions: augmenting cortisol level with oral hydrocortisone 50 mg, blocking cortisol response with the corticosteroid synthesis inhibitor metyrapone 1500 mg orally, or no premedication. Although the pharmacologic manipulations produced the expected hormonal changes, subjective response to the methamphetamine showed few differences. Diminishing cortisol response by pharmacologic blockade did not alter the pleasurable effects of methamphetamine. Hydrocortisone did increase self-reported 'bad drug effect' and decreased craving after saline placebo relative to the period following methamphetamine. Metyrapone was associated with significant premature ventricular complexes in two subjects during methamphetamine administration and may not be safe for those who use methamphetamine.

Adult↗

PubMed2002

Distinct responses of basal ganglia substance P systems to low and high doses of methamphetamine.

Substance P (SP) is a neuropeptide closely associated with basal ganglia dopaminergic neurons. Because some neuropeptide systems in the basal ganglia (i.e. neurotensin and metenkephalin) are differentially affected by treatment with low or high doses of methamphetamine, we determined if basal ganglia SP pathways were also differentially influenced in a dose-dependent manner by this psychostimulant. Employing in vivo microdialysis, it was observed that the low dose (0.5 mg/kg) of methamphetamine increased the extracellular concentration of SP in the substantia nigra, but not in globus pallidus or striatum. In contrast, the high dose (10 mg/kg) of methamphetamine did not increase extracellular SP content in any of these structures. The effect of the low-dose methamphetamine treatment on nigral extracellular SP levels was blocked by pre-treatment with either a D1 or D2 antagonist. In addition, 12 h after similar methamphetamine treatments, a dose-dependent differential response in SP tissue levels occurred in some of the regions examined. When these changes occurred, the low dose of methamphetamine usually reduced, whereas the high dose increased, SP tissue content. This study demonstrated opposite responses of the basal ganglia SP system to low and high doses of methamphetamine and suggested that a combination of dopamine D1 and D2 receptor activity contributed to these effects.

Animals↗

PubMed2002

Effect of single and repeated methamphetamine treatment on neurotransmitter release in substantia nigra and neostriatum of the rat.

The main purpose of this study was to characterize the initial neurotransmission cascade elicited by methamphetamine, analysing simultaneously with in vivo microdialysis monoamine, amino acid and neuropeptide release in substantia nigra and neostriatum of the rat. The main effect of a single systemic dose of methamphetamine (15 mg/kg, subcutaneously) was an increase in dopamine levels, both in substantia nigra ( approximately 10-fold) and neostriatum ( approximately 40-fold), accompanied by a significant, but lesser, increase in dynorphin B ( approximately two-fold, in both regions), and a decrease in monoamine metabolites. A similar effect was also observed after local administration of methamphetamine (100 microm) via the microdialysis probes, but restricted to the treated region. In other experiments, rats were repeatedly treated with methamphetamine or saline, with the last dose administered 12 h before microdialysis. Dopamine K+-stimulated release was decreased following repeated methamphetamine administration compared with that following saline, both in the substantia nigra (by approximately 65%) and neostriatum (by approximately 20%). In contrast, the effect of K+-depolarization on glutamate, aspartate and GABA levels was increased following repeated administration of methamphetamine. In conclusion, apart from an impairment of monoamine neurotransmission, repeated methamphetamine produces changes in amino acid homeostasis, probably leading to NMDA-receptor overstimulation.

Amino Acids↗

PubMed2003

Distinct effects of methamphetamine and cocaine on preprodynorphin messenger RNA in rat striatal patch and matrix.

We and others previously reported that equimolar doses of methamphetamine and cocaine differentially increase preprodynorphin mRNA in striatum: methamphetamine causes a patchy increase, whereas cocaine produces a more homogenous one. The current study directly examined whether this effect reflects differential induction in the patch-matrix division of striatum, as identified by micro opioid receptor immunohistochemistry. In addition, we determined whether doses of cocaine (30 mg/kg) and methamphetamine (2 mg/kg) that produced equivalent increases in extracellular dopamine differentially affected preprodynorphin mRNA expression in striatum of male, Sprague-Dawley rats. In both experiments, methamphetamine and cocaine differentially affected preprodynorphin mRNA in striatum after 3 h. The high, equimolar dose of methamphetamine selectively increased preprodynorphin mRNA in the patch division of rostral striatum, whereas cocaine increased preprodynorphin mRNA throughout patch and matrix divisions of striatum. In contrast, a dose of methamphetamine (2.0 mg/kg) that caused an increase in extracellular dopamine similar to that produced by 30 mg/kg cocaine did not significantly affect preprodynorphin mRNA in any region of striatum. These data provide further evidence that cocaine and amphetamines exert distinct effects on the patch-matrix division of striatum and suggest further that the post-synaptic consequences of elevated extracellular dopamine produced by methamphetamine and cocaine are distinct.

Animals↗

PubMed2002

The emergence of potent forms of methamphetamine in Sydney, Australia: a case study of the IDRS as a strategic early warning system.

A striking finding of the Illicit Drug Reporting System (IDRS) in recent years has concerned the emergence in Sydney of a number of different forms of potent methamphetamine. This paper demonstrates the operation of the IDRS in detecting and documenting an increase in both the availability and use of these forms of methamphetamine in Sydney, and Australia more widely, since 1998. Data from different components of the IDRS are utilized to propose that there are currently at least three forms of methamphetamine available in Sydney that are considered by the market to be distinct commodities: methamphetamine powder ('speed'), base methamphetamine ('base') and crystalline methamphetamine ('ice'/'shabu'/'crystal meth'). Base and ice are more potent forms of methamphetamine than speed, and international experience, along with preliminary data obtained from the IDRS, suggest that their use is associated with harms in a number of domains.

Adolescent↗