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PubMed1986

Alteration of striatal dopaminergic functions implicated in methamphetamine-induced reverse tolerance in rats.

Rats were injected repeatedly with methamphetamine (6 mg/kg per day, for 14 days). The effects of the repeated treatment on the change of behaviors and striatal DA metabolism induced by challenge with DA agonists were studied 10 days after the last injection. Repeated methamphetamine administration decreased the sedative effect of low dose apomorphine, and enhanced apomorphine-induced stereotyped behavior but reduced in after pretreatment with tetrabenazine. Striatal DA, HVA and DOPAC contents, and striatal gamma-butyrolactone-induced DA or DOPA accumulation were not altered by repeated methamphetamine treatment. The effect of apomorphine to decrease DA metabolite content and DA or DOPA accumulation was not changed either. As evidenced by experiments using alpha-MT, repeated methamphetamine administration increased DA utilization after methamphetamine or low dose apomorphine challenge, although it did not change DA utilization at the steady state (without drug challenge). These findings suggest that methamphetamine-induced reverse tolerance is accompanied by an increase of DA utilization resulting from the subsensitivity of DA utilization-modulating autoreceptors.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1989

Effect of MK-801 on the decrease in tryptophan hydroxylase induced by methamphetamine and its methylenedioxy analog.

The role of N-methyl-D-aspartate (NMDA) receptors in the decrease in neostriatal tryptophan hydroxylase (TPH) activity induced by repeated high doses of methamphetamine or 3,4-methylenedioxymethamphetamine (MDMA) was evaluated. Rats received 4 injections of methamphetamine (15 mg/kg) or MDMA (10 mg/kg) at 6 h intervals, and were killed 18-20 h after the last administration. These treatments with methamphetamine or MDMA reduced neostriatal TPH activity to 26 and 34% of control, respectively. Coadministration of MK-801 (2.5 mg/kg) significantly attenuated the methamphetamine-induced decrease in TPH activity (66% of control), but did not alter the effect of MDMA. This study suggests that excitatory amino acids may participate in the methamphetamine-induced decline in central TPH activity, and that the mechanism by which MDMA and methamphetamine decreases TPH activity may differ.

3,4-Methylenedioxyamphetamine↗

PubMed1996

Prevention of methamphetamine-induced behavioral sensitization in rats by a cyclic AMP phosphodiesterase inhibitor, rolipram.

Effects of an interaction between rolipram, a cyclic adenosine 3', 5'-monophosphate (cyclic AMP) phosphodiesterase inhibitor, and methamphetamine on the development of behavioral sensitization were observed in rats. In vivo microdialysis showed that a single dose of 4 mg/kg methamphetamine (i.p.) significantly increased striatal dopamine levels while coadministration with 4 mg/kg rolipram (i.p.) did not affect these levels. Also, methamphetamine alone did not alter striatal cyclic AMP levels but coadministration with rolipram and rolipram alone significantly increased these levels. The administration of 4 mg/kg methamphetamine (i.p.) once a day for 5 days significantly enhanced hyperlocomotion and rearing induced by a 2-mg/kg methamphetamine challenge (i.p.) after a 1-week withdrawal period, compared with controls or coadministration with 4 mg/kg rolipram (i.p.). Striatal dopamine levels, detected by in vivo microdialysis, were increased following the challenge but were comparable between the groups. These findings suggest that rolipram prevents methamphetamine-induced behavioral sensitization by increasing cyclic AMP levels while not affecting dopamine-releasing processes.

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1988

Effects of dopaminergic and serotonergic receptor blockade on neurochemical changes induced by acute administration of methamphetamine and 3,4-methylenedioxymethamphetamine.

As dopamine (DA) causes neurochemical changes in the central serotonergic system after an acute injection of methamphetamine, the present study examined the possibility that this response is mediated through dopaminergic receptors. Pretreatment with the DA receptor antagonist, haloperidol, failed to prevent the decreases in the activity of tryptophan hydroxylase and the concentration of serotonin (5-HT) in the frontal cortex, hippocampus and neostriatum 1 hr after a single administration of methamphetamine. Because methamphetamine is also a potent releaser of 5-HT, the possibility that 5-HT receptors mediate the effects of methamphetamine was evaluated. Pretreatment with methiothepin an antagonist of both DA and 5-HT receptors, failed to prevent the decline in activity of tryptophan hydroxylase but did attenuate the decreases in concentrations of 5-HT measured in the frontal cortex and hippocampus. This attenuation is not mediated through 5-HT2 receptors, as ritanserin failed to interfere with the changes induced by methamphetamine. In addition, DA or 5-HT receptors were apparently not involved in the changes in activity of tryptophan hydroxylase and concentrations of 5-HT induced by another analogue of amphetamine, 3,4-methylenedioxymethamphetamine (MDMA). This study suggests different mechanisms are responsible for the acute and long-term changes observed in the central serotonergic system following a single or multiple doses of methamphetamine.

3,4-Methylenedioxyamphetamine↗

PubMed1993

DAMGO ([D-Ala2,NMePhe4,Gly-ol]enkephalin), but not DPLPE ([D-Pen2,L- Pen5]enkephalin), specifically inhibits methamphetamine-induced behavioral responses in the mouse.

The effects of intracerebroventricular (i.c.v.) injections of mu- and delta-selective opioid agonists on the methamphetamine-induced behavioral alterations in the mouse were determined by using multi-dimensional behavioral analyses. Methamphetamine (1.0 mg/kg) produced a marked increase in linear locomotion, circling, rearing and grooming behavior. Although the mu-selective opioid agonist [D-Ala2,NMePhe4,Gly-ol]enkephalin (DAMGO) (0.003 and 0.01 microgram) itself did not significantly affect different behavioral responses, DAMGO (0.003 and/or 0.01 microgram) antagonized the methamphetamine (1.0 mg/kg)-induced increase in behavioral responses such as linear locomotion, circling, rearing and grooming. Additionally, the effects of DAMGO (0.01 microgram) on the methamphetamine (1.0 mg/kg)-induced behavioral responses were fully reversed by pretreatment with the mu-selective alkylating agent beta-funaltrexamine (beta-FNA) (5.0 micrograms). In contrast, the delta-selective opioid agonist [D-Pen2,L-Pen5]enkephalin (DPLPE) (0.3 or 1.0 microgram) had no marked effects on the methamphetamine (1.0 mg/kg)-induced behavioral responses. These results suggest that the stimulation of mu but not delta opioid receptors plays an inhibitory role in the methamphetamine-induced behavioral responses.

Analgesics↗

PubMed1990

Antagonism of cocaine, amphetamine, and methamphetamine toxicity.

The effect of diazepam, haloperidol, MK-801, and propranolol in antagonizing behavioral symptoms induced by lethal doses of cocaine, amphetamine, and methamphetamine were studied in a rat model. Animals were first pretreated IP with potential antagonists, diazepam (2, 5, and 10 mg/kg), haloperidol (5, 10, and 20 mg/kg), propranolol (5, 10, and 20 mg/kg), MK-801 (0.5, 1.0, and 2.5 mg/kg), and then were challenged IP with cocaine (70 mg/kg) (LD85), d-amphetamine (75 mg/kg) (LD100), and methamphetamine (100 mg/kg) (LD90). Diazepam, at all doses, provided significant protection against cocaine- (p less than or equal to 0.01) and methamphetamine- (p less than or equal to 0.05) induced seizures and produced a dose-dependent effect against amphetamine-induced seizures. MK-801, at all doses, reduced seizures in all groups (p less than or equal to 0.01). Propranolol altered the incidence of methamphetamine-induced seizures. Significant protection against cocaine-induced death was afforded by diazepam (p less than or equal to 0.01) and propranolol (p less than or equal to 0.05). Significant protection against amphetamine-induced death was provided by haloperidol (all doses, p less than or equal to 0.1), MK-801 (all doses, p less than or equal to 0.1), and propranolol (10 and 20 mg/kg, p less than or equal to 0.1). No agent reduced the incidence of methamphetamine- (50 or 100 mg/kg) induced death. The failure of d-amphetamine antagonists to protect against methamphetamine-induced toxicity and death suggest that different mechanisms of toxicity may exist between these drugs.

Amphetamine↗

PubMed1987

Acute effects of methamphetamine applied microiontophoretically to nucleus accumbens neurons in rats.

Microiontophoretic studies were performed to elucidate the acute effects of methamphetamine on the nucleus accumbens (Acc) neurons receiving input from the parafascicular nucleus (Pf) of the thalamus using rats anesthetized with chloral hydrate. Spike generation upon Pf stimulation was inhibited by conditioning stimuli applied to the ventral tegmental area (VTA), which is rich in dopamine-containing neurons, and by iontophoretic application of methamphetamine as well as dopamine. The VTA-, methamphetamine- and dopamine-induced inhibition of the spikes elicited by Pf stimulation was antagonized during simultaneous application of haloperidol. Glutamate-induced firing was also inhibited during iontophoretic application of methamphetamine and dopamine in neurons receiving input from the Pf, and the inhibition was blocked by simultaneously applied haloperidol. In the reserpine-treated animals, however, the Pf-induced spikes were not affected by methamphetamine, but inhibited by dopamine. These results indicate that methamphetamine inhibits the Acc neurons receiving input from the Pf, probably by releasing dopamine from dopaminergic nerve terminals from the VTA.

Action Potentials↗

PubMed1995

A single injection of amphetamine or methamphetamine induces dynamic alterations in c-fos, zif/268 and preprodynorphin messenger RNA expression in rat forebrain.

In this study, the effects of a single dose of the indirect dopamine agonists amphetamine and methamphetamine on behavior and messenger RNA expression were evaluated. Expression of c-fos, a member of the leucine zipper family, zif/268 (NGFI-A, egr1 and Krox-24), a member of the zinc finger family, and the opioid peptide, preprodynorphin, was investigated in various regions of rat forebrain with quantitative in situ hybridization histochemistry 1, 2, 3, 6 or 30 h after injection. Behavioral observations indicated that a qualitatively different behavioral syndrome was induced following methamphetamine (15 mg/kg, i.p.) as compared with that observed after amphetamine (5 mg/kg, i.p.). Similarly, methamphetamine induced a different pattern of c-fos and zif/268 messenger RNA induction in sensory/motor cortex, dorsal striatum (caudatoputamen) and ventral striatum (nucleus accumbens) than did amphetamine. The increase in c-fos messenger RNA expression peaked at 1 h and returned to basal levels in all regions by 3 h. In contrast, the increase in zif/268 messenger RNA expression in the cortical regions was equally strong at 1 and 2 h, gradually returning to basal levels by 6 h after either drug. However, in the striatal regions, zif/268 messenger RNA levels peaked at 1 h and declined gradually to basal levels by 6 h. Interestingly, methamphetamine caused an actual suppression of zif/268 gene expression (> 50%) in both caudatoputamen and nucleus accumbens at 3 h. Preprodynorphin messenger RNA expression was increased in a patchy motif in the caudatoputamen and nucleus accumbens beginning at 2 h and returning to basal levels by 30 h after injection of either drug. This study, together with our recently published observation that preprodynorphin messenger RNA is induced in the caudate 3, 6 and 18 h after amphetamine or methamphetamine injection, provides a detailed dynamic description of the differential modulation of c-fos, zif/268 and preprodynorphin messenger RNA expression in the cerebral cortex and striatum by amphetamines over time. These data implicate immediate early gene and preprodynorphin gene expression in the differential response of medium spiny striatal neurons to methamphetamine and amphetamine.

Amphetamine↗

PubMed1995

Exacerbation of carbon tetrachloride-induced liver injury in the rat by methamphetamine.

The effect of methamphetamine cotreatment on carbon tetrachloride-induced liver toxicity was examined in male Sprague-Dawley rats. Concurrent administration of methamphetamine was found to greatly increase the extent of liver injury resulting from carbon tetrachloride treatment, as indicated both by measurement of serum alanine aminotransferase (ALT) activity and from direct histopathologic examination. Concurrent administration of methamphetamine doses less than 10 mg/kg (i.p.), or administration of methamphetamine either before (-3 h) or after (3-9 h) the carbon tetrachloride dose, did not significantly increase liver injury from carbon tetrachloride. These observations indicate that the potentiation by methamphetamine of carbon tetrachloride hepatoxicity previously observed in the mouse also occurs in the rat, and that the timing of the methamphetamine and carbon tetrachloride doses is critical for the interaction.

Alanine Transaminase↗

PubMed1988

Potentiation of lethality and increase in body temperature by combined use of d-methamphetamine and morphine in mice.

Lethality and change in body temperature in mice were examined after subcutaneous injection of d-methamphetamine and morphine alone or in combination. The LD50 values for methamphetamine and morphine were calculated to be 95 and 670 mg/kg body wt., respectively. When a non-lethal dose of morphine (300 mg/kg) was administered with various doses of methamphetamine, the LD50 for methamphetamine was reduced to 5 mg/kg, indicating a marked potentiation of toxicity by combined use of both drugs. Injection of 5 mg/kg of methamphetamine produced slight hyperthermia, while 300 mg/kg of morphine decreased the body temperature of mice. However, when both drugs were used concomitantly, a marked increase in body temperature was observed. Hyperthermia was also observed when the dose of morphine was reduced to 50 mg/kg. It is postulated that hyperthermia is probably one of the contributory factors in the potentiated toxicity by combined use of morphine and methamphetamine.

Animals↗

PubMed2005

A dissociation in attentional control: evidence from methamphetamine dependence.

BACKGROUND: Selective attention comprises multiple, dissociable component processes, including task shifting and selective inhibition. The goal of this study was to test whether task-shifting, selective inhibition, or both processes were impaired in long-term but currently abstinent methamphetamine-dependent individuals. METHODS: Participants were 34 methamphetamine-dependent subjects and 20 nonsubstance abusing controls who were tested on an alternating-runs switch task with conflict sequences that required subjects to switch tasks on every second trial (AABBAABB). RESULTS: Methamphetamine-dependent individuals committed more errors on trials that required inhibition of distracting information compared with controls (methamphetamine = 17%; controls = 13%; p = .02). By contrast, error rates did not differ between the groups on switch trials (methamphetamine = 7%; controls = 6%; p = .68). CONCLUSIONS: These results indicate that selective inhibition, but not task switching, is selectively compromised by methamphetamine.

Adult↗

PubMed2004

Behavioral treatment approaches for methamphetamine dependence and HIV-related sexual risk behaviors among urban gay and bisexual men.

BACKGROUND: Methamphetamine-dependent gay and bisexual men (GBM) are at high risk for HIV transmission, largely due to drug-associated sexual risk behaviors. This project evaluated the efficacy of four behavioral drug abuse treatments for reducing methamphetamine use and sexual risk behaviors among this population. METHODS: In this randomized controlled trial, 162 methamphetamine-dependent (SCID-verified) GBM in Los Angeles County were randomly assigned to one of four treatment conditions for 16 weeks: standard cognitive behavioral therapy (CBT, n=40), contingency management (CM, n=42), combined cognitive behavioral therapy and contingency management (CBT+CM, n=40), and a culturally tailored cognitive behavioral therapy (GCBT, n=40). Stimulant use was assessed thrice-weekly during treatment using urine drug screens (48 measures). Sexual risk behaviors were monitored monthly (four measures). Follow-up assessments were conducted at 6 (80.0%) and 12 months (79.9%). RESULTS: Statistically significant differences in retention (F(3,158)=3.78, p<.02), in longest period of consecutive urine samples negative for methamphetamine metabolites (F(3,158)=11.80, p<.001), and in the Treatment Effectiveness Score were observed by condition during treatment (F(3,158)=7.35, p<.001) with post hoc analyses showing the CM and CBT+CM conditions to perform better than standard CBT. GEE modeling results showed GCBT significantly reduced unprotected receptive anal intercourse (URAI) during the first 4 weeks of treatment (X2=6.75, p<.01). During treatment between-group differences disappeared at follow-up with overall reductions in outcomes sustained to 1-year. CONCLUSIONS: Among high-risk methamphetamine-dependent GBM, drug abuse treatments produced significant reductions in methamphetamine use and sexual risk behaviors. Drug abuse treatments merit consideration as a primary HIV prevention strategy for this population.

Acquired Immunodeficiency Syndrome↗

PubMed2006

Randomized, placebo-controlled trial of baclofen and gabapentin for the treatment of methamphetamine dependence.

OBJECTIVE: To conduct a 16-week, randomized, placebo-controlled, double-blind trial of two GABAergic medications, baclofen (20 mg tid) and gabapentin (800 mg tid), for the treatment of methamphetamine dependence. METHODS: Adults with methamphetamine dependence were randomized to one of three conditions for 16 weeks: baclofen (n = 25), gabapentin (n = 26) or placebo (n = 37). All participants attended clinic thrice weekly to receive study medication and psychosocial counseling, complete study assessments, and provide urine samples. RESULTS: No statistically significant main effects for baclofen or gabapentin in reducing methamphetamine use were observed using a generalized estimating equation (GEE). A significant treatment effect was found in post hoc analyses for baclofen, but not gabapentin, relative to placebo among participants who reported taking a higher percentage of study medication (significant treatment group and medication adherence interaction in GEE model of methamphetamine use). CONCLUSIONS: While gabapentin does not appear to be effective in treating methamphetamine dependence, baclofen may have a small treatment effect relative to placebo. Future studies evaluating the effectiveness of baclofen and other GABAergic agents for treatment of methamphetamine may be warranted.

Adult↗

PubMed2003

The role of hyperthermia and metabolism as mechanisms of tolerance to methamphetamine neurotoxicity.

Pretreatment with multiple methamphetamine injections prior to a high-dose methamphetamine challenge administration can attenuate long-term deficits in striatal and hippocampal serotonin content caused by the stimulant. The present data extend previous findings by demonstrating that rats pretreated with escalating doses methamphetamine did not exhibit dopamine deficits in the striatum, nor serotonin deficits in striatal, frontal cortical, or hippocampal tissues, 7 days after a challenge methamphetamine administration. This protection was not due to attenuation of methamphetamine-induced hyperthermia or altered brain methamphetamine concentrations. These data differ from previous findings thereby highlighting that different mechanisms contribute to the tolerance of the neurotoxic effects.

Animals↗

PubMed2005

Differential neurotensin responses to low and high doses of methamphetamine in the terminal regions of striatal efferents.

Neurotensin is a neuropeptide associated with basal ganglia dopaminergic neurons. Because levels of neurotensin in striatal tissue are differentially affected by low or high doses of methamphetamine, we employed microdialysis to assess the dose-dependent effects of methamphetamine on neurotensin release from the terminals of striatonigral and striatopallidal neurons. A low (0.5 mg/kg), but not high (10 mg/kg), dose of methamphetamine significantly increased nigral extracellular levels of neurotensin. The low-dose effect on extracellular nigral neurotensin levels was blocked by pretreatment with either a dopamine D1 or D2 receptor antagonist. In the globus pallidus, only half of the animals demonstrated increased neurotensin release after the low dose of methamphetamine. These findings suggest that low and high doses of methamphetamine differentially affect the release of neurotensin from the terminals of striatonigral neurons and that both dopamine D1 and D2 receptor activation contributes to the low-dose methamphetamine effects in the substantia nigra.

Analysis of Variance↗

PubMed2006

Effects of mu-, delta- and kappa-opioid receptor agonists on methamphetamine-induced self-injurious behavior in mice.

Opioid receptor agonists can differentially modify the behavioral effects of direct/indirect dopamine receptor agonists, such as methamphetamine, cocaine and apomorphine. However, the effects of opioid receptor agonists on high-dose methamphetamine-induced behavior have not yet been clarified. Therefore, the present study was undertaken to investigate the effects of mu (morphine)-, delta (SNC80)- and kappa (U50,488H)-opioid receptor agonists on methamphetamine-induced self-injurious behavior and locomotor activity in mice. Methamphetamine (20 mg/kg) induced severe self-injurious behavior. In a combination test, some opioid receptor agonists significantly attenuated methamphetamine-induced self-injurious behavior, with potencies in the order morphine>buprenorphine (mu-opioid and kappa-opioid receptor agonist/antagonist) >U50,488H, as maximum effects. These results suggest that the stimulation of mu- and kappa-opioid receptors plays an inhibitory role in high-dose methamphetamine-induced stereotypic self-injurious behavior in mice, without affecting locomotor activity.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

PubMed2005

Engineering of recombinant antibody fragments to methamphetamine by anchored periplasmic expression.

The detection of methamphetamine and other chemically related illicit drugs relies extensively on immunoassays. Here we report the cloning and affinity maturation of an anti-methamphetamine antibody which is being employed in the current commercial assays. An anti-methamphetamine scFv was cloned from hybridoma cells, expressed in bacteria and its affinity towards methamphetamine and N-ethylamphetamine (ethamphetamine) was determined by Surface Plasmon Resonance (SPR). The anti-methamphetamine scFv gene was subjected to random mutagenesis by error prone PCR and variants with improved affinity were isolated from the resulting library by a novel screening methodology termed Anchored Periplasmic Expression (APEx) [Harvey, B.R., Georgiou, G., Hayhurst, A., Jeong, K.J., Iverson, B.L., Rogers, G.K. (2004). Anchored periplasmic expression, a versatile technology for the isolation of high-affinity antibodies from Escherichia coli-expressed libraries. Proc. Natl. Acad. Sci. U. S. A. 101, 9193.]. The isolated clones exhibited improved affinity to these illicit drugs, yet maintained low cross-reactivity to over-the-counter drugs. In addition, all clones displayed improved expression characteristics in Escherichia coli. The affinity improved scFv antibodies are thus likely to be useful in methamphetamine class immunodiagnostics.

Amino Acid Sequence↗

PubMed2005

Differential effects of methamphetamine on expression of neuropeptide Y mRNA in hypothalamus and on serum leptin and ghrelin concentrations in ad libitum-fed and schedule-fed rats.

Relatively little is known concerning the interaction of psychostimulants with hypothalamic neuropeptide systems or metabolic hormones implicated in regulation of energy balance. The present studies tested whether methamphetamine alters the expression of neuropeptide Y (NPY) and agouti-related peptide (AgRP), two important orexigenic neuropeptides, or proopiomelanocortin (POMC), the precursor for the anorexigenic peptide alpha-melanocyte-stimulating hormone, or the secretion of leptin, insulin and ghrelin, concomitant with inhibition of food intake. Female rats were either fed ad libitum (AL) or placed on a scheduled feeding (SF) regimen, with access to food limited to 4 h/day. Administration of (+/-)-methamphetamine (7.5 mg/kg, i.p.) 2 h prior to food presentation significantly inhibited food intake in SF animals, but did not affect intake in AL animals. In a separate study, AL and SF animals were killed just prior to expected food presentation, and expression of NPY, AgRP and POMC mRNAs in hypothalamus was determined using in situ hybridisation; concentrations of leptin, insulin and ghrelin in serum were determined with radioimmunoassays. In saline-treated, SF controls, NPY and AgRP mRNA expression in arcuate nucleus and serum ghrelin were significantly elevated, and serum leptin and insulin were significantly reduced. Methamphetamine reversed the up-regulation of NPY mRNA expression observed in the SF condition, without affecting AgRP mRNA or the serum concentrations of metabolic hormones. However, in AL animals, NPY mRNA expression in arcuate and dorsomedial nuclei was significantly increased by methamphetamine, which also reduced serum leptin and insulin and increased serum ghrelin concentrations. These findings suggest that the inhibition of NPY expression in SF animals may be a mechanism underlying the anorexigenic effect of methamphetamine seen in this condition. The increase in NPY expression produced by methamphetamine in AL animals may be mediated by the ability of this drug to decrease secretion of leptin and insulin and increase secretion of ghrelin.

Agouti-Related Protein↗