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PubMed2006

Efficacy of a behavioral intervention for increasing safer sex behaviors in HIV-positive MSM methamphetamine users: results from the EDGE study.

BACKGROUND: Methamphetamine use has been associated with rising STI/HIV transmission rates, particularly among men who have sex with men (MSM). Interventions which successfully reduce risk for HIV transmission among this population are a public health priority. This study examined the efficacy of a behavioral intervention for increasing safer sex behaviors in the context of ongoing methamphetamine use in a sample of HIV-positive, methamphetamine-using MSM. METHODS: Three-hundred and forty-one participants from San Diego, CA were randomly assigned to receive either a safer sex behavioral intervention (EDGE) or a time-equivalent diet-and-exercise attention-control condition. Random effects regression analyses were used to evaluate change in safer sex behaviors over a 12-month period. RESULTS: Participants in the EDGE intervention engaged in significantly more protected sex acts at the 8-month (p=0.034) and 12-month assessment (p=0.007). By 12-months post-baseline, a greater percentage of protected sex acts was observed for EDGE (25.8%) vs. control participants (18.7%) (p=0.038). There was a significant time-by-intervention interaction (p=0.018) for self-efficacy for condom use, suggesting that EDGE participants' self-efficacy demonstrated a greater increase over time compared to control participants. CONCLUSIONS: These results suggest that it is possible to reduce high risk sexual behaviors in the context of ongoing methamphetamine use among HIV-infected MSM.

Adult↗

PubMed2004

Impurity profiling of methamphetamine hydrochloride drugs seized in the Philippines.

Methamphetamine hydrochloride is one of the most widely used illicit drugs in the Philippines. In this study, we describe the application of cluster analysis of trace impurities in the profiling of the seized methamphetamine drug samples. Thirty milligrams of a homogenized drug sample were dissolved in 1 mL of pH 10.5 buffer solution and extracted with ethyl acetate containing three internal standards. The trace impurities were identified using gas chromatography-mass spectrometry (GC-MS) and quantified by gas chromatography with a flame ionization detector (GC-FID). Following previously reported methodologies, 30 impurity peaks were selected from the GC-FID chromatograms. The peak areas and retention times were referenced to the internal standards. The peak areas of the selected peaks were then grouped for cluster analysis. In order to check for consistency of clustering, two further cluster analyses were performed using 40 and 50 impurity peaks. Changes in clustering were observed in going from 30 to 40 impurity peaks, while analyses using 40 and 50 impurity peaks gave similar results. Thus, for the seized drug samples used in this study, cluster analysis using at least 40 impurity peaks showed better consistency of clustering as compared to analysis using 30 peaks only. Ten of the impurity peaks were identified, of which four were identified for the first time in methamphetamine drug samples. These are p-bromotoluene, N-benzyl amphetamine, N-ethyl amphetamine, and N-ethyl methamphetamine. The presence of phenyl-2-propanone (P2P), N,N-dimethyl amphetamine, and N-formyl amphetamine is indicative that these casework samples were synthesized using the Leuckart method.

Amphetamines↗

PubMed2003

Chronic methamphetamine administration reduces histamine-stimulated phosphoinositide hydrolysis in mouse frontal cortex.

In the present study, it was hypothesized that in vivo pretreatment with repeated methamphetamine would alter the agonist-stimulated phosphoinositide hydrolysis in mouse frontal cortical slices. Male ICR mice that received the methamphetamine injection (1.0mg/kg, intraperitoneally) once a day for five consecutive days showed behavioral sensitization to the same dose of methamphetamine 5 days after the last injection of the initial chronic treatment regimen (test day 10). On test day 10, the reduction of histamine (0.1-1.0mM)-stimulated phosphoinositide hydrolysis in the mouse frontal cortex was observed. The reduction was specific to histamine, but not to norepinephrine (10 microM-0.1mM) or L-glutamate (0.1-0.5mM). The reduction occurred without any change in the expression level of histamine H(1) receptor mRNA. The reduction recovered 25 days after the last injection of the initial chronic treatment regimen (test day 30). The direct application to the slices of a pharmacologically effective concentration of methamphetamine in vitro (10 microM) did not alter the histamine signal transduction. The present results suggest that the reduction is probably one of neuroadaptations in the frontal cortex contributing to behavioral sensitization.

Animals↗

PubMed2000

Time-course of methamphetamine-induced neurotoxicity in rat caudate-putamen after single-dose treatment.

The time-course of monoamine and tyrosine hydroxylase depletion after single-dose administration of D-methamphetamine (40 mg/kg s.c.) was investigated in caudate-putamen of male Sprague-Dawley rats. Times evaluated were 6, 12, 48, 72 and 240 h following treatment. Tyrosine hydroxylase was significantly reduced by 29, 60, 66, 76 and 76% of control at each of the respective post-treatment time intervals. Dopamine was not reduced 6 h following treatment. Dopamine was significantly reduced by 53, 57, 68 and 74% 12, 48, 72 and 240 h post-treatment, respectively. Reductions in caudate-putamen serotonin began earlier and were ultimately larger than for dopamine, with significant reductions of 28, 33 55, 74 and 81% at each of the respective post-treatment intervals. Confirmation of neurotoxicity was provided by measurement of glial fibrillary acidic protein (GFAP) 240 h post-treatment. GFAP was increased at this time interval by 150% above control. Methamphetamine-induced hyperthermia during the 6 h immediately after treatment was comparable among the groups of animals used for analyses at each time interval. The results demonstrate that methamphetamine-induced monoamine reductions in the caudate-putamen occur rapidly, peak at 75-80% below controls, and last for at least 10 days after a single dose. These effects are as large or larger than those reported after the commonly used 10 mg/kgx4 dose treatment regimen administered at 2-h intervals and provides an alternate model for the investigation of methamphetamine-induced neurotoxicity.

Animals↗

PubMed2001

Dose-dependent protective effects of apomorphine against methamphetamine-induced nigrostriatal damage.

(R)-apomorphine is a non-selective dopamine (DA) agonist which is used in the treatment of Parkinson's disease. In addition to symptomatic effects, apomorphine exerts a neuroprotective activity in specific experimental models. For instance, apomorphine prevents experimental parkinsonism induced by the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. Neuroprotection obtained with apomorphine does not seem to be related to its dopamine (DA) agonist properties, instead it appears to be grounded on the antioxidant and the free radical scavenging effects of the compound. In this study, we sought to determine whether apomorphine protects against methamphetamine toxicity. We found that apomorphine (1; 5 and 10 mg/kg) dose-dependently protects against methamphetamine- (5 mg/kg X3, 2 h apart) induced striatal DA loss and reduction of tyrosine hydroxylase (TH) activity in the rat striatum. These protective effects are neither due to a decrease in the amount of striatal methamphetamine nor to hypothermia as indicated by measurement of striatal methamphetamine and body temperature at different time intervals after drug administration. The effects of apomorphine were neither opposite to, nor reversed by the DA antagonist haloperidol despite no decrease in body temperature was observed when apomorphine was given in combination with haloperidol. The present data are in line with recent studies suggesting a DA receptor-independent neuroprotective effect of apomorphine on DA neurons and call for further studies aimed at evaluating potential neuroprotective effects of apomorphine in Parkinson's disease.

Animals↗

PubMed2001

Caudate-putamen and nucleus accumbens extracellular acetylcholine responses to methamphetamine binges.

Exposure of experimental animals to an escalating dose, multiple binge pattern of methamphetamine administration results in the progressive emergence of a unique behavioral profile, which includes a significant decrease in the duration of the stereotypy phase as well as a profound increase and qualitative change in the locomotor activation. This behavioral profile is associated with a selective decrease in the caudate-putamen but not nucleus accumbens extracellular dopamine response. Since the acetylcholine interneurons in these regions are partly under the control of the mesostriatal and mesoaccumbens dopamine inputs, changes in the activation of these interneurons should parallel the regionally differential dopamine responses during multiple binge treatment. Therefore, we characterized the caudate-putamen and nucleus accumbens extracellular acetylcholine responses to escalating-dose, multiple binge methamphetamine administration. An acute methamphetamine binge decreased acetylcholine levels in caudate-putamen, but had no effect on levels in nucleus accumbens. Furthermore, corresponding to the selective decrease in the dopamine response, the caudate-putamen but not nucleus accumbens extracellular acetylcholine response exhibited tolerance with repeated binge exposures; i.e. the decrease in acetylcholine associated with the acute methamphetamine binge was attenuated with multiple binge exposure. These results are consistent with our hypothesis and suggest that the regionally differential acetylcholine responses reflect one functional consequence of the escalating-dose, multiple binge stimulant treatment.

Acetylcholine↗

PubMed1999

Ibogaine blocked methamphetamine-induced hyperthermia and induction of heat shock protein in mice.

Body temperature changes and heat shock protein (HSP-72) induction in the caudate nucleus were studied in female C57BL/6N mice pretreated with ibogaine (50 mg/kg) and sacrificed 48 h. after a single dose of methamphetamine (20 mg/kg). Methamphetamine injection resulted in hyperthermia and induced HSP-72 expression, whereas treatment with ibogaine alone produced hypothermia. The ibogaine followed by methamphetamine injection showed no hyperthermia and decreased HSP-72 expression. These data indicate that pretreatment with ibogaine can completely block methamphetamine-induced hyperthermia and HSP-72 expression in the striatum.

Animals↗

PubMed2000

Blockade of dopamine transporter and tyrosine hydroxylase activity loss by [D-Ala(2), D-Leu(5)]enkephalin in methamphetamine-treated CD-1 mice.

[D-Ala(2), D-Leu(5)]enkephalin (DADLE) has been previously reported to prolong the survival of tissues both in the periphery and in the central nervous system. Here, we show that DADLE was able to block the protein as well as the functional loss of dopamine transporter (DAT) and tyrosine hydroxylase (TH) induced by methamphetamine. Male CD-1 mice received four injections of methamphetamine (10 mg/kg, i.p. ) at 2-h intervals. DADLE (4 mg/kg, i.p.) was given 30 min before each injection of methamphetamine. Western blotting and enzymatic assays showed that DADLE blocked the protein loss and functional impairment of DAT and TH induced by methamphetamine.

Analysis of Variance↗

PubMed2001

Intravenous (+)-methamphetamine causes complex dose-dependent physiologic changes in awake rats.

Hemodynamic and temperature dose-response relationships were characterized in freely moving rats following i.v. (+)-methamphetamine administration to mimic the rapid onset of effects experienced by many human users. Rats received saline and (+)-methamphetamine in a repeated-measures, mixed-sequence design at 22+/-1 degrees C. Significantly greater blood pressure and heart rate elevations were observed after 1.0 and 3.0 mg/kg (+)-methamphetamine vs. 0.1 and 0.3 mg/kg. The time to peak hemodynamic values and the duration of effects were significantly greater after 3.0 mg/kg vs. the lower doses. The time to peak temperatures was significantly longer after 1.0 mg/kg vs. the lower doses. Following 3.0 mg/kg, all rats experienced temperature decreases before having elevated temperatures. The duration and magnitude of the delayed temperature elevations were significantly greater after 3.0 mg/kg vs. the lower doses. In conclusion, the (+)-methamphetamine-induced hemodynamic and temperature effects were not temporally synchronized, and the complex responses were not linearly related to dose.

Animals↗

PubMed2002

Differential involvement of 5-HT(2A) receptors in the discriminative-stimulus effects of cocaine and methamphetamine.

Involvement of 5-HT(2A) receptors in the discriminative-stimulus effects of cocaine versus methamphetamine was studied in Sprague Dawley rats (n=10) trained to discriminate 10 mg/kg cocaine, i.p., from saline under a fixed-ratio 10 (FR10) schedule of food presentation. The ability of (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT(2A) receptor agonist, and ketanserin, a 5-HT(2A) receptor antagonist, to either substitute for or block the discriminative-stimulus effects of cocaine, or to shift the cocaine dose-response curve, was evaluated. DOI (0.18-1.0 mg/kg) partially substituted for the training dose of 10 mg/kg cocaine, but only at doses that decreased rates of responding. At the highest dose of DOI tested (1.0 mg/kg), there was about 65% cocaine-appropriate responding. Substitution of DOI for cocaine and DOI-induced decreases in rates of responding were completely reversed by ketanserin (3.0 mg/kg). Ketanserin (3.0 mg/kg) also produced a significant shift to the right of the cocaine dose-response curve and antagonized increases in rates of responding produced by lower doses of cocaine. Ketanserin (1.0-10.0 mg/kg), however, did not block the discriminative-stimulus effects of the training dose of cocaine. When DOI (0.3 mg/kg) was co-administered with different doses of cocaine, there was a slight leftward shift in the cocaine dose-response curve, which was not significant and appeared to reflect simple additive effects of DOI and cocaine. In contrast, the same dose of DOI (0.3 mg/kg) produced a marked and highly significant shift to the left of the methamphetamine (0.18-1.0 mg/kg) dose-response curve in the same subjects and the effects of DOI and methamphetamine were clearly more than additive. The present findings provide new evidence that there is some serotonergic modulation of cocaine's discriminative-stimulus actions, which appears to involve stimulation of 5-HT(2A) receptors. However, involvement of 5-HT(2A) receptor activity in the discriminative-stimulus actions of cocaine appears to be less pronounced than in similar actions of methamphetamine.

Analysis of Variance↗

PubMed2002

Gender differences in the behavioral effects of methamphetamine.

The effects of methamphetamine were tested in male and female rats on two different behavioral tasks. Following habituation to a locomotor activity chamber, female rats were more sensitive to the locomotor activating effect of i.p. methamphetamine (0.1-3.0 mg/kg) than were male rats. A similar effect has been observed for other psychomotor stimulants, including cocaine and amphetamine. However, males and females did not differ on methamphetamine-induced place preference following eight conditioning trials with a wide range of doses (0.1-5.6 mg/kg). These results suggest that males and females differ in their response to methamphetamine for only some behavioral tasks.

Animals↗

PubMed2002

Effect of 7-nitroindazole on drug-priming reinstatement of D-methamphetamine-induced conditioned place preference.

The study investigated the role of nitric oxide (NO) in the relapse to drug-seeking behavior induced by D-methamphetamine. After the induction of D-methamphetamine (1 mg/kg) conditioned place preference, the rewarding effect became extinct 6 weeks later. The extinguished place preference was reinstated by D-methamphetamine (0.125 mg/kg) injection, an effect which was attenuated by 7-nitroindazole (12.5 and 25 mg/kg) pretreatment. The results demonstrate that NO is involved in relapse primed by D-methamphetamine injection.

Amphetamine-Related Disorders↗

PubMed1996

Effects of interdose interval on ambulatory sensitization to methamphetamine, cocaine and morphine in mice.

To determine the minimum interdose interval for induction of ambulatory sensitization to methamphetamine, cocaine and morphine, 3 sets of 5 groups of mice were treated with either methamphetamine (2 mg/kg s.c.), cocaine (10 mg/kg s.c.) or morphine (10 mg/kg s.c.) 3 times at intervals of 3, 6, 12, 24 or 48 h, and then 2 times at intervals of 3 days in all groups. During the first 3 administrations of both methamphetamine and cocaine, interdose intervals of 3-12 h did not produce a significant change in the ambulatory stimulation. However, 3 repeated administrations of morphine with interdose intervals of 3 and 6 h, but not 12 h, caused tolerance to the ambulatory stimulant effect. The administration of all drugs with interdose intervals of 24 and 48 h produced ambulatory sensitization. Furthermore, following the fourth and fifth administrations of each drug, all groups of mice demonstrated sensitization. These results indicate that an interdose interval of 24 h or longer is required for induction of ambulatory sensitization to methamphetamine, cocaine and morphine.

Animals↗

PubMed1997

A rapid and reversible change in dopamine transporters induced by methamphetamine.

Because high doses of methamphetamine promote free radical formation, and striatal dopamine transporters are rapidly inactivated by oxidative events, we determined the effect of a single high dose of methamphetamine on dopamine transporter activity in striatal synaptosomes. One hour after methamphetamine administration, dopamine uptake decreased by 48%. This dramatic decline was totally reversed by 24 h after treatment. These findings suggest that methamphetamine reversibly decreases dopamine transporter activity by oxidative mechanisms.

Animals↗

PubMed1982

Rapid and highly sensitive method for determination of methamphetamine and amphetamine in urine by electron-capture gas chromatography.

A rapid and sensitive method for determination of methamphetamine and amphetamine in urine was developed by using electron-capture gas chromatography. The extraction procedure, the experimental conditions for pentafluorobenzoyl derivative formation and the percentage recovery of the drugs from urine are described. The pentafluorobenzoyl derivative of methamphetamine showed a higher electron-capture sensitivity and was detected in at least 23-fold lower concentration than the heptafluorobutyryl derivative which is commonly used as a derivatizing agent for the amine. The detection limit of pentafluorobenzoyl derivatives of methamphetamine and amphetamine was ca. 10 pg. A concentration as low as 10 ng/ml of methamphetamine and amphetamine in urine was easily detected by this method.

Amphetamine↗

PubMed2002

Methamphetamine induces apoptosis in an immortalized rat striatal cell line by activating the mitochondrial cell death pathway.

Methamphetamine is a neurotoxic drug of abuse known to cause cell death both in vitro and in vivo. Nevertheless, the molecular and cellular mechanisms involved in this process remain to be clarified. Herein, we show that methamphetamine-induced apoptosis is associated with early (2 h) overexpression of bax, decreases of mitochondrial membrane potential and oxygen consumption as well as release of cytochrome c from mitochondria. In addition, activated caspase-9 was detected at 4 h post-METH exposure. Cell death was detectable by annexin V and propidium iodide staining after 8 h of methamphetamine exposure. At that time, the majority of the cells were stained by annexin V alone, with some cells being stained for both annexin V and propidium iodide. Moreover, cleavage of caspase-3, poly (ADP-ribose) polymerase and DNA fragmentation-related factor 45 was detected at 8 h post drug treatment. These results indicate that methamphetamine-induced apoptotic cell death results from early overexpression of bax, reduction of mitochondrial respiration and membrane potential and release of mitochondrial cytochrome c with subsequent activation of the caspase cascade.

Animals↗

PubMed2000

Effects of methamphetamine-induced neurotoxicity on the development of neural circuitry: a hypothesis.

Exposure of the developing brain to methamphetamine has well-studied biochemical and behavioral consequences. We review: (1) the effects of methamphetamine on mature serotonergic and dopaminergic pathways; (2) the mechanisms of methamphetamine neurotoxicity and (3) the role of serotonergic and dopaminergic signaling in sculpting developing neural circuitry. Consideration of these data suggest the types of neural circuit alterations that may result from exposure of the developing brain to methamphetamine and that may underlie functional defects.

Animals↗

PubMed2002

Preliminary evidence of reduced cognitive inhibition in methamphetamine-dependent individuals.

Chronic methamphetamine abuse is associated with disruption of frontostriatal function involving serotonin and dopamine circuitry. Clinically, methamphetamine-dependent (MD) individuals are highly distractible and have difficulty focussing. Here, we used a computerized single-trial version of the Stroop Test to examine selective attention and priming in MD. Subject groups comprised eight MD men (31.7+/-7.2 years of age), who had used methamphetamine for 15.75+/-8.4 years but were currently abstinent for 2-4 months, and 12 controls (35.7+9.7 years of age). Compared with the control group, the MD group exhibited significantly greater interference (P<0.05) despite intact priming. Error rates did not differ between the groups. This preliminary finding of reduced cognitive inhibition in MD individuals is consistent with the distractibility they show clinically. Furthermore, the dissociation between explicit attentional performance and priming effects suggests that some attentional functions are not as affected by long-term methamphetamine use as others.

Adult↗