This Conference was held at the Natcher Auditorium on the NIH Campus, July 19-20, 2001.
Comparative Effects of Substituted Amphetamines (PMA, MDMA, and METH ) on Monoamines in Rat Caudate: A Microdialysis Study
Bobby Gough, Syed Z. Imam, Bruce Blough, W. Slikker, Jr., Syed F. Ali
Division of Neurotoxicology
National Center for Toxicological Research/FDA
Paramethoxyamphetamine (PMA) is a methoxylated phenethylamine derivative that has been used illicitly in Australia since 1994. PMA is also becoming popular at rave parties in the United States. PMA raised a concern when a series of fatalities resulted after its use in South Australia, where it was marketed as "ecstasy," which is the colloquial name for MDMA. In the present study, we evaluated the comparative neurotoxicity of substituted amphetamines (PMA, MDMA, and METH) in rats. Extracellular levels of dopamine (DA), 3,4-dihydroxy-phenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and serotonin (5-HT) were assayed in the caudate of freely moving rats using microdialysis and HPLC-EC. Dialysates were assayed every 20 minutes for 4 hours following an intraperitoneal (IP) injection of PMA (2.5, 5, 10, 20 mg/kg), MDMA (10, 20 mg/kg), or METH (2.5 mg/kg). METH produced a significant increase in extracellular DA (700 percent) and significant decreases in extracellular DOPAC and HVA (30 and 50 percent), with no detectable changes in either HIAA or 5-HT. MDMA produced significant increases in DA (700 percent at 10 mg/kg; 950 percent at 20 mg/kg) and decreases in DOPAC (15 percent for both 10 and 20 mg/kg) and HVA (50 percent at 10 mg/kg; 35 percent at 20 mg/kg). MDMA also increased 5-HT (350 percent at 10 mg/kg;
575 percent at 20 mg/kg) and decreased 5-HIAA to 60 percent for both dose levels. PMA produced no detectable increases in DA at dose levels of 2.5, 5, or 10 mg/kg but significantly increased DA (975 percent) at a dose of 20 mg/kg. However, PMA significantly decreased DOPAC at all dose levels (75 percent at 2.5 mg/kg; 40 percent at 5 mg/kg; 30 percent at 10 mg/kg; 10 percent at 20 mg/kg), with comparable decreases in HVA at all dose levels. PMA also produced significant increases in 5-HT at 10 and 20 mg/kg (350 percent for both dose levels), with no detectable changes in 5-HT at 2.5 or 5 mg/kg. All dose levels of PMA significantly decreased 5-HIAA (50 to 70 percent). These data suggest that PMA, like MDMA and METH, is capable of producing dopaminergic and serotonergic neurotoxicity.
Neurocognitive Function in Recreational Users of MDMA
Karen L. Hanson, Monica Luciana, Ph.D.
Department of Psychology
University of Minnesota
Ecstasy [(+/-) 3,4-methylenedioxymethamphetamine: MDMA] is an increasingly popular recreational drug. Animal research has provided evidence that the high levels of serotonin released during MDMA use result in the destruction of serotonergic (5-HT) brain cells. 5-HT modulates several psychological functions, including mood and memory. Clinical studies have reported memory impairment and dysphoric mood symptoms secondary to MDMA use, possibly because of long-term alterations in 5HT function. In this study, we examined affect and neurocognitive functioning in abstinent recreational users of MDMA (ages 18-35 years) compared with age-matched non-using controls and a second control group of alcohol abusers. The dose, frequency, and duration of MDMA use were assessed through self-report questionnaires, and structured clinical interviews were used to rule out other pathology. Participants also completed a comprehensive neuropsychological testing battery including measures of IQ, motor skill, working and recognition memory, planning, set-shifting, verbal and nonverbal skill, and attention. Self-report measures of affect and personality traits were obtained. Preliminary data analyses suggest that ecstasy use may not be as detrimental to cognitive function as has been previously reported. Findings will be discussed in relation to serotonin's modulation of cognition, emotion, and their interactions within frontostriatal networks.
Working Memory and MDMA Use Among Gay Circuit Party Attendees
E. Isyanov, M.S., R. Reed, Ph.D., D. McKirnan, Ph.D., B. Hope, LCSW, E. Martin, Ph.D.
Department of Psychiatry
University of Illinois at Chicago
MDMA and HIV affect similar regions of prefrontal cortex and aspects of neurocognition. However, neurocognitive effects of MDMA have not been studied in men who have sex with men (MSM) who participate in the circuit party/dance club culture. This population is at high risk for HIV disease, and HIV-infected MSM who use MDMA may be at increased risk for neurocognitive deficits, which have serious implications for risk behavior and adherence to medication regimens.
In a preliminary study as part of a currently funded NIDA project, we studied working memory, an executive function mediated by prefrontal cortex and known to be defective in HIV-positive persons. We compared the performance of HIV-negative MSM with and without a history of MDMA use on a verbal working memory task with known sensitivity to HIV-related cognitive deficits in drug abusers.
MSM with a history of MDMA use showed significant defects in working memory compared with MSM with no history of MDMA use (p<.05). These preliminary data are encouraging in that working memory deficits can be detected in MSM users of MDMA. The next step is to determine whether MDMA users who are also HIV-positive are indeed at increased risk for cognitive defects.
Interactions of Acute and Chronic Stress With d-MDMAĐInduced
Dopaminergic Neurotoxicity in the Mouse
Elizabeth Anne Johnson, Stanley Benkovic, Alvin R. Little, Krishnan Sriram,
James P. O'Callaghan, Diane B. Miller
Chronic Stress and Molecular Neurotoxicology Laboratory
Toxicology and Molecular Biology Branch
There is a perception that stress may exacerbate toxic consequences of drug exposures, although this idea has not been extensively tested in an objective manner. We have examined the effects of a variety of forms of acute and chronic stress on the striatal dopaminergic neurotoxic effects of d-MDMA (15 mg/kg sc every 2 hours X 4) in mouse. End points used to assess neurotoxic damage include severe reduction of dopamine, associated metabolites, and tyrosine hydroxylase holoenzyme protein levels and marked elevation of striatal glial fibrillary acid protein, an index of astrogliosis. We found that acute stress induced in a variety of ways (including restraint, exposure to a 15°C ambient temperature, or administration of ethanol) is protective against the dopaminergic neurotoxicity caused by d-MDMA, whereas repeated exposure to stress causes a loss of its protective properties. Acute stress appears to cause physiologic changes at the time of drug administration that are protective, since restraint stress applied before drug administration is not protective against neurotoxic consequences. We also have found that exposure to chronic elevations of circulating corticosterone at supraphysiologic levels causes an enhancement of the striatal damage caused by d-MDMA, although it does not cause damage in hippocampus, a brain area thought to be susceptible to glucocorticoid neuroendangerment. Together these studies indicate that the physiologic changes induced by acute stress can be protective of the mouse brain against the neurotoxic effects of MDMA, whereas chronic stress either is not protective or may enhance MDMA-induced brain damage.
Behavioral Psychopharmacology of MDMA and Related Compounds:
A Review of Animal Studies
Diana L. Martinez-Price, Ph.D., Kirsten Krebs-Thomson, Ph.D., Stephanie Dulawa Ph.D., Mark A. Geyer, Ph.D.
Departments of Neuroscience and Psychiatry
University of California, San Diego
La Jolla, CA
Since being classified as a Schedule I controlled substance in 1985, MDMA (3,4-methylenedioxy-N-methylamphetamine, ecstasy) has been the subject of controversy regarding its potential therapeutic usage, mechanism of action, popularity with young people in the "rave" culture, and issues of potential neurotoxicity. While most attention has centered on issues of neurotoxicity and epidemiological aspects of MDMA use in humans, the basic behavioral pharmacology studies of MDMA have quietly continued to gather information regarding the mechanisms underlying the behavioral effects of MDMA in animals. This poster will review animal studies of the behavioral effects of MDMA and related compounds in locomotor activity and startle paradigms. MDMA and related compounds produce a unique behavioral profile in rodents that includes locomotor hyperactivity, reductions in exploratory behavior, and deficits in both habituation and prepulse inhibition of startle. These behavioral effects are attributable to the release of presynaptic serotonin and the consequent activation of multiple serotonin receptors. The precise sites and mechanisms of action for these behavioral effects are currently under investigation. Studies of MDMA and related compounds using animal subjects have provided, and will continue to provide, information that can be used to elucidate the complex mechanisms underlying drug abuse, cognition, arousal, and motor activity as well as mechanisms of neurotoxicity.
This work was supported by a grant from the National Institute on Drug Abuse (DA02925).
MDMA in Combination: "Trail Mix" and Other Powdered Drug Combinations
Rafael Narvaez, M.A.
Program in Urban Health
Department of Social Medicine
Harvard Medical School
Recent ethnographic research conducted in Boston and New York City on HIV risk behaviors among men who have sex with men (MSM) and use club drugs has revealed that MDMA users in this population rarely use MDMA alone. One emerging pattern is the intranasal use of MDMA in a powdered mix with other drugs. One such formulation is known by users as "trail mix," which is commonly understood to be a powdered combination of MDMA and ketamine with the addition of a stimulant (such as methamphetamine or cocaine) and sometimes ground Viagra or other drugs. Trail mix is not sold as such; rather, it is manufactured by users to achieve a variety of effects, such as enhancing sex by adding methamphetamine or Viagra. Accidental overdoses have occurred, which users attribute to poorly mixed combinations.
As this is an emerging drug pattern, there is little information regarding the clinical implications of powdered combinations of MDMA and potentially dangerous interactions between the constituent drugs. Although MSM in Boston and New York City have reduced their use of drugs such as GHB in response to perceived danger, prevention efforts have had little effect in reducing the use of MDMA. In the absence of data regarding MDMA in combination with other drugs, there is a significant challenge in mounting appropriate prevention efforts.
In order to develop appropriate interventions, future research studies should identify the characteristics of high-risk groups and address HIV risk behavior patterns associated with specific combinations of MDMA and other drugs.
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