Effect of acute monoamine depletion on 3,4-methylenedioxymethamphetamine-induced neurotoxicity

Brodkin, Jesse; Malyala, A; Nash, John J.

doi:10.1016/0091-3057(93)90520-4

Cited by 77 publications

(55 citation statements)

References 28 publications

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“…Gudelsky and Nash (1996) demonstrated that the co-administration of carbidopa/ 5-HTP and MDMA results in a dramatic increase in extracellular 5-HT that is 10 times greater than that produced by carbidopa/5-HTP alone. The contribution of newly synthesized 5-HT to the MDMA-stimulated release of 5-HT also was demonstrated by Brodkin et al (1993) who reported that inhibition of 5-HT synthesis markedly attenuates the MDMA-induced increase in extracellular 5-HT. Thus, the release of newly synthesized 5-HT that can be facilitated by treatment with precursors may be enhanced further by psychostimulants that activate the 5-HT transporter.…”

Section: Serotonergic Neuronsmentioning

confidence: 82%

Actions of 3,4-methylenedioxymethamphetamine (MDMA) on cerebral dopaminergic, serotonergic and cholinergic neurons

Gudelsky

Yamamoto

2008

Pharmacology Biochemistry and Behavior

120

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Abstract3,4-Methylenedioxymethamphetamine (MDMA) is an amphetamine derivative and a popular drug of abuse that exhibits mild hallucinogenic and rewarding properties and engenders feelings of connectedness and openness. The unique psychopharmacological profile of this drug of abuse most likely is derived from the property of MDMA to promote the release of dopamine and serotonin (5-HT) in multiple brain regions. The present review highlights primarily data from studies employing in vivo microdialysis that detail the actions of MDMA on the release of these neurotransmitters. Data from in vivo microdialysis experiments indicate that MDMA, like most amphetamine derivatives, increases the release of dopamine in the striatum, n. accumbens and prefrontal cortex. However, the release of dopamine evoked by MDMA in each of these brain regions appears to be modulated by concomitantly released 5-HT and the subsequent activation of 5-HT2A/C or 5-HT2B/C receptors. In addition to its stimulatory effect on the release of monoamines, MDMA also enhances the release of acetylcholine in the striatum, hippocampus and prefrontal cortex, and this cholinergic response appears to be secondary to the activation of histaminergic, dopaminergic and/or serotonergic receptors. Beyond the acute stimulatory effect of MDMA on neurotransmitter release, MDMA also increases the extracellular concentration of energy substrates, e.g., glucose and lactate in the brain. In contrast to the acute stimulatory actions of MDMA on the release of monoamines and acetylcholine, the repeated administration of high doses of MDMA is thought to result in a selective neurotoxicity to 5-HT axon terminals in the rat. Additional studies are reviewed that focus on the alterations in neurotransmitter responses to pharmacological and physiological stimuli that accompany MDMA-induced 5-HT neurotoxicity.

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Section: Serotonergic Neuronsmentioning

confidence: 82%

Actions of 3,4-methylenedioxymethamphetamine (MDMA) on cerebral dopaminergic, serotonergic and cholinergic neurons

Gudelsky

Yamamoto

2008

Pharmacology Biochemistry and Behavior

120

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“…Procedures which lead to an additional rise of free cytosolic 5-HT levels in the presynapse, such as stimulation of 5-HT synthesis or inhibition of 5-HT degradation, enhance 5-HT release (Iyer et al, 1994). Vice versa, the previous depletion of vesicular 5-HT stores or blockade of 5-HT synthesis attenuates the rise of extracellular 5-HT caused by substituted amphetamines (Brodkin et al, 1993).…”

Section: Mechanisms Of Actionsmentioning

confidence: 98%

Causes and consequences of the loss of serotonergic presynapses elicited by the consumption of 3,4-methylenedioxymethamphetamine (MDMA, ?ecstasy?) and its congeners

Huether

Zhou

Rüther

1997

J. Neural Transmission

125

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The massive and prolonged stimulation of serotonin (5-HT)-release and the increased dopaminergic activity are responsible for the acute psychomimetic and psychostimulatory effects of 3,4-methylenedioxy-methamphetamine (MDMA, "ecstasy") and its congeners. In vulnerable subjects, at high doses or repeated use, and under certain unfavorable conditions (crowding, high ambient temperature), severe, in some cases fatal, averse systemic reactions (hyperthermia, serotonin-syndrome) may occur during the first few hours. Animal experiments revealed the existence of similar differences in vulnerability and similar dose- and context-related influences on a similar sequence of acute responses. The severity of these acute systemic responses is closely related to the severity of the long-term damage to 5-HT axon terminals caused by the administration of substituted amphetamines. Attempts to identify the mechanisms involved in this selective degeneration of 5-HT presynapses brought to light a multitude of different factors and conditions which either attenuate or potentiate the loss of 5-HT terminals caused by MDMA and related amphetamine derivatives. These puzzling observations suggest that the degeneration of 5-HT presynapses represents only the final step in a sequence of events which compromise the ability of 5-HT terminals to maintain their functional and structural integrity. Substituted amphetamines selectively tax energy metabolism in 5-HT presynapses through their ability to exchange with 5-HT and to dissipate transmembrane ion gradients. The active carrier systems in the vesicular and presynaptic membrane operate at a permanently activated state. The resulting energy deficit can no longer adequately restored by the 5-HT presynapses when their availability of substrates for ATP production is additionally reduced by the hyperthermic and other energy consuming reactions which are elicited by the systemic administration of substituted amphetamines. The exhaustion of energy in 5-HT nerve terminals compromised all energy-requiring endogenous mechanisms involved in the regulation of transmembrane-ion exchange, internal Ca(++)-homeostasis, prevention of oxidative stress, detoxification, and repair. Above a critical threshold the failure of these self-protective mechanisms will lead to the degeneration of the 5-HT axon terminals. Based on the role of 5-HT as a global modulatory transmitter-system involved in the stabilization and integration of impulse flow between distributed multifocal neuronal networks, the partial loss of 5-HT presynapses must be expected to impair the ability of these networks to maintain the integrity of signal flow pattern, and increase the likelihood of switching to unstable information processing. Behavioral responding may therefore become more dominated by activities generated in individual networks, and hitherto "buffered" personality traits and predisposition may become manifested as defined psychiatric syndromes in certain predisposed subjects.

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“…MDMA releases 5-HT in vitro from synaptosomes (Berger et al 1992;Hekmatpanah and Peroutka 1990;McKenna et al 1991;Nichols et al 1982) and from cultured neurons (Gu and Azmitia 1993), as well as in vivo (Brodkin et al 1993;Schmidt 1987). MDMA-induced 5-HT release is blocked by different 5-HT uptake inhibitors in vitro (Gu and Azmitia 1993;Hekmatpanah and Peroutka 1990) and in vivo as demonstrated by microdialysis (Gudelsky and Nash 1996;Koch and Galloway 1997 (Rudnick and Wall 1992).…”

Section: Discussionmentioning

confidence: 99%

Acute Psychological Effects of 3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”) are Attenuated by the Serotonin Uptake Inhibitor Citalopram

Liechti

Baumann

Gamma

et al. 2000

Neuropsychopharmacology

213

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Effect of acute monoamine depletion on 3,4-methylenedioxymethamphetamine-induced neurotoxicity

Cited by 77 publications

References 28 publications

Actions of 3,4-methylenedioxymethamphetamine (MDMA) on cerebral dopaminergic, serotonergic and cholinergic neurons

Actions of 3,4-methylenedioxymethamphetamine (MDMA) on cerebral dopaminergic, serotonergic and cholinergic neurons

Causes and consequences of the loss of serotonergic presynapses elicited by the consumption of 3,4-methylenedioxymethamphetamine (MDMA, ?ecstasy?) and its congeners

Acute Psychological Effects of 3,4-Methylenedioxymethamphetamine (MDMA, “Ecstasy”) are Attenuated by the Serotonin Uptake Inhibitor Citalopram

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