94 lines
5.3 KiB
Plaintext
94 lines
5.3 KiB
Plaintext
Newsgroups: alt.drugs,alt.psychoactives
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Check this out for accuracy -- ignore spelling errors, i haven't bothered
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to run it through a spell-checker yet, which should catch them...
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If anyone has any suggestions of good introductions to neurpharm for the
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"public" along the lines of Synder's book, i'd appreciate it.
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MDMA Neuropharmacology
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MDMA is primarily a seritonergic (5-HTergic) drug. Serotonin
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(5-hydroxytrytamine, 5-HT) is one of the major neurotransmitters in the
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brain, and is synthesized from tryptophan through the intermediate
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5-hydroxytryptophan. It is synthesized in 5-HT neurons, and stored in
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synaptic vesicles. These vesicles release their 5-HT into the synaptic
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cleft in response to the firing of the 5-HT neurons. In the synaptic
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cleft the 5-HT neurotransmitter excerts its action on both pre- and
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post- synaptic receptor sites (sites on the 5-HT neuron itself, and on
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the neuron which it is communicating with.) 5-HT is then taken back
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into the 5-HT neuron via the synaptic membrane 5-HT transporter (aka
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"reuptake pump"), where it is again stored in the synaptic vesicles.
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5-HT is metabolized primarily by monoamine oxidase (MAO) into
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5-hydroxyindileacetic acid (5-HIAA).
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Serotonin is thought to be responsible for many psychological (and
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physiological) states including mood and sleep. It has been particularly
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associated with major depression and obsessive compulsive disorder, and
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drugs to treat these disorders tend to effect 5-HT (although things are
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not quite clear-cut).
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MDMA blocks the reuptake of 5-HT, similarly to SSRI (serotonin
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specific reuptake inhibiting) anti-depressants such as fluoxetine (Prozac),
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sertraline, and paroxetine. Unlike those drugs, however, MDMA appears
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to enter the neuron, either through passive diffusion or directly
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through the reuptake transporter, and causes the release of 5-HT. This
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release is calcium-independent (i.e. independent of the firing of the
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5-HT neuron) and appears to come from cytoplasmic stores rather than
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from synaptic vesicles. The released 5-HT then enters the synaptic cleft
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through the 5-HT transporter. MDMA thus acts on 5-HT similarly to the way
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amphetamines act on dopamine.
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It is thought that this efflux of 5-HT into the synaptic cleft, and
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the subsequent action of this 5-HT on pre- and post- synaptic binding
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sites is central to MDMA's neuropharmacology. MDMA, however, has
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micromolar potency for the serotonin 5-HT2, muscarinic M1, alpha-2 adrenergic
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and histamine H1 receptors. Agonist (stimulation rather than blocking)
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properties at the 5-HT2 receptor have been found to fairly universally be
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associated with "classical" psychedelic drugs such as LSD, psilocybin and
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mescaline. It is possible that some of MDMA's "psychedelic" effect occurs
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because of interactions with this receptor. The alpha-2 adrenergic receptor
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may be associated with some of the carciovascular effects of MDMA.
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MDMA also releases dopamine which may be central to both its
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psychological action and to its neurotoxicity in animal studies. Pre-
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treatment of an animal with a drug which blocks dopamine release will
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also block MDMA neurotoxicity. Also, serotonin specific releasing agents
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which are non-dopaminergic have been synthesized and been found to be
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devoid of MDMA's neurotoxicity in animals, they have also been found to
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be devoid of MDMA's psychological effects. MDMA tends to indirectly
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*inhibit* the firing and release of dopamine in nigrostriatal dopamine
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neurons (neurons projecting from the substantia nigra to the striatum) due
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to local 5-HT release.
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MDMA doses of 20mg/kg in animals can reduce levels of tryptophan
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hydroxylase, which is the rate-limiting enzyme in 5-HT synthesis. It is
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thought that this occurs because of oxidative stress which MDMA places
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on the neuron. This oxidative stress might occur through several
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possible channels (the metabolism of MDMA into a toxic Quinoid, 5-HT
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derived toxins, 5-HT mediated cellular events, or temporary inhibition
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of monoamine oxidase) and the exact mechanism is presently unknown. It is
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thought that this oxidative stress also leads to the neurodegenerative
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destruction of 5-HT axons which is observed to occur with large doses of
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MDMA in animals. Anti-oxidants, anti-dopaminergic agents, agents which
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block intracellular calcium increases and pre- or post- treatment (up to
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6 hours) with fluoxetine all block MDMA's neurotoxicity. Research
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ontinues on the exact mechanism of MDMA-induced toxicity.
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In summary, MDMA effects 5-HT similarly to the way that amphetamines
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effect dopamine, by inhibiting the reuptake and causing the release of 5-HT.
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This effect is somewhat similar to the effect that SSRI anti-depressant
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drugs have. It also effects the 5-HT2 (psychedelic) and alpha-2 adrenergic
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(cardiovascular) receptor sites. Also, its effects on dopamine appear, at
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this point, to be involved both with its neurotoxicity and psychological
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effects. For more information, see:
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Rattray-M. "Ecstasy: towards an understanding of the biochemical
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basis of the actions of MDMA." Essays in Biochemistry. 26:77-87.
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1991.
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And for general info:
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Synder, Solomon H. "Drugs and the Brain." Scientific American Books.
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1986. (slightly out of date, but a good introduction).
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Cooper-JR, Bloom-FE, Roth-RH. "The Biochemical Basis of Neuro-
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Pharmacology." Oxford Uniersity Press. 1991 (6th ed). (the bible
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for grad students)
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