Serotonin methamphetamine

Rawson RA, Gonzales R, Brethen P Treatment of methamphetamine use disorders an update. J Subst Abuse Treat 23 145—150, 2002a Rawson RA, Huber A, Brethen P, et al Status of methamphetamine users 2—5 years after outpatient treatment. J Addict Dis 21 107—119, 2002b Reneman L, Lavalaye J, Schmand B, et al Cortical serotonin transporter density and verbal memory in individuals who stopped using 3,4-methylenedioxymetham-phetamine (MDMA or ecstasy ) preliminary findings (comment). Arch Gen Psychiatry 58 901—906, 2001... 

In view of this neurotoxicity, we will review some data relevant to this process. First, we will review data showing that methamphetamine (METH), a prototypic psychomotor stimulant, which has been widely used for nonmedical purposes at doses often a good deal higher than therapeutie doses, is neurotoxic to dopamine (DA) and serotonin (5-hydroxytryptamine (5-HI)) systems. Second, we will examine the evidence that other substituted phenethylamines are also neurotoxic to certain transmitter systems. Last, we will examine the behavioral and pharmacological consequences of neurotoxicity that result from exposure to some of these amphetamine-related drugs. 

In other words, we do not have them self-administering these toxic doses. We have done it with some rhesus monkeys that were self-administering methamphetamine. If you give them a regime that depletes the dopamine and serotonin, and then see what alterations there are in self-administration, it does go down, but we have not looked at that. 

COMMENT You have presented some evidence that dopamine may be involved in the neurotoxic action of methamphetamine in terms of dopaminergic neurons, and you presented evidence suggesting that it may be involved in not only the dopamine system but also the serotonin system. 

As shown in table 6, we have compared the affinities of a series of methylenedioxy derivatives with those of the parent compounds (amphetamine and methamphetamine) at some of the recognition sites in brain at which MDMA exhibited the highest affinities. These comparative studies indicate that addition of the methylenedioxy subshtuent in the 3,4 position inereases their affinity at serotonin uptake, 5-HT2 serotonin, and M-1 muscarinic receptors, while the unsubstituted parent compounds appear to be more potent at Ct2-iadrenergic receptors. 

During the 1970s, evidence accumulated that amphetamine and methamphet-amine could also be neurotoxic (Ellison et al. 1978 Hotchkiss and Gibb 1980 Wagner et al. 1980). The effects of amphetamine seem mostly limited to dopamine neurons, whereas methamphetamine affects dopamine and serotonin neurons (Warren et al. 1984). Most recently, MDMA and MDA have been shown to produce neurotoxicity toward brain serotonin neurons much like that of the halogenated amphetamines (Ricaurte et al. 1985 Stone et al. 1986). 

Further investigation of the possibility that inhibitors of the serotonin uptake carrier protect against serotonin depletion by /r-chloroamphetamine, fenfluramine, MDMA, MDA, and methamphetamine because they prevent the accumulation of those drugs within serotonin nerve terminals is warranted, but at present compelling evidence for this mechanism does not exist. 

Rats that have lost dopamine and/or serotonin terminals following treatment with amphetamine, methamphetamine, MDMA, MDA, / -chloroamphetamine, or fenfluramine show little in the way of overt ehanges in appearanee or behavior. Dr. Rieaurte (this volume) emphasized the need for more studies in primates, since MPTP-treated miee also show little in the way of observable functional changes, whereas MPTP-treated monkeys show marked neurologie deficits. It may be neeessary to do more detailed analysis of speeifie behaviors and other funetional outputs that are influeneed by dopamine and/or serotonin neurons, to detect functional deficits induced by some neurotoxic drugs. For instance, specific behaviors sueh as appetite-eontrolled behavior (Leibowitz and Shor-Posner 1986), murieidal behavior (Katz 1980), and sexual behavior (Tucker and File 1983) elieited by drugs... 

Broening, H.W., Morford, L.L., Vorhees, C.V. Interactions of dopamine D, and D2 receptor antagonists with D-methamphetamine-induced hyperthermia and striatal dopamine and serotonin reductions. Synapse. 56 84, 2005. 

Rocher, C., Gardier, A.M. Effects of repeated systemic administration of d-fenflur amine on serotonin and glutamate release in rat ventral hippocampus comparison with methamphetamine using in vivo microdialysis. Naunyn Schmiedeberg s Arch. Pharmacol. 363 422, 2001. 

Kovachich, G.B., Aronson, C.E., Brunswick, D.J. Effects of high-dose methamphetamine administration on serotonin uptake sites in rat brain measured using [3H]cyanoimipramine autoradiography. Brain Res. 505 123, 1989. 

Schmidt, C.J., Gibb, J.W. Role of the serotonin uptake carrier in the neurochemical response to methamphetamine effects of citalopram and chlorimipramine. Neurochem. Res. 10 637, 1985. 

Kuczenski, R., Segal, D.S., Cho, A.K., Melega, W. Hippocampus norepinephrine, caudate dopamine and serotonin, and behavioral responses to the stereoisomers of amphetamine and methamphetamine. J. Neurosci. 15 1308, 1995. 

Munzar, P., Laufert, M.D., Kutkat, S.W., Novakova, J., Goldberg, S.R. Effects of various serotonin agonists, antagonists, and uptake inhibitors on the discriminative stimulus effects of methamphetamine in rats. J. Pharmacol. Exp. Ther. 291 239, 1999. 

Cass, W.A. Attenuation and recovery of evoked overflow of striatal serotonin in rats treated with neurotoxic doses of methamphetamine. J. Neurochem. 74 1079, 2000. 

Hirata, H., Asanuma, M., Cadet, J.L. Melatonin attenuates methamphetamine-induced toxic effects on dopamine and serotonin terminals in mouse brain. Synapse. 30 150, 1998. 

In the brain, methamphetamine causes massive amounts of the neurotransmitters dopamine, norepinephrine, and serotonin to be released from neurons in the brain, particularly in the limbic system and frontal cortex. Scientists believe the increased dopamine release in these brain regions is responsible for methamphetamine s ability to keep people awake, alert, energetic, active, and possibly addicted. Methamphetamine acts on a variety of brain regions to produce a number of different effects (Table 2.1). 

Recently, one of the central studies showing evidence that Ecstasy can damage brain cells was retracted because methamphetamine, not Ecstasy, was mistakenly used in the study s trial experiments. Nevertheless, there is still significant evidence that shows the harmful effects of Ecstasy. These deleterious effects include damage to serotonin neurons, problems forming new memories, depression, and heatstroke. More studies must be conducted to provide irrefutable evidence about Ecstasy s specific effects on the brain, however. 

Dopaminergic activity. Smoke was administered intranasally to mice for 20 minutes twice daily for 3 days before methamphet-amine treatment. The treatment significantly attenuated the neurotoxicity as judged by a lesser depletion of dopamine, dihydrophenylacetic acid, and homovanillic acid. The lesser effect of methamphetamine on the content of serotonin level was unaltered by prior inhalation of smoke h Tobacco glycoside, administered to mice, increased behavior via dopamine 2 neuronal activity but not dopamine 1 activity in a dose-dependent manner. The results indicated that smoking can affect the human brain function via not only the nicotinic cholinergic neuron but also the dopamine 2 neuron . 

MAOIs, monoamine oxidase inhibitors MDMA, methylenedioxy-methamphetamine (ecstasy) SSRIs, selective serotonin reuptake inhibitors. Serotonin Syndrome and Similar Syndromes... 

Together with GFIB and ecstasy, amphetamines are often referred to as "club drugs," because they are increasingly popular in the club scene. They are often produced in small clandestine laboratories, which makes their precise chemical identification difficult. They differ from ecstasy chiefly in the context of use intravenous administration and "hard core" addiction is far more common with amphetamines, especially methamphetamine. In general, amphetamines lead to elevated catecholamine levels that increase arousal and reduce sleep, whereas the effects on the dopamine system mediate euphoria but may also cause abnormal movements and precipitate psychotic episodes. Effects on serotonin transmission may play a role in the hallucinogenic and anorexigenic functions as well as in the hyperthermia often caused by amphetamines. 

EXTENSIONS AND COMMENTARY This is one of several candidates for clinical use as a substitute for MDMA, but there will ha ve to be a much broader study of its qualitative action in man. It is clearly not psychedelic at these modest levels, and in in vitro animal studies it was apparently inactive as a serotonin releaser. The warped logic for looking at phentermine analogs was discussed in the comments that concerned MDPH. The initials used here have been chosen with care. MDM should not be used as it has found some currency as an abbreviation for MDMA (Methylene-Dioxy-Methamphetamine). MDMP fits neatly with Methylene-Dioxy-Me-Phentermine. 

The diagnosis of GHB withdrawal may be difficult because it is similar to sedative or alcohol withdrawal syndromes, as well as to withdrawal from sympathomimetic agents such as cocaine, methamphetamine, and ecstasy. GHB withdrawal may also be confused with serotonin syndrome (a reaction caused by a combination of drugs, one of which increases serotonin levels in the body, such as Prozac) and neuroleptic malignant syndrome (a rare reaction to an antiseizure medication). 

Mescaline is not considered addictive the way drugs such as heroin or methamphetamines are. Nevertheless, this does not mean it is without possible health consequences. When the drug is discontinued, and there is a dip in serotonin activity, a condition called dysphoria may result. Dysphoria is an overall feeling of anxiety, depression, restlessness, and general dissatisfaction, for which fluoxetine (Prozac) is sometimes prescribed for three to six months. 

Two neurochemicals that are vitally important for the proper functioning of the CNS are dopamine and serotonin. By alternating the levels of both dopamine and serotonin in the CNS, methamphetamine is able to cause a wide range of physiological effects. 

Through its action on the dopamine and serotonin neurons in the brain, methamphetamine can cause paranoia, hallucinations, and severe mood disturbances. Methampethamine can also cause stroke through an increase in blood pressure, along with seizures. Other commonly seen side effects include irregular heart rate, damage to small blood vessels in the brain and eyes, and hyperthermia, which is an unregulated increase in the body s temperature. 

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