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Abstract

Methamphetamine is a drug that is significantly abused worldwide, Although long-lasting depletion of dopamine and other dopamine nerve terminal markers has been reported in striatum of nonhuman primates receiving very high doses of the psychostimulant, no information is available for humans. We found reduced levels of three dopamine nerve terminal markers (dopamine, tyrosine hydroxylase and the dopamine transporter) in post-mortem striatum (nucleus accumbens, caudate, putamen) of chronic methamphetamine users. However, levels of DOPA decarboxylase and the vesicular monoamine transporter, known to be reduced in Parkinson's disease, were normal. This suggests that chronic exposure to methamphetamine does not cause permanent degeneration of striatal dopamine nerve terminals at the doses used by the young subjects in our study. However, the dopamine reduction might explain some of the dysphoric effects of the drug, whereas the decreased dopamine transporter could provide the basis for dose escalation occurring in some methamphetamine users.

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Marked inhibition of mesolimbic dopamine release: a common feature of ethanol, morphine, cocaine and amphetamine abstinence in rats.

Zvani Rossetti, Yousef Hmaidan, Gian Luigi Gessa (1992)

Withdrawal of rats from chronic ethanol, morphine, cocaine and amphetamine resulted in a marked reduction in extracellular dopamine (DA) concentration in the ventral striatum as measured by microdialysis. Following ethanol and naloxone-precipitated morphine withdrawal, the time course of DA reduction paralleled that of the withdrawal symptomatology. On the other hand, following discontinuation of chronic cocaine, DA reduction was delayed by over 24 h but persisted for several days. After amphetamine withdrawal the fall in DA occurred more rapidly but the reduction also persisted for several days. The administration of the NMDA receptor antagonist, MK-801, to rats withdrawn from chronic ethanol, morphine or amphetamine, but not from chronic cocaine, readily reversed the fall in DA output. The reduction in extracellular DA during ethanol withdrawal was also reversed by SL 82.0715, another NMDA receptor antagonist.

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The role of dopamine in drug abuse viewed from the perspective of its role in motivation.

Gaetano Di Chiara (1995)

Drugs of abuse share with conventional reinforcers the activation of specific neural pathways in the CNS that are the substrate of their motivational properties. Dopamine is recognized as the transmitter of one such neural pathway, being involved in at least three major aspects of motivation: modulation of motivational state, acquisition (incentive learning) and expression of incentive properties by motivational stimuli. Drugs of abuse of different pharmacological classes stimulate in the low dose range dopamine transmission particularly in the ventral striatum. Apart from psychostimulants, the evidence that stimulation of dopamine transmission by drugs of abuse provides the primary motivational stimulus for drug self-administration is either unconvincing or negative. However, stimulation of dopamine transmission is essential for the activational properties of drugs of abuse and might be instrumental for the acquisition of responding to drug-related incentive stimuli (incentive learning). Dopamine is involved in the induction and in the expression of behavioural sensitization by repeated exposure to various drugs of abuse. Sensitization to the dopamine-stimulant properties of specific drug classes leading to facilitation of incentive learning of drug-related stimuli might account for the strong control over behaviour exerted by these stimuli in the addiction state. Withdrawal from drugs of abuse results in a reduction in basal dopamine transmission in vivo and in reduced responding for conventional reinforcers. Although these changes are likely to be the expression of a state of dependence of the dopamine system their contribution to the motivational state of drug addiction is unclear.

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Dopamine nerve terminal degeneration produced by high doses of methylamphetamine in the rat brain.

G.A. Ricaurte, R.W. Guillery, L.S. Seiden … (1982)

Numerous recent studies indicate that when amphetamines are administered continuously or in high doses, they exert long-lasting toxic effects on dopamine (DA) neurons in the central nervous system (CNS). Specifically, it has been shown that amphetamines can decrease the content of brain DA, reduce the number of synaptosomal DA uptake sites and selectively depress the in vitro activity of neostriatal tyrosine hydroxylase (TH). To date, however, anatomical evidence of DA neuronal destruction following amphetamines has not been reported. In this study, chemical methods were used in conjunction with the Fink-Heimer method which allows for the selective silver impregnation of degenerating nerve fibers, in order to determine whether methylamphetamine, a potent psychomotor stimulant often abused by man, causes actual DA neural degeneration. It has been found that methylamphetamine induces terminal degeneration along with correlative DA neurochemical deficits in the neostriatum and nucleus accumbens; furthermore, that in cresyl violet-stained sections of the substantia nigra (SN), pars compacta, and ventral tegmental area (VTA), there is no evidence of cell body loss in rats in which 50-60% of neostriatal DA terminals have been destroyed.

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PubMed ID:: 8640565

DOI:: 10.1038/nm0696-699

ScienceOpen disciplines: Chemistry

Keywords: Adult,Autopsy,Carrier Proteins,chemistry,Chronic Disease,Corpus Striatum,drug effects,Dopa Decarboxylase,Dopamine,Dopamine Agents,administration & dosage,adverse effects,pharmacology,Dopamine Plasma Membrane Transport Proteins,Drug Administration Schedule,Female,Humans,Male,Membrane Glycoproteins,Membrane Transport Proteins,Methamphetamine,Nerve Endings,metabolism,Nerve Tissue Proteins,Neuropeptides,Nucleus Accumbens,Putamen,Tyrosine 3-Monooxygenase,Vesicular Biogenic Amine Transport Proteins,Vesicular Monoamine Transport Proteins

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Striatal dopamine nerve terminal markers in human, chronic methamphetamine users.

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Marked inhibition of mesolimbic dopamine release: a common feature of ethanol, morphine, cocaine and amphetamine abstinence in rats.

The role of dopamine in drug abuse viewed from the perspective of its role in motivation.

Dopamine nerve terminal degeneration produced by high doses of methylamphetamine in the rat brain.

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