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.

For more than 50 years, methamphetamine has been a widely used stimulant drug taken to maintain wakefulness and performance and, in high doses, to cause intense euphoria. Animal studies show that methamphetamine can cause short-term and even persistent depletion of brain levels of the neurotransmitter dopamine. However, the clinical features of Parkinson's disease, a dopamine deficiency disorder of the brain, do not appear to be characteristic of human methamphetamine users. We compared dopamine levels in autopsied brain tissue of chronic methamphetamine users with those in patients with Parkinson's disease and in a control group. Mean dopamine levels in the methamphetamine users were reduced more in the caudate (-61%) than in the putamen (-50%), a pattern opposite to that of Parkinson's disease. Some methamphetamine users had severely decreased dopamine levels, within the parkinsonian range, in the caudate (up to 97% dopamine loss) but not in the putamen. As the putamen and caudate subserve aspects of motor and cognitive function, respectively, our data suggest that methamphetamine users are not parkinsonian because dopamine levels are not sufficiently decreased in the motor component of the striatum. However, the near-total reduction in the caudate could explain reports of cognitive disturbances, sometimes disabling, in some drug users, and suggests that treatment with dopamine substitution medication (e.g. levodopa) during drug rehabilitation might be helpful.

To establish whether chronic opiate exposure might impair brain dopaminergic or serotonergic function in humans, we assessed biochemical indices of monoaminergic neurotransmitter activity and integrity in post mortem striatum of nine chronic heroin users and 14 control subjects. Striatal levels of the vesicular monoamine transporter were normal, suggesting that the density of dopamine nerve terminals is not reduced in heroin users. In nucleus accumbens, levels of tyrosine hydroxylase protein (-25%) and those of the dopamine metabolite homovanillic acid (-33%) were reduced significantly together with a trend for decreased dopamine (-32%) An important feature of psychostimulant and opiate drugs of abuse is their ability, upon acute administration, to activate brain dopaminergic neurons as evidenced by increased striatal synaptic concentrations of dopamine (DiChiara 1995). Chronic dopaminergic overactivity caused by drugs of abuse leads to a variety of compensatory changes that could influence behavior of the drug user. Synaptic levels of dopamine are decreased in experimental animals withdrawn from chronic psychostimulants (cf. DiChiara 1995) whereas striatal tissue dopamine levels are reduced in human chronic psychostimulant users: moderately for methamphetamine users (Wilson et al. 1996a) or slightly for cocaine users (Wilson et al. 1996b). These changes could explain the dysphoric anhedonic motivational state during withdrawal to psychostimulant drugs. Both experimental animals and humans (cf. Wilson et al. 1996a,b) exposed to psychostimulants also demonstrate altered striatal levels of the dopamine transporter (DAT), a 24 , NO . 5 component of the dopamine nerve terminal critically involved in regulation of synaptic dopamine levels.Relatively less attention has been focused on longterm effects of opiate drugs of abuse on the dopamine system. In fact, it has been assumed that opiates do not produce "enduring changes" in dopaminergic transmission or cellularity (Rogers et al. 1999). Chronic administration of morphine or heroin to rodents, however, causes decreased striatal concentrations of synaptic dopamine (Acquas et al. 1991;Crippens and Robinson 1994), its biosynthetic enzyme tyrosine hydroxylase (Self et al. 1995) and those of DAT (Simantov 1993). Chronic morphine appears to damage dopaminergic neurons as indicated by impaired axonal transport from the dopamine cell body area of the ventral tegmental area (VTA) to nucleus accumbens, decreased size of dopaminergic cell bodies, and by increased expression in VTA of a marker of injury, glial fibrillary acidic protein (Beitner-Johnson et al. 1992;1993;Self et al. 1995; SklairTavron et al. 1996). As these animal data suggest that opiates might impair, reversibly or irreversibly, brain dopaminergic function in humans, we determined whether concentrations of biochemical markers of dopamine nerve terminal function and integrity are decreased in post mortem striatum (caudate, putamen, nucleus accumbens) of human chronic heroin users. The markers included ...

Animal data have long suggested that an adaptive upregulation of nucleus accumbens dopamine D1 receptor function might underlie part of the dependency on drugs of abuse. We measured by quantitative immunoblotting protein levels of dopamine D1 and, for comparison, D2 receptors in brain of chronic users of methamphetamine, cocaine, and heroin. As compared with the controls, brain dopamine D1 receptor concentrations were selectively increased (by 44%) in the nucleus accumbens of the methamphetamine users, whereas a trend was observed in this brain area for reduced protein levels of the dopamine D2 receptor in all three drug groups (؊25 to ؊37%; P < 0.05 for heroin group only). Our data support the hypothesis that aspects of the drug-dependent state in human methamphetamine users might be related to increased dopamine D1 receptor function in limbic brain. Molecular Psychiatry (2000) 5, 664-672.