Striatal dopamine nerve terminal markers in human, chronic methamphetamine users

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.

Profiles of Cognitive Dysfunction in Chronic Amphetamine and Heroin Abusers

“…They also matched data obtained in normal volunteers subjected to tryptophan depletion procedure. Together, these results are consistent with evidence that amphetamine abuse is associated with loss of 5-HT from the orbitofrontal cortex (Wilson et al 1996a). It is possible that the reductions in dopamine transporter activity also seen in that group (c.f.…”

Striatal Dopaminergic and Serotonergic Markers in Human Heroin Users

“…In the rat, lesion of serotonergic innervation to nucleus accumbens increases morphine self-administration (Smith et al 1987) whereas activation of the serotonin system by dexfenfluramine suppresses heroin self-administration (Wang et al 1995). In the human heroin users we did not find reduced levels of serotonin in striatum or, as was observed in our previous investigation of human methamphetamine users (Wilson et al 1996a), in orbitofrontal cortex (Brodmann areas 11 and 12; data not shown). This suggests that heroin is not toxic to brain serotonin neurons and does not cause depletion of tissue stores of the neurotransmitter in human users of the drug.…”

“…As most of striatal dopamine measured in post mortem human brain is intracellular, rather than synaptic, our finding of normal tissue concentrations of dopamine in the heroin users suggests that chronic heroin exposure, unlike that of methamphetamine (Wilson et al 1996a), does not lead to substantial depletion of tissue stores of dopamine in humans. Nevertheless, we did observe a trend for a modest (by 32%) dopamine reduction in the nucleus accumbens, with four of the nine heroin users having dopamine values below the lower limit of the control range in this brain area.…”

“…For example, based upon this assumption, a neuropsychological investigation into consequences of methamphetamine on human cognition has employed a group of heroin users as a "drug control" group (Rogers et al 1999). Although our post mortem findings do suggest that heroin exposure affects levels of monoaminergic neurotransmitter indices to a lesser extent than does exposure to the psychostimulant methamphetamine (Wilson et al 1996a), modest decreases in several brain dopaminergic and serotonergic indices were observed that could potentially modify behavior in human users of the drug. …”

“…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.…”