Dopamine transport function is elevated in cocaine users

Abstract

Dopaminergic transmission has been suggested to be a primary mechanism mediating reinforcement, withdrawal and craving associated with psychostimulant addiction. Pyschostimulants attenuate dopamine transporter (DAT) clearance efficiency, resulting in a net increase in synaptic dopamine levels. Re-uptake rate is determined by the number of functional DAT molecules at the membrane surface. Previous in vivo imaging studies in humans and in vitro studies in postmortem human brain have demonstrated that chronic cocaine abuse results in a neuroadaptive increase in DAT-binding site density in the limbic striatum. Whether this increase in DAT availability represents an increase in the functional activity of the transporter is unknown. Here, we present evidence that DAT function is elevated by chronic cocaine abuse. The effect of increasing post-mortem interval on the functional viability of synaptosomes was modeled in the baboon brain. Baboon brains sampled under conditions similar to human brain autopsies yielded synaptosomal preparations that were viable up to 24 h post-mortem. Dopamine (DA) uptake was elevated twofold in the ventral striatum from cocaine users as compared to age-matched drug-free control subjects. The levels of [ 3 H]DA uptake were not elevated in victims of excited cocaine delirium, who experienced paranoia and marked agitation prior to death. In keeping with the increase in DAT function, [ 3 H]WIN 35,428 binding was increased in the cocaine users, but not in the victims of excited delirium. These results demonstrate that DA uptake function assayed in cryopreserved human brain synaptosomes is a suitable approach for testing hypotheses of the mechanisms underlying human brain disorders and for studying the actions of addictive drugs in man.

A dopamine transporter gene functional variant associated with cocaine abuse in a Brazilian sample

“…Nevertheless, what we were able to ascertain about the regulatory properties of the Int8-VNTR domain clearly suggests a mechanism by which this polymorphism can be associated with cocaine abuse by altering the tissue-specific or stimulusinducible expression of the DAT1 gene. A previous study investigating the effect of cocaine abuse in the postmortem human brain demonstrated that, in cocaine users, DAT1 levels and DA uptake were elevated in the ventral striatum when compared with control subjects, providing further evidence of adaptation in DA uptake after chronic cocaine exposure (33).…”

One hour, but not six hours, of daily access to self-administered cocaine results in elevated levels of the dopamine transporter

“…Specifically, DAT levels were found to increase, decrease, or stay unchanged in post mortem examinations of the brains of cocaine addicts by different researchers (Little et al, 1998a(Little et al, ,b, 1999Malison et al, 1998;Mash et al, 2002;Hitri et al, 1994;Hurd and Herkenham, 1993;Wilson et al, 1996). Some of this variability can be accounted for by the different procedures and ligands used by the different researchers.…”

“…For example, Mash et al, (2002) observed directionally opposite changes in two different populations of cocaine addicts. Moreover, all of the studies cited above were conducted post mortem, where the length of withdrawal from cocaine, if any, is unknown, as is the cause of death.…”

Mechanisms of Acute Cocaine Toxicity

“…While genetic differences in receptor number and binding are likely to occur, there is also evidence that environmental effects can play a significant role. Chronic cocaine users have altered regional density of several neurotransmitter receptors and monoamine transporters compared to non-cocaine users [94][95][96][97][98]. This group has suggested that these changes increase the susceptibility of chronic users to severe cocaine toxicity.…”