Brain vesicular acetylcholine transporter in human users of drugs of abuse

Abstract

Limited animal data suggest that the dopaminergic neurotoxin methamphetamine is not toxic to brain (striatal) cholinergic neurons. However, we previously reported that activity of choline acetyltransferase (ChAT), the cholinergic marker synthetic enzyme, can be very low in brain of some human high-dose methamphetamine users. We measured, by quantitative immunoblotting, concentrations of a second cholinergic marker, the vesicular acetylcholine transporter (VAChT), considered to be a "stable" marker of cholinergic neurons, in autopsied brain (caudate, hippocampus) of chronic users of methamphetamine and, for comparison, in brain of users of cocaine, heroin, and matched controls. Western blot analyses showed normal levels of VAChT immunoreactivity in hippocampus of all drug user groups, whereas in the dopamine-rich caudate VAChT levels were selectively elevated (+48%) in the methamphetamine group, including the three high-dose methamphetamine users who had severely reduced ChAT activity. To the extent that cholinergic neuron integrity can be inferred from VAChT concentration, our data suggest that methamphetamine does not cause loss of striatal cholinergic neurons, but might damage/downregulate brain ChAT in some high-dose users. However, the finding of increased VAChT levels suggests that brain VAChT concentration might be subject to up- and downregulation as part of a compensatory process to maintain homeostasis of neuronal cholinergic activity. This possibility should be taken into account when utilizing VAChT as a neuroimaging outcome marker for cholinergic neuron number in human studies.

Suppression of methamphetamine-seeking behavior by nicotinic agonists

“…These results suggest that the inactivation of nicotinic acetylcholinergic transmission is an essential factor for the appearance of MAP-seeking behavior, and, thus, the normalization of the inactivated state may result in the suppression of the reinstatement. In a clinical study, it has been demonstrated that the down-regulation of choline acetyltransferase and elevation of the expression of the vesicular acetylcholine (ACh) transporter develop in a MAP user's brain (2). This result suggests that elevation of the expression of the vesicular ACh transporter may be due to compensation for the down-regulation of choline acetyltransferase and that these changes may lead to the inactivated state of nicotinic acetylcholinergic transmission.…”

“…1b). Scopolamine, a muscarinic antagonist, did not block the nicotineinduced attenuation of cue-induced and MAP-primed reinstatement (F [2,21] ϭ 0.9 and 0.4; P Ͼ 0.4 compared with the cued and MAP-primed nicotine-pretreated group, respectively). In addition, mecamylamine blocked the effects of donepezil on reinstatement induced by a cue and MAP priming (F[2,21] ϭ 59.9 and 114.8; P Ͻ 0.001 compared with the donepezil-pretreated group given the cue and MAP priming, respectively), whereas scopolamine did not antagonize the effect of donepezil on reinstatement induced by a cue and MAP priming (F[2,21] ϭ 1.3 and 0.3; P Ͼ 0.3 compared with the cued and MAP-primed donepezil-pretreated group).…”

“…With regard to the MAP-primed reinstatement, intra-NAcC mecamylamine prevented the attenuating effect of systemic nicotine and donepezil (F[2,18] ϭ 34.3 and 41.3; P Ͻ 0.001 compared with MAP-primed nicotine-and donepezil-pretreated groups, respectively); however, intra-NAcC scopolamine did not affect the nicotine-or donepezil-induced attenuating effect on both the cue-induced and MAP-primed reinstatement (P Ͼ 0.1 compared with cued or MAP-primed nicotine-and donepezil-pretreated groups). In other regions, including the PrC, BLA, CeA, VH, and DH, intracranial mecamylamine in cue-induced reinstatement attenuated the blocking effect of nicotine (F [2,18] …”

“…Recently, the down-regulation of choline acetyltransferase and elevation of the expression of the vesicular acetylcholine transporter have been demonstrated in a MAP user's brain (2), suggesting an inactivated state of acetylcholinergic transmission in the user's brain. In addition, Hikida et al (3) reported that donepezil, an acetylcholinesterase inhibitor, blocked cocaine-induced behavioral sensitization by means of acetylcholinergic activation in the nucleus accumbens.…”

The Role of Acetylcholine in Cocaine Addiction

“…Preliminary findings suggest regional-specific changes in cerebral blood flow following the infusion of physostigmine or scopolamine compared to saline (Adinoff et al, 2005). To date, the only published studies exploring neural cholinergic systems in this population have reported that ChAT and vesicular ACh transporter (VAChT) concentrations in the autopsied brains of cocaine-addicted subjects did not differ from those of heroin-addicted (VAChT, ChAT) or control subjects (VAChT) (Kish et al, 1999;Siegal et al, 2004).…”