In Vivo Evidence for Low Striatal Vesicular Monoamine Transporter 2 (VMAT2) Availability in Cocaine Abusers

Narendran, Rajesh; Lopresti, Brian J.; Martínez, Diana; Mason, N. Scott; Himes, Michael L.; May, Maureen A.; Daley, Dennis C.; Price, Julie C.; Mathis, Chester A.; Frankle, W. Gordon

doi:10.1176/appi.ajp.2011.11010126

Cited by 45 publications

(29 citation statements)

References 37 publications

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“…Results of our autopsied brain and brain PET investigations of 'dopamine' measures are generally similar to the currently reported finding and point to differences in the actions of MA vs cocaine in human brain: MA users having marked differences relative to HC (Moszczynska et al, 2004;Wilson et al, 1996a), whereas cocaine users have, at most, only modest differences (Narendran et al, 2012;Wilson et al, 1996b, see Kish, 2014.…”

Section: Discussionsupporting

confidence: 85%

Rapid Recovery of Vesicular Dopamine Levels in Methamphetamine Users in Early Abstinence

Boileau

McCluskey

Tong

et al. 2015

Neuropsychopharmacol

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We previously reported very low levels of dopamine in post-mortem striatum of chronic methamphetamine users, raising the possibility that restoration of normal dopamine levels could help in this addiction and perhaps prevent early relapse. To establish relevance of this finding to the living brain, we tested whether striatal [ 11 C]-(+)-dihydrotetrabenazine binding, a vesicular monoamine transporter probe sensitive to changes in (stored) vesicular dopamine, is elevated in methamphetamine users. Chronic methamphetamine users underwent [ 11 C]-(+)-dihydrotetrabenazine positron emission tomography scans during early (mean 2.6 days) and later (~10 days) abstinence. Striatal [ 11 C]-(+)-dihydrotetrabenazine binding was elevated (suggesting low stored dopamine) in methamphetamine users (n = 28; 2.6 days after last use) relative to controls (n = 22) (+28%, po0.0001) and correlated with severity and recency of drug use and with cognitive impairment and withdrawal symptoms. Mean [ 11 C]-(+)-dihydrotetrabenazine binding levels in the subgroup of methamphetamine users who could remain abstinent~10 days following last use (n = 17) were normal at the follow-up scan. Our imaging data support postmortem findings and suggest that chronic methamphetamine users have low brain levels of stored dopamine during very early abstinence from MA, which could contribute to behavioral and cognitive deficits. Findings also suggest a rapid recovery of stored dopamine in some methamphetamine users who become abstinent and who therefore might not benefit from dopamine replacement medication (eg, levodopa). Further study is necessary to establish whether those users who could not maintain abstinence for the second scan might have a more severe and persistent dopamine deficiency and who could benefit from this medication.

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Section: Discussionsupporting

confidence: 85%

Rapid Recovery of Vesicular Dopamine Levels in Methamphetamine Users in Early Abstinence

Boileau

McCluskey

Tong

et al. 2015

Neuropsychopharmacol

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“…A recent in vivo PET study with [ 11 C] DTBZ confirmed the previous in vitro findings, suggesting compensatory down-regulation of the DA storage vesicles in response to chronic cocaine abuse and/ or a loss of dopaminergic terminals [45] .…”

Section: Pet Studies Of Vesicular Monoamine Transportersupporting

confidence: 72%

Brain dopaminergic system changes in drug addiction: a review of positron emission tomography findings

et al. 2014

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Dopamine (DA) is considered crucial for the rewarding effects of drugs of abuse, but its role in addiction remains unclear. Positron emission tomography (PET) is the fi rst technology used for in vivo measurement of components of the dopaminergic system in the human brain. In this article, we review the major fi ndings from PET imaging studies on the involvement of DA in drug addiction, including presynaptic DA synthesis, vesicular monoamine transporter 2, the DA transporter, and postsynaptic DA receptors. These results have corroborated the role of DA in addiction and increased the understanding of its underlying mechanisms.Keywords: dopamine; dopaminergic system; drug addiction; positron emission tomography ·Review· Brain Dopaminergic System Dopamine (DA) is a catecholamine neurotransmitter in the nervous system. It has many functions in the brain, including punishment, reward, voluntary movement, mood, attention, motivation, sleep, working memory, and learning [1] .DA is synthesized by the hydroxylation and decarboxylation of L-tyrosine in DA neurons and, before being released into the synapse in response to an action potential, it is stored within presynaptic vesicles (Fig. 1). The action of DA occurs by binding to postsynaptic DA receptors, resulting in the formation of second messengers. There are fi ve subtypes of DA receptors, which can be grouped into two classes or families: D1-like and D-2 like [1,2] . The D1-like receptor family comprises the D1 and D5 receptors, encoded by genes with no introns, acting by way of Gs-proteins and activating adenylyl cyclase, thus increasing cAMP production [3,4] .The D2-like receptor family comprises the D2, D3, and D4 receptors, encoded by genes containing introns. D2-like receptors act via Gi-proteins, inhibit adenylyl cyclase activity, and thus decrease cAMP activity [3,5] .The action of DA in the synapse is terminated primarily by reuptake to the presynaptic membrane through the dopamine transporter (DAT) [6] . Otherwise, DA is partially removed by oxidation by monoamine oxidase orcatechol-O-methyltransferase in the synaptic cleft (Fig. 1).T h e d o p a m i n e r g i c n e u r o n s , w h o s e p r i m a r y neurotransmitter is DA, interconnect many areas of the brain to form a system which originates in the substantia nigra (SN) pars compacta, ventral tegmental area (VTA), and hypothalamus. The dopaminergic system is typically divided into four major pathways: mesocortical (from the VTA to the frontal cortex), mesolimbic (from the VTA to the nucleus accumbens), nigrostriatal (from the SN to the striatum), and tuberoinfundibular (from the hypothalamus to the pituitary gland). The mesostriatal and mesocortical pathways are currently recognized to contribute most to drug addiction [7] . Neurosci Bull October 1, 2014, 30(5): 765-776 766 Drug AddictionThe term addiction is derived from the Latin verb addicere, which referred to the Roman court action of binding a person to another. From the 17th century, addiction has been used to refer to psychoactive substances (...

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“…Some reports demonstrate reduced DAT and VMAT2 protein levels, but normal DAT binding (Wilson et al, 1996), in cocaine-abusing subjects postmortem (Wilson et al, 1996;Little et al, 2003). Recently abstinent cocaine users also have reductions in dihydrotetrabenazine binding of VMAT2 in vivo (Narendran et al, 2012). Interestingly, recent data indicate that cocaine abuse, in contrast with METH/AMPH abuse, does not lead to PD (Curtin et al, 2015).…”

Section: Dopamine Transporter Vesicular Monoaminementioning

confidence: 99%

Regulation of the Dopamine and Vesicular Monoamine Transporters: Pharmacological Targets and Implications for Disease

et al. 2015

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In Vivo Evidence for Low Striatal Vesicular Monoamine Transporter 2 (VMAT2) Availability in Cocaine Abusers

Cited by 45 publications

References 37 publications

Rapid Recovery of Vesicular Dopamine Levels in Methamphetamine Users in Early Abstinence

Rapid Recovery of Vesicular Dopamine Levels in Methamphetamine Users in Early Abstinence

Brain dopaminergic system changes in drug addiction: a review of positron emission tomography findings

Regulation of the Dopamine and Vesicular Monoamine Transporters: Pharmacological Targets and Implications for Disease

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