PET imaging of dopamine D2 receptors during chronic cocaine self-administration in monkeys

Nader, Michael A.; Morgan, Drake; Gage, H. Donald; Nader, Susan H.; Calhoun, Tonya; Buchheimer, Nancy; Ehrenkaufer, Richard L.; Mach, Robert H.

doi:10.1038/nn1737

Cited by 426 publications

(391 citation statements)

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Section: Pet Studies Of Postsynaptic Da Receptorsmentioning

confidence: 99%

“…labeled benzamide derivative that binds reversibly to D2 receptors [81] . In PET imaging with [ 18 F] FCP, Nader and colleagues [82] found that the baseline D2 receptor availability is negatively correlated with the rate of cocaine self-administration.[ fallypride PET imaging study, nicotine-dependent smokers displayed signifi cantly less availability of D2/D3 receptors within the bilateral putamen, functionally covering parts of the dorsal striatum, compared to never-smoking subjects [83] .[ 18 F] desmethoxyfallypride ([ 18 F] DMFP), another selective D2/D3 receptor antagonist, has also been developed and used to fi nd that a low availability of D2/3 receptors in the ventral striatum and adjacent putamen is associated with a high level of craving for alcohol [33] .For the D1 receptor, [ 11 C] NNC 112, a new benzazepine [(+)-8-chloro-5-(7-benzofuranyl)-7-hydroxy-3-methyl-2,3,4,5-tetra-hydro-lH-3-benzazepine], has been reported to be a useful PET radioligand for the quantitation of D1 receptors in humans [84] , and its D1 receptor selectivity has recently been re-evaluated [85] . With PET and the radiotracer [ 11 C] NNC 112, Martinez et al [86] found no difference between cocaine abusers and normal controls.…”

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confidence: 99%

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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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Section: Pet Studies Of Postsynaptic Da Receptorsmentioning

confidence: 99%

mentioning

confidence: 99%

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

et al. 2014

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“…Volkow Tomasi et al, 2010), as highlighted by Colzato et al (2009a) it is also possible that a number of pre-existing factors might account for the observed cognitive deficits either directly or via increasing the likelihood that certain individuals will use the drug. Such vulnerability factors might include cognitive disturbance (Bechara, 2005), dopaminergic receptor dysfunction (Nader et al, 2006) or preexisting personality traits, such as impulsivity (Verdejo-Garcia et al, 2008) or schizotypy.…”

Section: Introductionmentioning

confidence: 99%

Neuropsychological effects associated with recreational cocaine use

et al. 2012

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“…1−6 Modulation of the dopaminergic pathways is also thought to occur as a consequence of acute or chronic abuse of pyschostimulants. 7,8 Previous studies have defined two types of dopamine receptors, the D1-like (D1 and D5 subtypes) and D2-like (D2, D3, and D4 subtypes) receptors. D1-like receptors are linked to the activation of adenylyl cyclase via coupling to the Gs/Golf class of G proteins.…”

Section: Introductionmentioning

confidence: 99%

Comparison of the Binding and Functional Properties of Two Structurally Different D2 Dopamine Receptor Subtype Selective Compounds

Luedtke

Murti

Wang

et al. 2012

ACS Chem. Neurosci.

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ABSTRACT:We previously reported on the synthesis of substituted phenyl-4-hydroxy-1-piperidyl indole analogues with nanomolar affinity at D2 dopamine receptors, ranging from 10-to 100-fold selective for D2 compared to the D3 dopamine receptor subtype. More recently, we evaluated a panel of aripiprazole analogues, identifying several analogues that also exhibit D2 vs D3 dopamine receptor binding selectivity. These studies further characterize the intrinsic efficacy of the compound with the greatest binding selectivity from each chemical class, 1-((5-methoxy-1H-indol-3-yl)methyl)-4-(4-(methylthio)phenyl)piperidin-4-ol (SV 293) and 7-(4-(4-(2-methoxyphenyl)piperazin-1-yl)butoxy)-3,4-dihydroquinolin-2(1H)-one (SV-III-130s), using an adenylyl cyclase inhibition assay, a G-protein-coupled inward-rectifying potassium (GIRK) channel activation assay, and a cell based phospho-MAPK (pERK1/2) assay. SV 293 was found to be a neutral antagonist at D2 dopamine receptors using all three assays. SV-III-130s is a partial agonist using an adenylyl cyclase inhibition assay but an antagonist in the GIRK and phospho ERK1/2 assays. To define the molecular basis for the binding selectivity, the affinity of these two compounds was evaluated using (a) wild type human D2 and D3 receptors and (b) a panel of chimeric D2/D3 dopamine receptors. Computer-assisted modeling techniques were used to dock these compounds to the human D2 and D3 dopamine receptor subtypes. It is hoped that these studies on D2 receptor selective ligands will be useful in the future design of (a) receptor selective ligands used to define the function of D2-like receptor subtypes, (b) novel pharmacotherapeutic agents, and/or (c) in vitro and in vivo imaging agents. KEYWORDS: Dopamine receptors, binding selectivity, functional selectivity, GPCR structure, D2-like dopamine receptors, GPCR model building, ligand−receptor docking T here are three dopaminergic pathways in the brain: the nigrostriatal pathway, the mesocorticolimbic pathway, and the tuberoinfundibular pathway. These pathways are involved in movement coordination, cognition, emotion, memory, reward, and regulation of prolactin secretion. Alterations in the dopaminergic pathways are thought to be involved in the pathogenesis of neurological, neuropsychiatric, and hormonal disorders. 1−6 Modulation of the dopaminergic pathways is also thought to occur as a consequence of acute or chronic abuse of pyschostimulants. 7,8 Previous studies have defined two types of dopamine receptors, the D1-like (D1 and D5 subtypes) and D2-like (D2, D3, and D4 subtypes) receptors. D1-like receptors are linked to the activation of adenylyl cyclase via coupling to the Gs/Golf class of G proteins. 9 Stimulation of the D2-like receptors results in coupling with the Gi/Go class of G proteins, leading to the inhibition of adenylyl cyclase activity. 10,11 Agonist activation of D2-like receptors can also lead to (a) activation of G-protein-coupled inward rectifying potassium (GIRK) channels, (b) stimulation of mitogenesis, (c) an increase in...

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PET imaging of dopamine D2 receptors during chronic cocaine self-administration in monkeys

Cited by 426 publications

References 40 publications

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

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

Neuropsychological effects associated with recreational cocaine use

Comparison of the Binding and Functional Properties of Two Structurally Different D2 Dopamine Receptor Subtype Selective Compounds

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