Quantitative autoradiography of the rat brain vesicular monoamine transporter using the binding of [3H]dihydrotetrabenazine and 7-amino-8-[125I]iodoketanserin

Darchen, François; Masuo, Yoshinori; Vial, Micheline; Rostène, William; Scherman, Daniel

doi:10.1016/0306-4522(89)90214-5

Cited by 53 publications

(24 citation statements)

References 26 publications

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“…To our knowledge, however, there has been no demonstration of serotonin transporters in the pineal gland. Ligands for the serotonin transporter have been shown to label the vesicular monoamine transporters in the pineal gland (Segonzac et al, 1985;Darchen et al, 1989), a property that may be shared with [ 3 H]MADAM. Vesicular monoamine transporters, however, are located in most brain regions (Darchen et al, 1989), and it is therefore unlikely that the exceptional binding of [ 3 H]MADAM in the pineal gland is to a vesicular monoamine transporters.…”

Section: Discussionmentioning

confidence: 99%

“…Ligands for the serotonin transporter have been shown to label the vesicular monoamine transporters in the pineal gland (Segonzac et al, 1985;Darchen et al, 1989), a property that may be shared with [ 3 H]MADAM. Vesicular monoamine transporters, however, are located in most brain regions (Darchen et al, 1989), and it is therefore unlikely that the exceptional binding of [ 3 H]MADAM in the pineal gland is to a vesicular monoamine transporters. Previous findings have shown high levels of norepinephrine transporters to the pineal gland (Madras and Kaufman, 1994) (Halldin et al, 2001b), is a new argument for future use of this ligand for in vivo studies of the distribution, pharmacology, and pathophysiology of the serotonin transporter in the human brain with PET.…”

Section: Discussionmentioning

confidence: 99%

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Pharmacological Characterization ofN,N-Dimethyl-2-(2-amino-4-methylphenyl thio)benzylamine as a Ligand of the Serotonin Transporter with High Affinity and Selectivity

Chalon

Tarkiainen²,

Garreau³

et al. 2003

J Pharmacol Exp Ther

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Serotonin transporter has a key-role in regulation of serotoninergic function, and is involved in numerous neurodegenerative and psychiatric disorders. To obtain an efficient radioactive ligand allowing the study of this transporter in vitro and in vivo, we synthesized a new diphenyl sulfide derivative, N,N-dimethyl-2-(2-amino-4-methylphenylthio)benzylamine or MADAM. We present here extensive pharmacological characterization of this compound.[3 H]MADAM bound to serotonin transporters with a very high affinity in vitro on rat cortical membranes, at least 2 times better than the most commonly used radioactive probes (K d , 60 pM; B max , 543 fmol/mg of protein). Competition studies showed few inhibitory effect of nisoxetine (K i ϭ 270 nM), no inhibitory effect of desipramine or 1-[2-(diphenylmethoxy) ethyl]-4-(3-phenylpropyl)piperazine (GBR 12935) (K i Ͼ1000 nM), and strong effect of paroxetine (K i ϭ 0.32 nM) and citalopram (K i ϭ 1.57 nM). Therefore, MADAM has around 1000-fold better selectivity for the serotonin transporter than for other transporters. Autoradiographic studies both on rat and postmortem human brain slices demonstrated that the distribution of

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Pharmacological Characterization ofN,N-Dimethyl-2-(2-amino-4-methylphenyl thio)benzylamine as a Ligand of the Serotonin Transporter with High Affinity and Selectivity

Chalon

Tarkiainen²,

Garreau³

et al. 2003

J Pharmacol Exp Ther

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“…Currently, the occipital cortex appears to be a preferred reference region in human brain imaging studies apparently because the data obtained are less variable and of consistently higher values as compared with those using cerebellar cortex as the reference region (Chan et al, 1999). However, animal studies have repeatedly showed that the cerebellar cortex contains less DTBZ-binding sites than cerebral cortices (Scherman et al, 1988;Darchen et al, 1989;Vander Borght et al, 1995) and in the development of new DTBZ-based PET tracers the cerebellum, for practical reasons, continues to be used as the reference region in preclinical studies (Kilbourn et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Distribution of Vesicular Monoamine Transporter 2 Protein in Human Brain: Implications for Brain Imaging Studies

Tong

Boileau

Furukawa

et al. 2011

J Cereb Blood Flow Metab

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The choice of reference region in positron emission tomography (PET) human brain imaging of the vesicular monoamine transporter 2 (VMAT2), a marker of striatal dopamine innervation, has been arbitrary, with cerebellar, whole cerebral, frontal, or occipital cortices used. To establish whether levels of VMAT2 are in fact low in these cortical areas, we measured VMAT2 protein distribution by quantitative immunoblotting in autopsied normal human brain (n = 6). Four or five species of VMAT2 immunoreactivity (75, 55, 52, 45, 35 kDa) were detected, which were all markedly reduced in intensity in nigrostriatal regions of patients with parkinsonian conditions versus matched controls (n = 9 to 10 each). Using the intact VMAT2 immunoreactivity, cerebellar and cerebral neocortices had levels of the transporter > 100-fold lower than the VMAT2-rich striatum and with no significant differences among the cortical regions. We conclude that human cerebellar and cerebral cortices contain negligible VMAT2 protein versus the striatum and, in this respect, all satisfy a criterion for a useful reference region for VMAT2 imaging. The slightly lower PET signal for VMAT2 binding in occipital (the currently preferred reference region) versus cerebellar cortex might not therefore be explained by differences in VMAT2 protein itself but possibly by other imaging variables, for example, partial volume effects.

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“…thaw-mounted onto gelatin-coated glass slides and stored at -8 0°C until use. Cryostat eye sections were incubated with [3H]TBZOH (at a 5 nM concentration for autoradiography) and an 0.8-9.5 nM for saturation experiments in a 10 nM HEPES buffer (pH 8.0) con taining 0.3 M sucrose at 20°C [5]. Nonspecific binding was determined on alternate sections in the presence of 5 pAf unlabeled tetrabenazinc added in the incubation medium.…”

Section: Methodsmentioning

confidence: 99%

“…Five freshly enucleated eyeballs from human donors (ages 46-78 years, with no known neurological or psychiatric diseases) were obtained within 6 h after death. Eyes were processed as already described [5]. Cryostat sections (20 pm thick) were cut.…”

Section: Methodsmentioning

confidence: 99%

Autoradiographic Distribution of the Eye Monoaminergic Synaptic Vesicles

Denis

Nordmann

Scherman³

et al. 1994

Ophthalmic Res

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The ligand [³H]dihydrotetrabenazine ([³H]TBZOH), a tri-tiated derivative of the monoamine depleting agent tetrabena-zine, has been reported to bind specifically to the transporter present on the membrane of monoaminergic synaptic vesicles. We have studied the pharmacological characteristics of [³H]TBZOH binding to rabbit eye sections and the anatomical distribution of [³H]TBZOH binding sites in rabbit, rat and human eyes by in vitro autoradiography. In rabbit eye sections, [³H]TBZOH binding bound to a single class of binding sites (K_d = 4.1 nM, B_max = 30.6 fmol/mg protein). When animals were kept for various times after death before removal of the eyes, the mean density of [³H]TBZOH binding sites decreased to 94 and 93% of control values after 24 and 48 h, respectively. In both species, the topographical distribution of [³H]TBZOH sites shows a pattern of distribution similar to that of monoaminergic innervation of the eye. The present data demonstrate that [³H]TBZOH can be used for the identification and the quantitation of monoamine-containing neurons in the mammalian eye.

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Quantitative autoradiography of the rat brain vesicular monoamine transporter using the binding of [3H]dihydrotetrabenazine and 7-amino-8-[125I]iodoketanserin

Cited by 53 publications

References 26 publications

Pharmacological Characterization ofN,N-Dimethyl-2-(2-amino-4-methylphenyl thio)benzylamine as a Ligand of the Serotonin Transporter with High Affinity and Selectivity

Pharmacological Characterization ofN,N-Dimethyl-2-(2-amino-4-methylphenyl thio)benzylamine as a Ligand of the Serotonin Transporter with High Affinity and Selectivity

Distribution of Vesicular Monoamine Transporter 2 Protein in Human Brain: Implications for Brain Imaging Studies

Autoradiographic Distribution of the Eye Monoaminergic Synaptic Vesicles

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