[3H]Nisoxetine: a new radioligand for norepinephrine uptake sites in brain

Tejani‐Butt, Shanaz M.; Brunswick, David J.; Frazer, Alan

doi:10.1016/0014-2999(90)94155-q

Cited by 109 publications

(76 citation statements)

References 7 publications

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“…NET assays used [ 3 H]nisoxetine (0.4 nM) in cortical membranes with desipramine (1.0 mM) to define nonspecific binding (Tejani-Butt et al, 1990). SERT assays used [ For the six types of binding assays performed, specific radioligand binding was 77-92% of the total binding.…”

Section: Methodsmentioning

confidence: 99%

Relationship between Cerebral Sigma-1 Receptor Occupancy and Attenuation of Cocaine’s Motor Stimulatory Effects in Mice by PD144418

Lever

Miller

Fergason-Cantrell

et al. 2014

J Pharmacol Exp Ther

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Psychostimulant effects of cocaine are mediated partly by agonist actions at sigma-1 (s 1 ) receptors. Selective s 1 receptor antagonists attenuate these effects and provide a potential avenue for pharmacotherapy. However, the selective and high affinity s 1 antagonist PD144418 (1,2,3,6-tetrahydro-5-[3-(4-methylphenyl)-5-isoxazolyl]-1-propylpyridine) has been reported not to inhibit cocaine-induced hyperactivity. To address this apparent paradox, we evaluated aspects of PD144418 binding in vitro, investigated s 1 receptor and dopamine transporter (DAT) occupancy in vivo, and re-examined effects on locomotor activity. PD144418 displayed high affinity for s 1 sites (K i 0.46 nM) and 3596-fold selectivity over s 2 sites (K i 1654 nM) in guinea pig brain membranes. No appreciable affinity was noted for serotonin and norepinephrine transporters (K i .100 mM), and the DAT interaction was weak (K i 9.0 mM). In vivo, PD144418 bound to central and peripheral s 1 sites in mouse, with an ED 50 of 0.22 mmol/kg in whole brain. No DAT occupancy by PD144418 (10.0 mmol/kg) or possible metabolites were observed. At doses that did not affect basal locomotor activity, PD144418 (1, 3.16, and 10 mmol/kg) attenuated cocaine-induced hyperactivity in a dosedependent manner in mice. There was good correlation (r 2 5 0.88) of hyperactivity reduction with increasing cerebral s 1 receptor occupancy. The behavioral ED 50 of 0.79 mmol/kg corresponded to 80% occupancy. Significant s 1 receptor occupancy and the ability to mitigate cocaine's motor stimulatory effects were observed for 16 hours after a single 10.0 mmol/kg dose of PD144418.

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Section: Methodsmentioning

confidence: 99%

Relationship between Cerebral Sigma-1 Receptor Occupancy and Attenuation of Cocaine’s Motor Stimulatory Effects in Mice by PD144418

Lever

Miller

Fergason-Cantrell

et al. 2014

J Pharmacol Exp Ther

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“…Washed membranes were prepared from brain regions and were incubated with tritiated ligands as described (23)(24)(25)(26)(27)(28)(29)(30). Reactions were terminated by the addition of ice-cold buffered solutions as described (23)(24)(25)(26)(27)(28)(29)(30), and membrane-associated ligand estimated after rapid filtration over Whatman GF͞B filters using a Brandel apparatus. VMAT2, serotonin transporter, norepinephrine transporter, dopamine transporter, dopamine D 1 and D 2 receptor, serotonin 5HT 1 Measurement of Blood Pressure and Heart Rates.…”

Section: Methodsmentioning

confidence: 99%

VMAT2 knockout mice: Heterozygotes display reduced amphetamine-conditioned reward, enhanced amphetamine locomotion, and enhanced MPTP toxicity

Takahashi

Miner

Sora

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

379

312

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The brain vesicular monoamine transporter (VMAT2) pumps monoamine neurotransmitters and Parkinsonism-inducing dopamine neurotoxins such as 1-methyl-4-phenyl-phenypyridinium (MPP ؉ ) from neuronal cytoplasm into synaptic vesicles, from which amphetamines cause their release. Amphetamines and MPP ؉ each also act at nonvesicular sites, providing current uncertainties about the contributions of vesicular actions to their in vivo effects. To assess vesicular contributions to amphetamine-induced locomotion, amphetamine-induced reward, and sequestration and resistance to dopaminergic neurotoxins, we have constructed transgenic VMAT2 knockout mice. Heterozygous VMAT2 knockouts are viable into adult life and display VMAT2 levels one-half that of wild-type values, accompanied by smaller changes in monoaminergic markers, heart rate, and blood pressure. Weight gain, fertility, habituation, passive avoidance, and locomotor activities are similar to wild-type littermates. In these heterozygotes, amphetamine produces enhanced locomotion but diminished behavioral reward, as measured by conditioned place preference. Administration of the MPP ؉ precursor N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine to heterozygotes produces more than twice the dopamine cell losses found in wild-type mice. These mice provide novel information about the contributions of synaptic vesicular actions of monoaminergic drugs and neurotoxins and suggest that intact synaptic vesicle function may contribute more to amphetamine-conditioned reward than to amphetamine-induced locomotion.

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“…In rats, mRNA for the NET is localized in cell bodies of noradrenergic neurons in the brainstem, including the locus coeruleus (Pacholczyk et al, 1991). Autoradiography of the binding of the highly selective NET radioligand [ 3 H]nisoxetine has revealed NET binding in the immediate region of the locus coeruleus, concentrations of which are the highest in the rat brain (Tejani-Butt et al, 1990;Tejani-Butt, 1992). Interestingly, moderate concentrations of [ 3 H]nisoxetine binding in a serotonergic cell body region, the dorsal raphe nucleus, have also been reported in rats (Tejani-Butt, 1992) and humans (Donnan et al, 1991).…”

Section: Abstract: Norepinephrine Transporters; Norepinephrine Uptakmentioning

confidence: 99%

“…In this study, we used [ 3 H]nisoxetine to determine the distribution of NETs within the human locus coeruleus and dorsal raphe. [ 3 H]nisoxetine has a high affinity for NETs (Tejani-Butt et al, 1990;TejaniButt, 1992;Tejani-Butt and Ordway, 1992) and does not possess the complications of other ligands used for analysis of NETs, i.e., binding to intracellular nonadrenergic sites (Laduron et al, 1982;Backstrom et al, 1989; Backstrom and Marcusson, 1990). …”

Section: Abstract: Norepinephrine Transporters; Norepinephrine Uptakmentioning

confidence: 99%

“…In contrast to these radioligands, [ 3 H]nisoxetine does not possess such complications. [ 3 H]nisoxetine has a high affinity for NETs (K D ϭ 0.7 nM) and a low affinity for serotonin transporters (K D Ͼ 1 mM) and dopamine transporters (K D Ͼ 1 mM; S. Tejani-Butt, personal communication) (Tejani-Butt et al, 1990;Tejani-Butt, 1992). [ 3 H]nisoxetine has been used previously to measure NETs in rat and human brain (Tejani-Butt, 1992;Tejani-Butt and Ordway, 1992;Tejani-Butt et al, 1993).…”

Section: Although [mentioning

confidence: 99%

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Pharmacology and Distribution of Norepinephrine Transporters in the Human Locus Coeruleus and Raphe Nuclei

et al. 1997

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The norepinephrine transporter (NET ) is a site of action for tricyclic antidepressant drugs and for drugs of abuse such as amphetamine and cocaine. In this study, the binding of [ 3 H]nisoxetine to NETs in the noradrenergic cell group, the locus coeruleus, and the serotonergic cell groups, the dorsal raphe nuclei, was measured autoradiographically in postmortem human brain. 3 H]nisoxetine binding to NETs in monoaminergic nuclei was assessed by measuring the inhibition of its binding by desipramine, imipramine, or citalopram. The order of affinities of these drugs was identical in the locus coeruleus and dorsal and median raphe and was characteristic of binding to NETs (desipramine Ͼ imipramine Ͼ citalopram). Thus, high levels of NETs and an uneven distribution of NETs occur in the locus coeruleus as well as in the dorsal raphe nuclei of the human.

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[3H]Nisoxetine: a new radioligand for norepinephrine uptake sites in brain

Cited by 109 publications

References 7 publications

Relationship between Cerebral Sigma-1 Receptor Occupancy and Attenuation of Cocaine’s Motor Stimulatory Effects in Mice by PD144418

Relationship between Cerebral Sigma-1 Receptor Occupancy and Attenuation of Cocaine’s Motor Stimulatory Effects in Mice by PD144418

VMAT2 knockout mice: Heterozygotes display reduced amphetamine-conditioned reward, enhanced amphetamine locomotion, and enhanced MPTP toxicity

Pharmacology and Distribution of Norepinephrine Transporters in the Human Locus Coeruleus and Raphe Nuclei

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