Abstract | BACKGROUND: METHODS: We explored the use of the novel α2C-adrenoceptor antagonist PET tracer [(11)C]ORM-13070 for measurement of amphetamine-induced changes in synaptic norepinephrine. The effect of amphetamine on [(11)C]ORM-13070 binding was evaluated ex vivo in rat brain sections and in vivo with PET imaging in monkeys. RESULTS: Microdialysis experiments confirmed amphetamine-induced elevations in rat striatal norepinephrine and dopamine concentrations. Regional [(11)C]ORM-13070 receptor binding was high in the striatum and low in the cerebellum. After injection of [(11)C]ORM-13070 in rats, mean striatal specific binding ratios, determined using cerebellum as a reference region, were 1.4±0.3 after vehicle pretreatment and 1.2±0.2 after amphetamine administration (0.3mg/kg, subcutaneous). Injection of [(11)C]ORM-13070 in non-human primates resulted in mean striatal binding potential (BP ND) estimates of 0.65±0.12 at baseline. Intravenous administration of amphetamine (0.5 and 1.0mg/kg, i.v.) reduced BP ND values by 31-50%. Amphetamine (0.3mg/kg, subcutaneous) increased extracellular norepinephrine (by 400%) and dopamine (by 270%) in rat striata. CONCLUSIONS: Together, these results indicate that [(11)C]ORM-13070 may be a useful tool for evaluation of synaptic norepinephrine concentrations in vivo. Future studies are required to further understand a potential contribution of dopamine to the amphetamine-induced effect.
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Authors | Sjoerd J Finnema, Zoë A Hughes, Merja Haaparanta-Solin, Vladimir Stepanov, Ryuji Nakao, Katarina Varnäs, Andrea Varrone, Eveliina Arponen, Päivi Marjamäki, Katariina Pohjanoksa, Lauri Vuorilehto, Phebian A Babalola, Olof Solin, Sarah Grimwood, Jukka Sallinen, Lars Farde, Mika Scheinin, Christer Halldin |
Journal | The international journal of neuropsychopharmacology
(Int J Neuropsychopharmacol)
Vol. 18
Issue 3
(Dec 13 2014)
ISSN: 1469-5111 [Electronic] England |
PMID | 25522417
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Copyright | © The Author 2015. Published by Oxford University Press on behalf of CINP. |
Chemical References |
- 1-(1-(2,3-dihydrobenzo(1,4)dioxin-2-yl)methyl)-4-(3-methoxymethylpyridin-2-yl)piperazine
- Adrenergic Uptake Inhibitors
- Adrenergic alpha-2 Receptor Antagonists
- Central Nervous System Stimulants
- Dioxanes
- Imidazoles
- Piperazines
- Propylamines
- Radiopharmaceuticals
- Receptors, Adrenergic, alpha-2
- atipamezole
- Atomoxetine Hydrochloride
- Amphetamine
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Topics |
- Adrenergic Uptake Inhibitors
(pharmacology)
- Adrenergic alpha-2 Receptor Antagonists
(pharmacology)
- Amphetamine
(pharmacology)
- Animals
- Atomoxetine Hydrochloride
- Brain
(drug effects)
- Central Nervous System Stimulants
(pharmacology)
- Dioxanes
(metabolism)
- Female
- Humans
- Imidazoles
(pharmacology)
- Macaca fascicularis
- Male
- Piperazines
(metabolism)
- Positron-Emission Tomography
- Propylamines
(pharmacology)
- Protein Binding
(drug effects)
- Radiopharmaceuticals
(metabolism)
- Rats
- Rats, Sprague-Dawley
- Receptors, Adrenergic, alpha-2
(metabolism)
- Time Factors
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