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1.
Int J Neuropsychopharmacol ; 21(2): 145-153, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29045739

RESUMO

Background: Comprehensive description of ketamine's molecular binding profile becomes increasingly pressing as use in real-life patient cohorts widens. Animal studies attribute a significant role in the substance's antidepressant effects to the serotonergic system. The serotonin transporter is a highly relevant target in this context, because it is central to depressive pathophysiology and treatment. This is, to our knowledge, the first study investigating ketamine's serotonin transporter binding in vivo in humans. Methods: Twelve healthy subjects were assessed twice using [11C]DASB positron emission tomography. A total of 0.50 mg/kg bodyweight ketamine was administered once i.v. prior to the second positron emission tomography scan. Ketamine plasma levels were determined during positron emission tomography. Serotonin transporter nondisplaceable binding potential was computed using a reference region model, and occupancy was calculated for 4 serotonin transporter-rich regions (caudate, putamen, thalamus, midbrain) and a whole-brain region of interest. Results: After administration of the routine antidepressant dose, ketamine showed <10% occupancy of the serotonin transporter, which is within the test-retest variability of [11C]DASB. A positive correlation between ketamine plasma levels and occupancy was shown. Conclusions: Measurable occupancy of the serotonin transporter was not detectable after administration of an antidepressant dose of ketamine. This might suggest that ketamine binding of the serotonin transporter is unlikely to be a primary antidepressant mechanism at routine antidepressant doses, as substances that facilitate antidepressant effects via serotonin transporter binding (e.g., selective serotonin reuptake inhibitors) show 70% to 80% occupancy. Administration of high-dose ketamine is widening. Based on the positive relationship we find between ketamine plasma levels and occupancy, there is a need for investigation of ketamine's serotonin transporter binding at higher doses.


Assuntos
Compostos de Anilina , Antidepressivos/farmacocinética , Ketamina/farmacocinética , Mesencéfalo/efeitos dos fármacos , Neostriado/efeitos dos fármacos , Tomografia por Emissão de Pósitrons/métodos , Serotoninérgicos , Proteínas da Membrana Plasmática de Transporte de Serotonina/efeitos dos fármacos , Sulfetos , Tálamo/efeitos dos fármacos , Adulto , Antidepressivos/administração & dosagem , Humanos , Ketamina/administração & dosagem , Masculino , Mesencéfalo/diagnóstico por imagem , Neostriado/diagnóstico por imagem , Tálamo/diagnóstico por imagem , Adulto Jovem
2.
Neuropharmacology ; 39(13): 2663-72, 2000 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11044736

RESUMO

The study of the modulatory effects of nicotinic acetylcholine receptor (nAChR) agonists on neurotransmitter release from tissue slices has been hampered by laborious and limiting superfusion techniques. A new methodology was developed utilizing 96-well filter plates. This new method produced comparable results to previously published data, yet expanded throughput to permit more complete pharmacological characterization. Rat brain slices, preloaded with [(3)H]-norepinephrine ([(3)H]-NE), were distributed onto 96-well filter plates. Following a 5 min preincubation, the slices were incubated for 5 min with nicotinic agonists or antagonists. (-)-Nicotine (NIC) and 1,1-dimethyl-4-phenylpiperazine (DMPP) evoked release of [(3)H]-NE from a number of brain regions and spinal cord, with the highest response seen in the hippocampus. Concentration-response curves revealed a rank order of potency of (+/-)-epibatidine>>anatoxin-a>A-85380>DMPP=NIC=(-)-cytisine in the hippocampus, thalamus, and frontal cortex. EC(50) values were approximately 0.005, 0.2, 1, 5, 5 and 5 microM, respectively. Concentration-inhibition curves of nicotine evoked [(3)H]-NE release from hippocampal and thalamic slices resulted in a rank order of potency of mecamylamine>hexamethonium>d-tubocurare>DHbetaE. Schild analysis revealed apparent noncompetitive antagonism of [(3)H]-NE release from hippocampus by mecamylamine, hexamethonium, and DHbetaE. In contrast, DHbetaE antagonism of [(3)H]-dopamine release from striatal slices using a similar methodology was competitive.


Assuntos
Química Encefálica/fisiologia , Norepinefrina/metabolismo , Receptores Nicotínicos/metabolismo , Animais , Iodeto de Dimetilfenilpiperazina/farmacologia , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Técnicas In Vitro , Cinética , Masculino , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Antagonistas Nicotínicos/farmacologia , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores Nicotínicos/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/metabolismo , Tálamo/efeitos dos fármacos , Tálamo/metabolismo
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