Neurochemical effects of the endocannabinoid uptake inhibitor UCM707 in various rat brain regions.
To date, UCM707, (5Z,8Z,11Z,14Z)-N-(3-furylmethyl)eicosa-5,8,11,14-tetraenamide, has the highest potency and selectivity in vitro and in vivo as inhibitor of the endocannabinoid uptake. Its biochemical, pharmacological and therapeutic properties have been intensely studied recently, but the information on its capability to modify neurotransmitter activity, which obviously underlies the above properties, is still limited. In the present study, we conducted a time-course experiment in rats aimed at examining the neurochemical effects of UCM707 in several brain regions following a subchronic administration (5 injections during 2.5 days) of this inhibitor in a dose of 5 mg/kg weight. In the hypothalamus, the administration of UCM707 did not modify GABA contents but reduced norepinephrine levels at 5 h after administration, followed by an increase at 12 h. Similar trends were observed for dopamine, whereas serotonin content remained elevated at 1 and, in particular, 5 and 12 h after administration. In the case of the basal ganglia, UCM707 reduced GABA content in the substantia nigra but only at longer (5 or 12 h) times after administration. There were no changes in serotonin content, but a marked reduction in its metabolite 5HIAA was recorded in the substantia nigra. The same pattern was found for dopamine, contents of which were not altered by UCM707 in the caudate-putamen, but its major metabolite DOPAC exhibited a marked decrease at 5 h. In the cerebellum, UCM707 reduced GABA, serotonin and norepinephrine content, but only the reduction found for norepinephrine at 5 h reached statistical significance. The administration of UCM707 did not modify the contents of these neurotransmitters in the hippocampus and the frontal cortex. Lastly, in the case of limbic structures, the administration of UCM707 markedly reduced dopamine content in the nucleus accumbens at 5 h, whereas GABA content remained unchanged in this structure and also in the ventral-tegmental area and the amygdala. By contrast, norepinephrine and serotonin content increased at 5 h in the nucleus accumbens, but not in the other two limbic structures. In summary, UCM707 administered subchronically modified the contents of serotonin, GABA, dopamine and/or norepinephrine with a pattern strongly different in each brain region. So, changes in GABA transmission (decrease) were restricted to the substantia nigra, but did not appear in other regions, whereas dopamine transmission was also altered in the caudate-putamen and the nucleus accumbens. By contrast, norepinephrine and serotonin were altered by UCM707 in the hypothalamus, cerebellum (only norepinephrine), and nucleus accumbens, exhibiting biphasic effects in some cases.
de Lago
Eva
E
Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, 28040 Madrid, Spain.
Ortega-Gutiérrez
Silvia
S
Ramos
José A
JA
López Rodríguez
Maria L
ML
Fernández-Ruiz
Javier
J
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology*; D001923:Brain Chemistry / Q000187:drug effects*; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000378:metabolism; D004563:Electrochemistry; D063388:Endocannabinoids; D005663:Furans / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D009638:Norepinephrine / Q000378:metabolism; D053284:Polyunsaturated Alkamides / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005663:Furans; C443680:N-(3-furylmethyl)eicosa-5,8,11,14-tetraenamide; D053284:Polyunsaturated Alkamides; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D005680:gamma-Aminobutyric Acid; D004298:Dopamine; D009638:Norepinephrine