Altered serotonin and dopamine metabolism in the CNS of serotonin 5-HT(1A) or 5-HT(1B) receptor knockout mice.
Measurements of serotonin (5-HT), dopamine (DA), and noradrenaline, and of 5-HT and DA metabolites, were obtained by HPLC from 16 brain regions and the spinal cord of 5-HT(1A) or 5-HT(1B) knockout and wild-type mice of the 129/Sv strain. In 5-HT(1A) knockouts, 5-HT concentrations were unchanged throughout, but levels of 5-HT metabolites were higher than those of the wild type in dorsal/medial raphe nuclei, olfactory bulb, substantia nigra, and locus coeruleus. This was taken as an indication of increased 5-HT turnover, reflecting an augmented basal activity of midbrain raphe neurons and consequent increase in their somatodendritic and axon terminal release of 5-HT. It provided a likely explanation for the increased anxious-like behavior observed in 5-HT(1A) knockout mice. Concomitant increases in DA content and/or DA turnover were interpreted as the result of a disinhibition of DA, whereas increases in noradrenaline concentration in some territories of projection of the locus coeruleus could reflect a diminished activity of its neurons. In 5-HT(1B) knockouts, 5-HT concentrations were lower than those of the wild type in nucleus accumbens, locus coeruleus, spinal cord, and probably also several other territories of 5-HT innervation. A decrease in DA, associated with increased DA turnover, was measured in nucleus accumbens. These changes in 5-HT and DA metabolism were consistent with the increased aggressiveness and the supersensitivity to cocaine reported in 5-HT(1B) knockout mice. Thus, markedly different alterations in CNS monoamine metabolism may contribute to the opposite behavioral phenotypes of these two knockouts.
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Départment de Physiologie, Faculté de Médecine, Université de Montréal, Montréal, Québec, Canada.
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D015102:3,4-Dihydroxyphenylacetic Acid / Q000032:analysis; D000818:Animals; D001345:Autoradiography; D001479:Basal Ganglia / Q000737:chemistry / Q000378:metabolism; D002490:Central Nervous System / Q000737:chemistry / Q000378:metabolism*; D002531:Cerebellum / Q000737:chemistry / Q000378:metabolism; D002540:Cerebral Cortex / Q000737:chemistry / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D004298:Dopamine / Q000031:analogs & derivatives* / Q000032:analysis / Q000378:metabolism*; D005260:Female; D006719:Homovanillic Acid / Q000032:analysis; D006897:Hydroxyindoleacetic Acid / Q000032:analysis; D006917:Hydroxytryptophol / Q000032:analysis; D007031:Hypothalamus / Q000737:chemistry / Q000378:metabolism; D008297:Male; D008636:Mesencephalon / Q000737:chemistry / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009638:Norepinephrine / Q000032:analysis; D009830:Olfactory Bulb / Q000737:chemistry / Q000378:metabolism; D009928:Organ Specificity; D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin / Q000172:deficiency / Q000235:genetics*; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin / Q000032:analysis / Q000378:metabolism*; D013116:Spinal Cord / Q000737:chemistry / Q000378:metabolism
D044302:Receptor, Serotonin, 5-HT1B; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D015102:3,4-Dihydroxyphenylacetic Acid; D006917:Hydroxytryptophol; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; C001746:3-methoxytyramine; D004298:Dopamine; D009638:Norepinephrine; D006719:Homovanillic Acid