Altered Serotonin and Dopamine Metabolism in the CNS of Serotonin 5‐HT1A or 5‐HT1B Receptor Knockout Mice

: Measurements of serotonin (5‐HT), dopamine (DA), andnoradrenaline, and of 5‐HT and DA metabolites, were obtained by HPLC from 16brain regions and the spinal cord of 5‐HT1A or 5‐HT1Bknockout and wild‐type mice of the 129/Sv strain. In 5‐HT1Aknockouts, 5‐HT concentrations were unchanged throughout, but levels of 5‐HTmetabolites were higher than those of the wild type in dorsal/medial raphenuclei, olfactory bulb, substantia nigra, and locus coeruleus. This was takenas an indication of increased 5‐HT turnover, reflecting an augmented basalactivity of midbrain raphe neurons and consequent increase in theirsomatodendritic and axon terminal release of 5‐HT. It provided a likelyexplanation for the increased anxious‐like behavior observed in5‐HT1A knockout mice. Concomitant increases in DA content and/or DAturnover were interpreted as the result of a disinhibition of DA, whereasincreases in noradrenaline concentration in some territories of projection ofthe locus coeruleus could reflect a diminished activity of its neurons. In5‐HT1B knockouts, 5‐HT concentrations were lower than those of thewild type in nucleus accumbens, locus coeruleus, spinal cord, and probablyalso 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 increasedaggressiveness and the supersensitivity to cocaine reported in5‐HT1B knockout mice. Thus, markedly different alterations in CNSmonoamine metabolism may contribute to the opposite behavioral phenotypes ofthese two knockouts.