PT - JOURNAL ARTICLE AU - Clotilde Mannoury la Cour AU - Claudette Boni AU - Naı̈ma Hanoun AU - Klaus-Peter Lesch AU - Michel Hamon AU - Laurence Lanfumey TI - Functional Consequences of 5-HT Transporter Gene Disruption on 5-HT<sub>1A</sub> Receptor-Mediated Regulation of Dorsal Raphe and Hippocampal Cell Activity AID - 10.1523/JNEUROSCI.21-06-02178.2001 DP - 2001 Mar 15 TA - The Journal of Neuroscience PG - 2178--2185 VI - 21 IP - 6 4099 - http://www.jneurosci.org/content/21/6/2178.short 4100 - http://www.jneurosci.org/content/21/6/2178.full SO - J. Neurosci.2001 Mar 15; 21 AB - The consequences of the absence of 5-HT reuptake on the functional properties of 5-HT1A receptors were examined in the dorsal raphe nucleus and the hippocampus of knock-out mice lacking the serotonin transporter (5-HTT). Extracellular recordings showed that application of selective 5-HT reuptake inhibitors such as paroxetine and citalopram onto brainstem slices resulted in a concentration-dependent inhibition of 5-HT neuron firing in the dorsal raphe nucleus of wild-type 5-HTT+/+ mice, but not 5-HTT−/− mutants. By contrast, the 5-HT1A receptor agonists ipsapirone and 5-carboxamidotryptamine inhibited the discharge in both groups. However, the potency of these agonists was markedly decreased (by ∼55- and ∼6-fold, respectively) in 5-HTT−/− compared with 5-HTT+/+ animals. Similarly, intracellular recordings showed that the potency of 5-carboxamidotryptamine to hyperpolarize 5-HT neurons in the dorsal raphe nucleus was significantly lower in 5-HTT−/− than in 5-HTT+/+ animals. These data contrasted with those obtained with hippocampal slices in which 5-carboxamidotryptamine was equipotent to hyperpolarize CA1 pyramidal neurons in both mutant and wild-type mice. As expected from their mediation through 5-HT1A receptors, the effects of ipsapirone and 5-carboxamidotryptamine were competitively inhibited by the selective 5-HT1A antagonist WAY 100635 in both groups. These data showed that 5-HTT gene knock-out induced a marked desensitization of 5-HT1A autoreceptors in the dorsal raphe nucleus without altering postsynaptic 5-HT1A receptor functioning in the hippocampus. Similarities between these changes and those evoked by chronic treatment with 5-HT reuptake inhibitors emphasize the existence of regional differences in 5-HT1A receptor regulatory mechanisms.