Biomedical subjects

René Hen

Publications and source records attributed to René Hen.

4 recordsLinked to original sources

PubMed2002

Serotonin1A receptor acts during development to establish normal anxiety-like behaviour in the adult.

Serotonin is implicated in mood regulation, and drugs acting via the serotonergic system are effective in treating anxiety and depression. Specifically, agonists of the serotonin1A receptor have anxiolytic properties, and knockout mice lacking this receptor show increased anxiety-like behaviour. Here we use a tissue-specific, conditional rescue strategy to show that expression of the serotonin1A receptor primarily in the hippocampus and cortex, but not in the raphe nuclei, is sufficient to rescue the behavioural phenotype of the knockout mice. Furthermore, using the conditional nature of these transgenic mice, we suggest that receptor expression during the early postnatal period, but not in the adult, is necessary for this behavioural rescue. These findings show that postnatal developmental processes help to establish adult anxiety-like behaviour. In addition, the normal role of the serotonin1A receptor during development may be different from its function when this receptor is activated by therapeutic intervention in adulthood.

Aging↗

PubMed2002

Modification of serotonin neuron properties in mice lacking 5-HT1A receptors.

Using null mutant mice for the 5-HT1A receptor (5-HT1A-/-), extracellular electrophysiological recordings were first conducted to evaluate the impact of its genetic deletion on the firing rate of dorsal raphe 5-hydroxytryptamine (5-HT) neurons. Experiments were also done using brain slices to assess whether any compensation phenomenon had taken place in key receptors known to control 5-HT and norepinephrine release. The mean firing rate of 5-HT neurons was nearly doubled in 5-HT1A-/- mice, although 65% of the neurons were firing in their normal range. In preloaded brain slices, the 5-HT1D/B receptor agonist sumatriptan equally inhibited the electrically evoked release of [3H]5-HT in mesencephalic slices (containing the dorsal and median raphe) from wildtype and 5-HT1A-/- mice. The 5-HT1B receptor agonist CP 93129 (1,4-dihydro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-5H-pyrrol (3, 2-b) pyridin-5-one) and the alpha2-adrenoceptor agonist UK14,304 (5-bromo-N-(4, 5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine) produced the same inhibitory effect in both groups of mice in hippocampus and frontal cortex slices. No difference was observed on the UK14,304-mediated inhibition of [3H]norepinephrine from preloaded slices of the two latter structures between the two groups of mice. In conclusion, the loss of control of the 5-HT1A autoreceptor in 5-HT1A-/- mice lead to a significant enhancement of 5-HT neuronal firing, but it did not alter 5-HT or norepinephrine release in any of the brain structures examined. In addition, it was not associated with changes in the function of 5-HT1D and 5-HT1B autoreceptors and of alpha2-adrenergic heteroreceptors on 5-HT neurons, nor of that of alpha2-adrenoceptors on norepinephrine terminals.

Animals↗

PubMed2002

5-HT(1B) receptor knockout mice show no adaptive changes in 5-HT(1A) receptor function as measured telemetrically on body temperature and heart rate responses.

Two presynaptic receptors play an important role in the regulation of serotonergic neurotransmission, i.e., the 5-HT(1A) and 5-HT(1B) receptor. The present study focuses on putative adaptive changes in the 5-HT(1A) receptor system in mice that lack 5-HT(1B) receptors (5-HT(1B) KO). 5-HT(1A) receptor sensitivity was assessed in vivo in two models of presynaptic 5-HT(1A) receptor activity: agonist-induced hypothermia and prevention of stress-induced hyperthermia. The effects of 5-HT(1A) receptor activation by flesinoxan (0.1-3.0 mg/kg s.c.) were determined telemetrically on body temperature and heart rate in 5-HT(1B) KO and wild-type (WT) mice. Flesinoxan induced hypothermia dose-dependently without affecting heart rate and prevented stress-induced hyperthermia and tachycardia equipotently in both genotypes. Specificity of these responses was confirmed by blockade with the selective 5-HT(1A) receptor antagonist WAY100635 (1.0 mg/kg s.c.). The importance of continuous sampling in freely moving subjects to improve appropriate characterization of mutants is discussed. 5-HT(1B) KO mice showed no shift in 5-HT(1A) receptor sensitivity compared to WT mice. This study found no indications for adaptive changes in presynaptic 5-HT(1A) receptor function in 5-HT(1B) KO mice as measured telemetrically on body temperature and heart rate responses.

Adaptation, Physiological↗

PubMed1999

Knockout Corner.

Serotonin (5-hydroxytryptamine, 5-HT) is a neurotransmitter involved in a number of physiological functions including sleep, appetite, pain perception, and sexual activity. Several pathological states such as migraine, depression, and anxiety have been linked to the serotonergic system, and serotonergic drugs have been used to treat these disorders. To date, there are 14 known serotonin receptor subtypes through which serotonin exerts its multiple actions. The classic pharmacological approach to study how these individual receptor subtypes contribute to various behaviours has been to use selective drugs that either block or activate certain receptor subtypes, and then study the effects of these compounds on physiology and behaviour. A complementary genetic approach is the technique of gene targeting. Using this technology, we and others have begun to examine the contribution of several serotonin receptor subtypes to complex behaviours through the generation of knockout mice that lack the genes encoding these receptors. In this review, we will describe what we have learned about the serotonergic system and the function of the 5-HT(1B) receptor by the analysis of 5-HT(1B) receptor knockout mice. Furthermore, we will discuss the implications of these findings and our plans for future studies.

Journal Article↗