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.

The present study examined the regional localization of corticotropin-releasing factor (CRF)-and 5-hydroxytryptamine (5-HT)-immunoreactive (IR) fibers within the rat dorsal raphe nucleus (DRN) using immunohistochemistry. Additionally, the effects of CRF, administered intracerebroventricularly (0.1-3.0 g) or intraraphe (0.3-30 ng), on discharge rates of putative 5-HT DRN neurons Corticotropin-releasing factor (CRF) has a diverse range of physiological and behavioral effects, acting both as a neurohormone at the level of the anterior pituitary and as a neurotransmitter in brain. As a neurohormone, CRF initiates the release of adrenocorticotropic hormone which triggers the endocrine limb of the stress response . Anatomical evidence of a widespread distribution of CRF-immunoreactive (IR) terminals and receptors throughout the brain De Souza et al. 1985;Potter et al. 1994;Sakanaka et al. 1987;Swanson et al. 1983) provides support for the additional role of CRF as a brain neurotransmitter. An example of a potential neurotransmitter action of CRF is its action on the locus coeruleus (LC)-norepinephrine system. Intracerebroventricular (i.c.v.) or intracoerulear administration of CRF increases activity of LC neurons Page and Abercrombie 1999;Valentino et al. 1983) and stimulates NE release in terminal fields of the LC (Lavicky and Dunn 1993;Page and Abercrombie 1999;Smagin et al. 1995). Moreover, activation of LC neurons by certain physiological stimuli is attenuated by CRF antagonists administered into the LC (Curtis et al. 1994;Lechner et al. 1997).Anatomical evidence suggests that CRF is also positioned to affect activity of the dorsal raphe nucleus Philadelphia, PA 19102. Received May 17, 1999; revised July 28, 1999; accepted August 3, 1999. N EUROPSYCHOPHARMACOLOGY 2000 -VOL . 22 , NO . 2 CRF Effects on 5-HT Neurons 149 (DRN)-5-hydroxytryptamine (5-HT) system. Thus, CRF receptor binding sites (De Souza et al. 1985) and mRNA Potter et al. 1994) as well as CRF-IR terminals (Sakanaka et al. 1987;Swanson et al. 1983) are localized in the DRN, a primary site of 5-HT cell bodies projecting to the forebrain. Recent studies demonstrated that relatively low doses of CRF (administered i.c.v.) inhibit 5-HT release in two different terminal regions of the DRN (i.e., striatum and lateral septum), suggesting that the site of action of CRF effects on 5-HT release is at the level of the cell bodies in the DRN . Consistent with this, electrophysiological recordings indicated that a low dose of CRF (administered i.c.v.) that decreased extracellular levels of 5-HT in striatum also decreased DRN discharge rate . In contrast to the effects of low doses of CRF, higher doses were found to not alter or to increase extracellular 5-HT levels in the lateral septum or striatum, respectively. The complex dose-related effects of CRF on 5-HT release could be a function of multiple CRF receptor subtypes within the DRN and/or different sites of action (cell bodies vs. terminals) of i.c.v. administered CRF.The present study was designed t...

The membrane properties and receptor-mediated responses of rat dorsal raphe nucleus neurons were measured using intracellular recording techniques in a slice preparation. After each experiment, the recorded neuron was filled with neurobiotin and immunohistochemically identified as 5-hydroxytryptamine (5-HT)-immunopositive or 5-HT-immunonegative. The cellular characteristics of all recorded neurons conformed to previously determined classic properties of serotonergic dorsal raphe nucleus neurons: slow, rhythmic activity in spontaneously active cells, broad action potential and large afterhyperpolarization potential. Two electrophysiological characteristics were identified that distinguished 5-HT from non-5-HT-containing cells in this study. In 5-HT-immunopositive cells, the initial phase of the afterhyperpolarization potential was gradual (tau=7.3±1.9) and in 5-HTimmunonegative cells it was abrupt (tau=1.8±0.6). In addition, 5-HT-immunopositive cells had a shorter membrane time constant (tau=21.4±4.4) than 5-HT-immunonegative cells (tau=33.5±4.2). Interestingly, almost all recorded neurons were hyperpolarized in response to stimulation of the inhibitory 5-HT 1A receptor. These results suggested that 5-HT 1A receptors are present on non-5-HT as well as 5-HT neurons. This was confirmed by immunohistochemistry showing that although the majority of 5-HT-immunopositive cells in the dorsal raphe nucleus were double-labeled for 5-HT 1A receptor-IR, a small but significant population of 5-HT-immunonegative cells expressed the 5-HT 1A receptor. These results underscore the heterogeneous nature of the dorsal raphe nucleus and highlight two membrane properties that may better distinguish 5-HT from non-5-HT cells than those typically reported in the literature. In addition, these results present electrophysiological and anatomical evidence for the presence of 5-HT 1A receptors on non-5-HT neurons in the dorsal raphe nucleus.Keywords 5-HT; 5-HT 1A receptor; intracellular; slice; rat The dorsal raphe nucleus (DRN) is generally considered a serotonergic nucleus because it is the largest source of 5-hydroxytryptamine (5-HT) terminals in the forebrain. However, substantial evidence points to the heterogeneous nature of the DRN. For example, the proportion of 5-HT-containing cells in the DRN is estimated to range from one to two thirds (Steinbusch et al., 1980;Descarries et al., 1982;Jacobs and Azmitia, 1992;Baumgarten and Grozdanovic, 1997). The remaining non-serotonergic cells contain a variety of other neurotransmitters and neuromodulators including dopamine, norepinephrine, glutamate, *Corresponding author: Tel: +1-215-590-0656; fax: +1-215-590-0109. kirbyl@email.chop.edu (L. G. Kirby). NIH Public Access Author ManuscriptNeuroscience. Author manuscript; available in PMC 2010 March 5. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptGABA, enkephalin, substance P, neuropeptide Y, thyrotropin-releasing hormone, vasoactive intestinal polypeptide, cholecystokinin, gastrin and neurotensin (for review...

Depletion of serotonin prevented the behavioral effects of the selective serotonin reuptake inhibitor fluoxetine in the rat FST. Furthermore, depletion of serotonin had no impact on the behavioral effects induced by the selective norepinephrine reuptake inhibitor, desipramine. The effects of antidepressant drugs on FST-induced immobility may be exerted by distinguishable contributions from different neurotransmitter systems.

The dorsal (DR) and median raphe (MR) nuclei contain 5-hydroxytryptamine (serotonin, 5-HT) cell bodies that give rise to the majority of the ascending 5-HT projections to the forebrain limbic areas that control emotional behavior. In the past, the electrophysiological identification of neurochemically identified 5-HT neurons has been limited. Recent technical developments have made it possible to re-examine the electrophysiological characteristics of identified 5-HT- and non-5-HT-containing neurons. Visualized whole cell electrophysiological techniques in combination with fluorescence immunohistochemistry for 5-HT were used. In the DR, both 5-HT- and non-5-HT-containing neurons exhibited similar characteristics that have historically been attributed to putative 5-HT neurons. In contrast, in the MR, the 5-HT-and non-5-HT-containing neurons had very different characteristics. Interestingly, the MR 5-HT-containing neurons had a shorter time constant and larger afterhyperpolarization (AHP) amplitude than DR 5-HT-containing neurons. The 5-HT(1A) receptor-mediated response was also measured. The efficacy of the response elicited by 5-HT(1A) receptor activation was greater in 5-HT-containing neurons in the DR than the MR, whereas the potency was similar, implicating greater autoinhibition in the DR. Non-5-HT-containing neurons in the DR were responsive to 5-HT(1A) receptor activation, whereas the non-5-HT-containing neurons in the MR were not. These differences in the cellular characteristics and 5-HT(1A) receptor-mediated responses between the MR and DR neurons may be extremely important in understanding the role of these two 5-HT circuits in normal physiological processes and in the etiology and treatment of pathophysiological states.