Chronic low dose ovine corticotropin releasing factor or urocortin II into the rostral dorsal raphe alters exploratory behavior and serotonergic gene expression in specific subregions of the dorsal raphe

Abstract

Corticotropin releasing factor (CRF) family peptides play key roles in integrating neural responses to stress. Both major CRF receptors have been pharmacologically identified in the dorsal raphe nucleus (DRN), a stress sensitive and internally heterogeneous nucleus supplying many forebrain regions with serotonergic input. Despite the involvement of chronic stress and serotonergic dysfunction in human mood and anxiety disorders, little is known about the effects of chronic CRF receptor activation on the DRN. We infused ovine CRF (1ng/hr), urocortin II (UCNII, 1ng/hr), or vehicle alone into rat DRN over 6 days. During infusion, animals were allowed to freely explore an open field for 15 minutes on each of two days, with the addition of a novel object on the second day. Following behavioral testing, 5-HT 1A , 5-HT 1B , serotonin transporter (SERT), and tryptophan hydroxylase-2 (Tph2) expression were examined through the DRN by in situ hybridization. Ovine CRF infusion resulted in significantly decreased novel object touches, climbs, as well as increased latency to first novel object contact. UCNII had a similar but less dramatic effect, decreasing only climbing behavior. Both ovine CRF and UCNII blunted the decrease in corner time expected on reexposure to the open field. Both peptides also produced regionally specific changes in gene expression: 5-HT 1A expression was increased 30% in the mid-rostral ventromedial DRN, while SERT was decreased by 30% in the mid-caudal shell dorsomedial DRN. There also appeared to be a shift in the relative level of Tph2 expression between the ventromedial and core dorsomedial DRN at the mid-rostral level. Changes in 5-HT 1A , SERT, and relative Tph2 mRNA abundance were correlated with novel object exploration. These findings suggest chronic intra-DRN administration of CRF agonists decreases exploratory behavior, while producing subregionally limited changes in serotonergic gene expression. These studies may be relevant to mechanisms underlying behavioral changes after chronic stress. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptDepression and anxiety disorders are among the leading causes of morbidity, mortality, and disability in the United States (Greenberg et al., 2003). They are often comorbid, and both are highly associated with chronic exposure to stress. Multiple lines of evidence suggest that chronic and inescapable stress produce long lasting effects on brain function and behavior that play a prominent role in the development, maintenance, and recurrence of both depression and a variety of anxiety disorders (Gulley and Nemeroff, 1993, Arborelius et al., 1999, Ressler and Nemeroff, 2000.Altered serotonin neurotransmission appears to be a central mechanism inducing both depressive (Maes and Meltzer, 1995) and anxiety disorders (Ressler and Nemeroff, 2000). The majority of serotonergic fibers to forebrain regions thought to be involved in mood and anxiety regulation arise from the dorsal raphe nucleus (DRN) and median raphe nucleus (MRN) ...

Restraint stress increases serotonin release in the central nucleus of the amygdala via activation of corticotropin-releasing factor receptors

“…Furthermore, CRF 2 receptor activation in the dRN by urocortin II produces increased 5-HT release in the basolateral amygdala [2]. Finally, chronic activation of CRF 2 receptors in the dRN result in altered serotonergic gene expression and corresponding behavioral changes that resemble those induced by chronic stress of rats, such as decreased novel object and open field exploration [12]. Subsequent work should determine whether CRF 2 receptors in the dRN are required for stress-induced increases in CeA 5-HT release, as would be predicted by results from previous studies.…”

Interactions of Corticotropin-Releasing Factor, Urocortin and Citalopram in a Primate Model of Stress-Induced Amenorrhea

“…CRF innervation of the serotonergic dorsal raphe nucleus has been described and CRF receptors are found in the dorsal raphe of rodents [23,43,44]. Moreover, CRF regulates serotonin release [28,45,46,47]. …”

“…Moreover, UCN1 neurons respond to alcohol and may affect alcohol preference and consumption [27]. Evidence from rodents suggests that, once released into the raphe, CRF and UCN1 bind to CRF receptor 1 (CRF-R1) and CRF receptor 2 (CRF-R2) and regulate serotonin neurotransmission [28,29,30,31]. …”

Urocortin II increases spontaneous parental behavior in prairie voles (Microtus ochrogaster)

“…Central administration of UCN II increased anxiety-like behavior when given intracerebroventricularly (ICV) thirty minutes before a plus maze test [7;8]. It also caused increased anxiety when administered by osmotic minipump infusion during a novel object exploration task [9]. However, UCN II minipump administration caused no differences in open field behavior [9].…”

“…It also caused increased anxiety when administered by osmotic minipump infusion during a novel object exploration task [9]. However, UCN II minipump administration caused no differences in open field behavior [9]. In another study, ICV UCN II caused no change in plus-maze behavior either ten minutes or one hour postinjection [10]; however, animals tested four hours post-administration showed a decrease in anxiety-like behavior.…”