Regulation Of Depressive-like Behaviors Research Articles

Optogenetic activation of the lateral habenulaD1R-ventral tegmental area circuit induces depression-like behavior in mice.

A number of different receptors are distributed in glutamatergic neurons of the lateral habenula (LHb). These glutamatergic neurons are involved in different neural pathways, which may identify how the LHb regulates various physiological functions. However, the role of dopamine D1 receptor (D1R)-expressing habenular neurons projecting to the ventral tegmental area (VTA) (LHbD1R-VTA) remains not well understood. In the current study, to determine the activity of D1R-expressing neurons in LHb, D1R-Cre mice were used to establish the chronic restraint stress (CRS) depression model. Adeno-associated virus was injected into bilateral LHb in D1R-Cre mice to examine whether optogenetic activation of the LHb D1R-expressing neurons and their projections could induce depression-like behavior. Optical fibers were implanted in the LHb and VTA, respectively. To investigate whether optogenetic inhibition of the LHbD1R-VTA circuit could produce antidepressant-like effects, the adeno-associated virus was injected into the bilateral LHb in the D1R-Cre CRS model, and optical fibers were implanted in the bilateral VTA. The D1R-expressing neuronal activity in the LHb was increased in the CRS depression model. Optogenetic activation of the D1R-expressing neurons in LHb induced behavioral despair and anhedonia, which could also be induced by activation of the LHbD1R-VTA axons. Conversely, optogenetic inhibition of the LHbD1R-VTA circuit improved behavioral despair and anhedonia in the CRS depression model. D1R-expressing glutamatergic neurons in the LHb and their projections to the VTA are involved in the occurrence and regulation of depressive-like behavior.

5-HT1B receptor-AC-PKA signal pathway in the lateral habenula is involved in the regulation of depressive-like behaviors in 6-hydroxydopamine-induced Parkinson’s rats

ABSTRACT Objective The aim of the present study was to investigate whether serotonin1B (5-HT1B) receptor-adenylate cyclase (AC)-protein kinase A (PKA) signal pathway in the lateral habenula (LHb) is involved in Parkinson’s disease-related depression in sham-lesioned and substantia nigra pars compacta (SNc)-lesioned rats. Methods The sucrose preference and forced swim tests were used to measure depressive-like behaviors. In vivo electrophysiology and microdialysis were performed to observe the firing activity of LHb neurons and GABA and glutamate release in the LHb, respectively. Western blotting was used to analyze protein expression of 5-HT1B receptors, AC and phosphorylated PKA at threonine 197 site (p-PKA-Thr197) in the LHb. Results Unilateral 6-hydroxydopamine lesions of the SNc in rats induced depressive-like behaviors. Intra-LHb injection of 5-HT1B receptor agonist CP93129 produced antidepressant-like effects and the antagonist SB216641 induced depressive-like behaviors in sham-lesioned and SNc-lesioned rats. Further, pretreatment with AC inhibitor SQ22536 and PKA inhibitor KT5720 blocked the behavioral effects of CP93129 in the two groups of rats, respectively. CP93129 decreased the firing rate of LHb neurons and release of GABA and glutamate, but increased the GABA/glutamate ratio, while SB216641 induced the opposite effects. Compared with sham-lesioned rats, effects of CP93129 and SB216641 on the depressive-like behaviors, electrophysiology, and microdialysis were decreased in SNc-lesioned rats, which were associated with decreased expression of 5-HT1B receptors, AC and p-PKA-Thr197 in the LHb. Conclusion 5-HT1B receptor-AC-PKA signal pathway in the LHb is involved in the regulation of depressive-like behaviors, and depletion of DA reduces activity of 5-HT1B receptor-AC-PKA signal pathway.

Psychological stress induces depressive-like behavior associated with bone marrow-derived monocyte infiltration into the hippocampus independent of blood–brain barrier disruption

BackgroundPsychological stress is one of the most important factors that trigger emotional disorders, such as depression and anxiety. Emerging evidence suggests that neuroinflammation exacerbated by bidirectional communication between the peripheral immune system and the central nervous system facilitates abnormal psychiatric symptoms. This study aimed to investigate the hippocampal migration of bone marrow (BM)-derived monocytes and its role in regulating depressive-like behaviors using the chronic psychological stress (CPS) mouse model. More importantly, whether the central migration of these peripheral BM-derived cells depend on the disruption of the blood–brain barrier (BBB) was also investigated.Methods and findingsGreen fluorescent protein-positive (GFP+) BM chimeric mice were used to distinguish BM-derived monocytes within the brain. A CPS mouse model was established to explore the effect of CPS on hippocampal migration of BM-derived monocytes and its role in the regulation of depressive-like behaviors. The results revealed that BM-derived GFP+ cells accumulated in the hippocampus and differentiated into microglia-like cells after exposure to CPS. Interestingly, this migration was not associated with BBB disruption. Furthermore, treatment with C–C chemokine receptor 2 (CCR2) antagonist (RS102895) suppressed the recruitment of BM-derived monocytes to the hippocampus and alleviated depressive-like symptoms.ConclusionThese findings indicate that monocyte recruitment to the hippocampus in response to psychological stress may represent a novel cellular mechanism that contributes to the development of depression.

Involvement of the Dorsal Hippocampus 5-HT1A Receptors in the Regulation of Depressive-Like Behaviors in Hemiparkinsonian Rats

Background: Depression is one of the most common neuropsychiatric disturbances in Parkinson’s disease (PD), but its pathophysiology is not definite. Lines of evidence have indicated that the hippocampus and serotonin 1A (5-HT_1A) receptors are related to the regulation of depression. Objective:The purpose of the present study was to observe the effect of 5-HT_1A receptors in the dorsal hippocampus (dHIP) on PD-related depression in rats. Methods: Unilateral 6-hydroxydopamine lesioning of the medial forebrain bundle (MFB) was used to establish the hemiparkinsonian rat model. The effects of intra-dHIP injection of the 5-HT_1A receptor ­agonist 8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT) or antagonist WAY-100635 on depressive-like behaviors were observed in sucrose preference and forced swim tests in control and lesioned rats. Monoamine levels including dopamine (DA), 5-HT, and noradrenaline (NA) in depression-related brain regions were determined by a neurochemical method in all groups. Results: Behavioral results showed that MFB lesions induced depressive-like behaviors. Intra-dHIP injection of 8-OH-DPAT produced antidepressant effects, while WAY-100635 induced or increased the depressive-like behaviors in both control and the lesioned rats. Neurochemical results found that intra-dHIP injection of 8-OH-DPAT significantly increased DA and 5-HT levels in the medial prefrontal cortex (mPFC), lateral habenula (LHb), ventral hippocampus and amygdala in the lesioned group and decreased NA levels in the mPFC and LHb in the control group. Moreover, after injection of WAY-100635, NA levels in all these regions of the lesioned group were significantly increased. Conclusions: These findings suggest that hippocampal 5-HT_1A receptors regulate depression and PD-related depression by neurochemical mechanisms.

Neonatal treatment with clomipramine modifies the expression of estrogen receptors in brain areas of male adult rats

The participation of estrogens in depression has been well recognized. To exert its effects, estradiol binds mainly to estrogen receptors ESR1 and ESR2 (α and β, respectively), expressed in brain regions including the hippocampus, limbic regions and hypothalamic nuclei. In rodents, modified estrogen receptors expression in brain areas have been implicated in different signs similar to those observed in depressive patients. Neonatal clomipramine (CMI) treatment is a pharmacological manipulation that generates behavioral and neurochemical changes that persist throughout adulthood and resemble human depression.The aim of this study was to analyze whether CMI neonatal treatment modifies the expression of nuclear ESR1 and ESR2 in the hippocampus, amygdala basolateral (BLA), amygdala medial (MeA), hypothalamic medial preoptic area (mPOA) and raphe nucleus in male rats. Our results indicate that CMI treatment significantly induced an mRNA increase of ESR1 in the hypothalamus, additionally produce a reduction in the mRNA ESR2 expression in raphe accompanied of an increase in hypothalamus and amygdala. CMI treated rats show more immunorreactive cells to ESR1 (ESR1-ir) in mPOA, BLA, MeA, together with a reduction of these cells in the hippocampal CA1 region. Moreover, an increase in the number of immunorreactive cells to ESR2 (ESR2-ir), in BLA and MeA, was observed in CMI treated rats. Additionally, the hippocampal CA2 region and raphe nucleus showed a decrease in these cells. Also, neonatal CMI treatment induced a decrease in the number of cells of the pyramidal layer in CA1. Overall, the results suggest that neonatal CMI treatment in rats (during brain development) induces changes in estrogen receptors in different brain areas involved with the regulation of depressive-like behaviors.

The Impact of Hippocampal Sex Hormones Receptors in Modulation of Depressive-Like Behavior Following Chronic Anabolic Androgenic Steroids and Exercise Protocols in Rats.

The aim of this study was to evaluate alterations in depressive-like behaviors in rats following chronic administration of a supraphysiological dose of anabolic androgenic steroids (AASs) as well as exposure to a prolonged exercise protocol. The role of hippocampal sex hormones receptors in the modulation of depressive-like behavior was also assessed. A total of 48 male Wistar albino rats were divided into six groups: control, exercise (1 h/day, five consecutive days), nandrolone-decanoate (ND, 20 mg/kg/week, in a single dose), exercise plus ND, testosterone-enanthate (TE, 20 mg/kg/week, in a single dose), and exercise plus TE. After the 6-week protocols were complete, the rats underwent behavioral testing in the tail suspension test (TST). Rats were sacrificed for the collection of blood samples, to determine sex hormones levels, and isolation of the hippocampus, to determine [androgen receptors (AR) and estrogen receptors α (ERα)] expression. ND and TE treatment induced significant depressive-like behavior, opposing the antidepressant effect of exercise. Chronic TE administration elevated testosterone (T) and dihydrotestosterone (DHT) serum levels, and this was augmented by exercise. In contrast, ND and exercise alone did not alter T or DHT levels. There were no changes in serum estradiol levels in any of the groups. Immunohistochemical analysis showed that exercise reduced AR immunoreactivity in all hippocampal regions and increased the ERα expression in the CA1, dentate gyrus (DG), and total hippocampal sections, but not in the CA2/3 region. AASs administration increased AR expression in all hippocampal regions, although not the total hippocampal section in the TE group and did not significantly decrease ERα. The hippocampal AR/ERα expression index was lowered while parvalbumin (PV)-immunoreactivity was enhanced by exercise. AASs administration increased the AR/ERα index and reduced PV-immunoreactivity in the hippocampus. The number of PV-immunoreactive neurons negatively correlated with the antidepressant effects and the AR/ERα ratio. Our results suggest a potential role of the numerical relationship between two sex hormones receptors (stronger correlation than for each individual receptor) in the regulation of depressive-like behavior via the hippocampal GABAergic system in rats, which allow better understanding of the hippocampal sex hormones receptors role in modulation of depressive-like behavior.

Melanin-Concentrating Hormone (MCH) and MCH-R1 in the Locus Coeruleus May Be Involved in the Regulation of Depressive-Like Behavior

BackgroundPrevious anatomical and behavioral studies have shown that melanin-concentrating hormone is involved in the modulation of emotional states. However, little is known about brain regions other than the dorsal raphe nucleus that relate the melanin-concentrating hormone-ergic system to depressive states. Numerous studies have shown that the locus coeruleus is involved in the regulation of depression and sleep. Although direct physiological evidence is lacking, previous studies suggest that melanin-concentrating hormone release in the locus coeruleus decreases neuronal discharge. However, remaining unclear is whether the melanin-concentrating hormone-ergic system in the locus coeruleus is related to depressive-like behavior.MethodWe treated rats with an intra-locus coeruleus injection of melanin-concentrating hormone, intracerebroventricular injection of melanin-concentrating hormone, or chronic subcutaneous injections of corticosterone to induce different depressive-like phenotypes. We then assessed the effects of the melanin-concentrating hormone receptor 1 antagonist SNAP-94847 on depressive-like behavior in the forced swim test and the sucrose preference test.ResultsThe intra-locus coeruleus and intracerebroventricular injections of melanin-concentrating hormone and chronic injections of corticosterone increased immobility time in the forced swim test and decreased sucrose preference in the sucrose preference test. All these depressive-like behaviors were reversed by an intra-locus coeruleus microinjection of SNAP-94847.ConclusionsThese results suggest that the melanin-concentrating hormone-ergic system in the locus coeruleus might play an important role in the regulation of depressive-like behavior.

Prelimbic α1-adrenoceptors are involved in the regulation of depressive-like behaviors in the hemiparkinsonian rats.

At present, it is not clear whether α1-adrenoceptors in the prelimbic cortex (PrL) are involved in Parkinson's disease-related depression. Here we examined effects of PrL α1-adrenoceptors on depressive-like behaviors in rats with unilateral 6-hydroxydopamine lesions of the medial forebrain bundle. The lesion induced depressive-like responses as measured by the sucrose preference and forced swim tests compared to sham-operated rats. Intra-PrL injection of α1-adrenoceptor agonist phenylephrine induced or increased the expression of depressive-like behaviors in sham-operated and the lesioned rats. Further, intra-PrL injection of α1-adrenoceptor antagonist benoxathian produced antidepressant effects in two groups of rats. Intra-PrL injection of phenylephrine increased the mean firing rate of PrL pyramidal neurons in both sham-operated and the lesioned rats, while benoxathian decreased the mean firing rate of the neurons. Compared to sham-operated rats, the duration of phenylephrine and benoxathian action on the firing rate of the pyramidal neurons was shortened in the lesioned rats. Neurochemical results showed that intra-PrL injection of phenylephrine or benoxathian increased or decreased dopamine and noradrenaline and serotonin levels in the medial prefrontal cortex, ventral hippocampus and habenula in sham-operated and the lesioned rats, respectively. Altogether, these results suggest that activation and blockade of α1-adrenoceptors in the PrL change the firing activity of the pyramidal neurons, and then increase or decrease levels of three monoamines in the limbic and limbic-related brain regions, which are involved in the regulation of depressive-like behaviors. Additionally, the results also suggest that the dopaminergic lesion leads to hypofunctionality of α1-adrenoceptors on pyramidal neurons of the PrL.

Interleukin-4 is a participant in the regulation of depressive-like behavior

Inflammatory immune activation has been frequently associated with the development of major depression. Microglia might serve as an important interface in this immune system-to-brain communication. Interleukin-4, the major Th2 type cytokine, might be protective against depression due to its ability to counter-regulate inflammation and to inhibit serotonin transporter activity. By using an Interferon-α mouse model, we show that a decreased IL-4 responsiveness of microglia was specifically related to the development of depressive-like behavior. IL-4 deficient mice in a BALB/cJ background showed a considerable increase of depressive-like behavior in the forced swim (FST) and tail suspension test (TST) and reduced avoidance behavior in an active avoidance task. Prior conditioning with unescapable foot shocks further decreased avoidance behavior (learned helplessness) but to a similar level as in the wild type strain. IFN-α treatment was not able to further enhance the already increased level of depressive-like behavior in the FST and TST. Thus, IL-4 seems to be a critical participant in the regulation of depressive-like behavior in an untreated baseline condition. Increase of depressive-like behavior during inflammation in wild-type mice might be mediated to some extent by a reduction of IL-4 signaling.

Activation and blockade of prelimbic 5-HT6 receptors produce different effects on depressive-like behaviors in unilateral 6-hydroxydopamine-induced Parkinson's rats

The role of prelimbic (PrL) 5-HT6 receptors in depression is poorly understood, particularly in Parkinson's disease-related depression. Here we reported that 6-hydroxydopamine lesions in rats decreased sucrose preference and increased immobility time as measured by the sucrose preference and forced swim tests when compared to sham-operated rats, indicating the induction of depressive-like behaviors. Intra-PrL injection of 5-HT6 receptor agonist WAY208466 induced depressive-like responses in sham-operated rats, and produced antidepressant-like effects in the lesioned rats. However, 5-HT6 receptor antagonist SB258585 produced antidepressant-like effects in sham-operated rats, and increased the expression of depressive-like behaviors in the lesioned rats. Neurochemical results showed that intra-PrL injection of WAY208466 and SB258585 decreased or increased dopamine (DA) and noradrenaline (NA) levels in the medial prefrontal cortex, amygdala, habenula and ventral hippocampus in sham-operated and the lesioned rats, respectively. WAY208466 increased the firing rate of PrL glutamate neurons in the two groups of rats, while SB258585 decreased the firing rate of the neurons. Compared to sham-operated rats, the duration of WAY208466 and SB258585 action on the firing rate of glutamate neurons was markedly prolonged in the lesioned rats. The lesion did not change the co-localization of 5-HT6 receptor and glutamate neurons in the PrL. These findings indicate that 5-HT6 receptors in the PrL are involved in the regulation of depressive-like behaviors, which attribute to changes in DA and NA levels in the limbic and limbic-related brain regions. Additionally, the results suggest that the lesion leads to a supersensitization of 5-HT6 receptors on glutamate neurons in the PrL.

Serotonin7 receptors in the lateral habenular nucleus regulate depressive-like behaviors in the hemiparkinsonian rats

Preclinical studies indicate that serotonin7 (5-HT7) receptors may regulate depressive-like behaviors. Depression is a common symptom in Parkinson's disease (PD); however, its pathophysiology is unclear. Here we examined whether 5-HT7 receptors in the lateral habenular nucleus (LHb) involve in the regulation of PD-related depression. Unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta in rats induced depressive-like responses as measured by the sucrose preference and forced swim tests when compared to sham-operated rats. Intra-LHb injection of 5-HT7 receptor agonist AS19 (1, 2 and 4μg/rat) induced or increased the expression of depressive-like behaviors in sham-operated and the lesioned rats. Further, intra-LHb injection of 5-HT7 receptor antagonist SB269970 (1.5, 3 and 6μg/rat) produced antidepressant effects in the two groups of rats. However, the doses producing these effects in the lesioned rats were higher than those in sham-operated rats. Neurochemical results showed that intra-LHb injection of AS19 (4μg/rat) decreased dopamine and 5-HT levels in the medial prefrontal cortex, habenula and hippocampus in sham-operated and the lesioned rats; whereas SB269970 (6μg/rat) increased dopamine and 5-HT levels in these structures. In addition, noradrenaline levels in these structures were not changed after intra-LHb injection of AS19 or SB269970 in the two groups of rats. These findings suggest that activation or blockade of 5-HT7 receptors in the LHb may change the activity of LHb glutamate neurons, and then decreases or increases dopamine and 5-HT levels in the limbic and limbic-related brain regions, which are involved in the regulation of depressive-like behaviors.

Activation and blockade of serotonin7 receptors in the prelimbic cortex regulate depressive-like behaviors in a 6-hydroxydopamine-induced Parkinson’s disease rat model

The role of serotonin7 (5-HT7) receptors in the regulation of depression is poorly understood, particularly in Parkinson’s disease-associated depression. Here we examined whether 5-HT7 receptors in the prelimbic (PrL) sub-region of the ventral medial prefrontal cortex (mPFC) involve in the regulation of depressive-like behaviors in sham-operated rats and rats with unilateral 6-hydroxydopamine lesions of the medial forebrain bundle. The lesion induced depressive-like responses as measured by the sucrose preference and forced swim tests when compared to sham-operated rats. Intra-PrL injection of 5-HT7 receptor agonist AS19 (0.5, 1 and 2μg/rat) increased sucrose consumption, and decreased immobility time in sham-operated and the lesioned rats, indicating the induction of antidepressant-like effects. Further, intra-PrL injection of 5-HT7 receptor antagonist SB269970 (1.5, 3 and 6μg/rat) decreased sucrose consumption, and increased immobility time, indicating the induction of depressive-like responses. However, the doses producing these effects in the lesioned rats were higher than those in sham-operated rats. Neurochemical results showed that intra-PrL injection of AS19 (2μg/rat) increased dopamine, 5-hydroxytryptamine (5-HT) and noradrenaline (NA) levels in the mPFC, habenula and ventral hippocampus (vHip) in sham-operated and the lesioned rats; whereas SB269970 (6μg/rat) decreased 5-HT levels in the habenula and vHip, and the levels of NA in the mPFC, habenula and vHip in the two groups of rats. The results suggest that 5-HT7 receptors in the PrL play an important role in the regulation of these behaviors, which attribute to changes in monoamine levels in the limbic and limbic-related brain regions after activation and blockade of 5-HT7 receptors.

Pituitary adenylate cyclase-activating polypeptide induces a depressive-like phenotype in rats.

Major depressive disorder (MDD) is a chronic, life-threatening psychiatric condition characterized by depressed mood, psychomotor alterations, and a markedly diminished interest or pleasure in most activities known as anhedonia. Available pharmacotherapies have limited success and the need for new strategies is clear. Recent studies attribute a major role to the pituitary adenylate cyclase-activating polypeptide (PACAP) system in mediating the response to stress. PACAP knockout mice display profound alterations in depressive-like behaviors, and genetic association studies have demonstrated that genetic variants of the PACAP gene are associated with MDD. However, the effects of PACAP administration on depressive-like behaviors in rodents have not yet been systematically examined. The present study investigated the effects of central administration of PACAP in rats on depressive-like behaviors, using well-established animal models that represent some of the endophenotypes of depression. We used intracranial self-stimulation (ICSS) to assess the brain reward function, saccharin preference test to assess anhedonia, social interaction to assess social withdrawal, and forced swim test (FST) to assess behavioral despair. PACAP raised the current threshold for ICSS, elevation blocked by the PACAP antagonist PACAP(6-38). PACAP reduced the preference for a sweet saccharin solution and reduced the time the rats spent interacting with a novel animal. Interestingly, PACAP administration did not affect immobility in the FST. Our results demonstrate a role for the central PACAP/PAC1R system in the regulation of depressive-like behaviors and suggest that hyperactivity of the PACAP/PAC1R system may contribute to the pathophysiology of depression, particularly the associated anhedonic symptomatology and social dysfunction.

S.22.04 Depression and suicide following subthalamic stimulation: basic mechanisms

Preclinical studies indicate that serotonin7 (5-HT7) receptors may regulate depressive-like behaviors. Depression is a common symptom in Parkinson's disease (PD); however, its pathophysiology is unclear. Here we examined whether 5-HT7 receptors in the lateral habenular nucleus (LHb) involve in the regulation of PD-related depression. Unilateral 6-hydroxydopamine lesions of the substantia nigra pars compacta in rats induced depressive-like responses as measured by the sucrose preference and forced swim tests when compared to sham-operated rats. Intra-LHb injection of 5-HT7 receptor agonist AS19 (1, 2 and 4 μg/rat) induced or increased the expression of depressive-like behaviors in sham-operated and the lesioned rats. Further, intra-LHb injection of 5-HT7 receptor antagonist SB269970 (1.5, 3 and 6 μg/rat) produced antidepressant effects in the two groups of rats. However, the doses producing these effects in the lesioned rats were higher than those in sham-operated rats. Neurochemical results showed that intra-LHb injection of AS19 (4 μg/rat) decreased dopamine and 5-HT levels in the medial prefrontal cortex, habenula and hippocampus in sham-operated and the lesioned rats; whereas SB269970 (6 μg/rat) increased dopamine and 5-HT levels in these structures. In addition, noradrenaline levels in these structures were not changed after intra-LHb injection of AS19 or SB269970 in the two groups of rats. These findings suggest that activation or blockade of 5-HT7 receptors in the LHb may change the activity of LHb glutamate neurons, and then decreases or increases dopamine and 5-HT levels in the limbic and limbic-related brain regions, which are involved in the regulation of depressive-like behaviors.

Hippocampal CA3 calcineurin activity participates in depressive‐like behavior in rats

Calcineurin is a serine/threonine protein phosphatase that regulates neurotransmission, neuronal structure and plasticity, and neuronal excitability in mood disorders, including depression. Increasing evidence has suggested that calcineurin is involved in the regulation of depressive-like behavior. However, little is known about the neurobiological mechanisms that underlie the mood-regulating effects of calcineurin. We investigated the potential mechanism by which calcineurin mediates the development of depressive-like behavior and the involvement of calcineurin in the action of antidepressant medication in the chronic mild stress (CMS) model. The results showed that rats exposed to CMS had decreased calcineurin activity, measured by increased phospho-synapsin I S62/67 (pSynapsin) and decreased calcineurin-Aα levels, specifically in the CA3 but not CA1 or dentate gyrus (DG) subfields of the hippocampus. Calcineurin inhibition in the CA3 but not DG by microinfusion of cyclosporine-A (2 μg) induced depressive-like behavior in normal rats and exacerbated depressive-like performance in CMS-treated rats. Additionally, calcineurin inhibition in the CA3 but not DG reversed the antidepressant-like activity of venlafaxine. Calcineurin inhibition in the CA3 also reduced metabotropic glutamate 2/3 receptor (mGluR2/3) expression levels. mGluR2/3 activation by its agonist LY354740 (100 ng) in the CA3 reversed the depressive-like behavior induced by cyclosporine-A administration. Finally, chronic venlafaxine (40 mg/kg) treatment increased calcineurin activity, reflected by decreased pSynapsin and increased calcineurin-Aα protein levels in the CA3 but not CA1 or DG. These findings indicate that CA3 calcineurin signaling probably mediated through mGluR2/3 participates in the development of depression and the behavioral responses to antidepressant treatment.

CRF Receptors as a Potential Target in the Development of Novel Pharmacotherapies for Depression

Depression is a highly prevalent form of mental illness. This condition is often considered a stress-related disorder because some form of stressful life event frequently triggers depressive symptoms. Corticotropin-releasing factor (CRF) is a 41 amino acid neuropeptide involved in mediating neuroendocrine, autonomic and behavioral responses to environmental demands, and has long been considered one of the body's major regulators of the stress response. Results from clinical studies suggest that normal functioning of the CRF system is altered in patients diagnosed with depression. Two genes encoding distinct G-protein coupled CRF receptors have been identified, the CRF(1) receptor and CRF(2) receptor. Originally, the belief was that activation of the CRF system would lead to increases in the stress response. Recent characterization of the CRF receptor subtypes and CRF receptor specific ligands, however, suggests that there may be a differential regulation of stress within this system and that imbalances in receptor activation could lead to the development of stress-related psychiatric disorders. Preclinical models show evidence for increased CRF(1) receptor activity in the regulation of depressive-like behaviors, and a number of nonpeptide CRF(1) receptor antagonists have recently been developed as potential antidepressant medications. Although, the role of CRF(2) receptors remains unclear in depression, preclinical evidence suggests that under activation of this receptor may be involved in the regulation of increased depression-like behavior in animals. The present article will review the role of CRF receptors and CRF-related ligands in depression and proposes targeting the CRF system as a potential pharmacotherapy for depressive disorders.