Novelty-induced Hypophagia Research Articles

Antidepressant-like and anxiolytic-like effects following activation of the μ-δ opioid receptor heteromer in the nucleus accumbens

Treatment-resistant major depressive disorder remains inadequately treated with currently available antidepressants. Opioid receptors (ORs) are involved in the pathophysiology of depression yet remain an untapped therapeutic intervention. The μ-δ OR heteromer represents a unique signaling complex with distinct properties compared with μ- and δ-OR homomers; however, its role in depression has not been characterized. As there are no ligands exclusively targeting the μ-δ heteromer, we devised a strategy to selectively antagonize the function of the μ-δOR complex using a specific interfering peptide derived from the δOR distal carboxyl tail, a sequence implicated in μ-δOR heteromerization. In vitro studies using a minigene expressing this peptide demonstrated a loss of the unique pharmacological and trafficking properties of δ-agonists at the μ-δ heteromer, with no effect on μ- or δ-OR homomers, and a dissociation of the μ-δOR complex. Intra-accumbens administration of the TAT-conjugated interfering peptide abolished the antidepressant-like and anxiolytic-like actions of the δ-agonist UFP-512 (H-Dmt-Tic-NH-CH(CH2-COOH)-Bid) measured in the forced swim test, novelty-induced hypophagia and elevated plus maze paradigms in rats. UFP-512's antidepressant-like and anxiolytic-like actions were abolished by pretreatment with either μOR or δOR antagonists. Overall, these findings demonstrate that the μ-δ heteromer may be a potential suitable therapeutic target for treatment-resistant depression and anxiety disorders.

Increased Hippocampal Neurogenesis and Accelerated Response to Antidepressants in Mice with Specific Deletion of CREB in the Hippocampus: Role of cAMP Response-Element Modulator τ

The transcription factor cAMP response element-binding protein (CREB) has been implicated in the pathophysiology of depression as well as in the efficacy of antidepressant treatment. However, altering CREB levels appears to have differing effects on anxiety- and depression-related behaviors, depending on which brain region is examined. Furthermore, many manipulations of CREB lead to corresponding changes in other CREB family proteins, and the impact of these changes has been largely ignored. To further investigate the region-specific importance of CREB in depression-related behavior and antidepressant response, we used Creb(loxP/loxP) mice to localize CREB deletion to the hippocampus. In an assay sensitive to chronic antidepressant response, the novelty-induced hypophagia procedure, hippocampal CREB deletion, did not alter the response to chronic antidepressant treatment. In contrast, mice with hippocampal CREB deletion responded to acute antidepressant treatment in this task, and this accelerated response was accompanied by an increase in hippocampal neurogenesis. Upregulation of the CREB-family protein cAMP response-element modulator (CREM) was observed after CREB deletion. Viral overexpression of the activator isoform of CREM, CREMτ, in the hippocampus also resulted in an accelerated response to antidepressants as well as increased hippocampal neurogenesis. This is the first demonstration of CREMτ within the brain playing a role in behavior and specifically in behavioral outcomes following antidepressant treatment. The current results suggest that activation of CREMτ may provide a means to accelerate the therapeutic efficacy of current antidepressant treatment.

Divergent Functional Effects of Sazetidine-A and Varenicline During Nicotine Withdrawal

Smoking is the largest preventable cause of death in the United States. Furthermore, a recent study found that <10% of quit attempts resulted in continuous abstinence for 1 year. With the introduction of pharmacotherapies like Chantix (varenicline), a selective α4β2 nicotinic partial agonist, successful quit attempts have significantly increased. Therefore, novel subtype-specific nicotinic drugs, such as sazetidine-A, present a rich area for investigation of therapeutic potential in smoking cessation. The present studies examine the anxiety-related behavioral and functional effects of the nicotinic partial agonists varenicline and sazetidine-A during withdrawal from chronic nicotine in mice. Our studies indicate that ventral hippocampal-specific infusions of sazetidine-A, but not varenicline, are efficacious in reducing nicotine withdrawal-related anxiety-like phenotypes in the novelty-induced hypophagia (NIH) paradigm. To further investigate functional differences between these partial agonists, we utilized voltage-sensitive dye imaging (VSDi) in ventral hippocampal slices to determine the effects of sazetidine-A and varenicline in animals chronically treated with saline, nicotine, or undergoing 24 h withdrawal. These studies demonstrate a functional dissociation of varenicline and sazetidine-A on hippocampal network activity, which is directly related to previous drug exposure. Furthermore, the effects of the nicotinic partial agonists in VSDi assays are significantly correlated with their behavioral effects in the NIH test. These findings highlight the importance of drug history in understanding the mechanisms through which nicotinic compounds may be aiding smoking cessation in individuals experiencing withdrawal-associated anxiety.

Serotonin 2C receptor antagonism ameliorates novelty-induced hypophagia in aged mice

This study was conducted to clarify the role of serotonin (5-hydroxytryptamine, 5-HT) 2C receptor (5-HT2CR) signaling during novelty-induced hypophagia in aged mice. Male C57BL/6J mice [6-week-old (young) and 79-80-week-old (aged) mice] were exposed to a novel environment, and its effects on feeding behavior, stress hormones, and appetite-related factors were examined. Exposure of aged mice to a novel environment suppressed food intake and increased corticosterone secretion. These responses were marked compared with those in young mice. The expression in hypothalamic corticotropin-releasing factor (CRF), pituitary CRF1R and proopiomelanocortin mRNA in aged mice exposed to a novel environment was increased or tended to increase, compared to control mice. 5-HT2CR antagonist, SB242084 or rikkunshito administration attenuated the decrease in food intake and increased stress hormone levels in aged mice exposed to the environmental change. The 5-HT2CR mRNA expression in paraventricular nucleus was significantly enhanced, when aged mice was exposure to the novel environment. Thus, novelty-induced hypophagia in aged mice resulted, at least in part, from up-regulated hypothalamic 5-HT2CR function. In conclusion, 5-HT2CR signaling enhancement and the subsequent activation of the CRF neuron were involved in novelty-induced hypophagia in aged mice, and the 5-HT2CR antagonists offer a promising therapeutic option for depression.

The tryptophan hydroxylase 2 (Tph2) polymorphism C2432T mediates mRNA expression and responses to antidepressant treatment in a sex‐specific manner

The mechanisms behind successful treatment response in Major Depressive Disorder remain unclear. We examined whether a novel single nucleotide polymorphism (SNP) C2432T in the Tph2 gene mediates differences in response to SSRIs between two mouse strains: MRL/MpJ (MRL; SSRI‐responding, T/T) versus C57Bl/6J (C57; SSRI‐nonresponding, C/C) (Balu et al, 2009). We cross‐bred the MRL and C57 strains to isolate C2432T in the F2 generation and determined functionality using the response to SSRIs in the tail suspension test (TST). F2 T/T females showed an enhanced citalopram response (p&lt;0.001, n=10), while males showed no genotype‐specific effects. The C2432T SNP also mediated Tph2 mRNA expression, with T/T animals showing increased expression in the midbrain (p&lt;0.05, n=11–16). However, in response to chronic SSRI treatment, there was no difference by genotype in F2 generation animals in measures of hippocampal neurogenesis or novelty‐induced hypophagia behavior. The C2432T SNP may mediate serotonin involvement to acute antidepressant response in a sex‐specific manner, but did not mediate the effects of chronic antidepressant treatment.

Dissociable effects of CB1 receptor blockade on anxiety-like and consummatory behaviors in the novelty-induced hypophagia test in mice

Central CB1 cannabinoid receptors regulate anxiety-like and appetitive consummatory behaviors. Pharmacological antagonism/inverse-agonism of CB1 receptors increases anxiety and decreases appetitive behaviors; however, neither well-defined dose nor context dependence of these effects has been simultaneously assessed in one behavioral assay. We sought to determine the context and dose dependence of the effects of CB1 receptor blockade on anxiety-like and consummatory behaviors in a model that allowed for simultaneous detection of anxiety-like and consummatory-related behaviors. We determined the effects of the CB1 receptor antagonist/inverse-agonist, rimonabant, in the novelty-induced hypophagia (NIH) assay in juvenile male ICR mice. Rimonabant dose-dependently decreased consumption of a palatable reward solution completely independent of contextual novelty. Grooming and scratching behavior was also increased by rimonabant in a context-independent manner. In contrast, rimonabant increased feeding latency, a measure of anxiety-like behaviors, only in a novel, mildly anxiogenic context. The effects of rimonabant were specific since no effects of rimonabant on despair-like behavior were observed in the tail suspension assay. Blockade of CB2 receptors had no effect on novelty-induced increases in feeding latency or palatable food consumption. Our findings indicate that CB1 receptor blockade decreases the hedonic value of palatable food irrespective of environmental novelty, whereas the anxiogenic-like effects are highly context-dependent. Blockade of CB2 receptors does not regulate either anxiety-like or consummatory behaviors in the NIH assay. These findings suggest that rimonabant modulates distinct and dissociable neural processes regulating anxiety and consummatory behavior to sculpt complex and context-dependent behavioral repertories.

Lithium augmentation of the effects of desipramine in a mouse model of treatment-resistant depression: A role for hippocampal cell proliferation

Approximately 50% of patients with a major depressive episode fail to achieve remission with first-line antidepressant treatments. Second-line treatment strategies for such patients include lithium augmentation of antidepressants, particularly with tricyclic antidepressants. The neurobiological mechanisms underlying the therapeutic effects of lithium augmentation are not yet fully understood. Unravelling these mechanisms could aid the development of more effective antidepressant drugs. In the present study, we investigated whether chronic treatment with a combination of lithium and the tricyclic antidepressant, desipramine, could produce antidepressant-like behaviour in a mouse strain (BALB/cOLaHsd) that exhibited reduced sensitivity to the behavioural effects of chronic desipramine treatment in the novelty-induced hypophagia test. Since chronic treatment with antidepressant drugs increases the proliferation of newly-born cells in the hippocampus, and hippocampal cell proliferation is required for the behavioural effects of at least some antidepressants in neohypophagia tests, the present study also investigated whether lithium plus desipramine increased cell proliferation in the hippocampus. Chronic treatment with lithium plus desipramine but neither drug alone, induced antidepressant-like behaviour and increased hippocampal cell proliferation, thus suggesting that increased hippocampal cell proliferation may be a mechanism underlying lithium augmentation of antidepressants. Moreover, since BALB/cOLaHsd mice respond to lithium plus desipramine but not to either drug alone, they may become useful in the development of a mouse model of treatment-refractory depression for which there is an unmet need.

Deletion of CREB-Regulated Transcription Coactivator 1 Induces Pathological Aggression, Depression-Related Behaviors, and Neuroplasticity Genes Dysregulation in Mice

Mood disorders are polygenic disorders in which the alteration of several susceptibility genes results in dysfunctional mood regulation. However, the molecular mechanisms underlying their transcriptional dysregulation are still unclear. The transcription factor cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) and the neurotrophin brain-derived neurotrophic factor (BDNF) have been implicated in rodent models of depression. We previously provided evidence that Bdnf expression critically rely on a potent CREB coactivator called CREB-regulated transcription coactivator 1 (CRTC1). To further evaluate the role of CRTC1 in the brain, we generated a knockout mouse line and analyzed its behavioral and molecular phenotype. We found that mice lacking CRTC1 associate neurobehavioral endophenotypes related to mood disorders. Crtc1(-/-) mice exhibit impulsive aggressiveness, social withdrawal, and decreased sexual motivation, together with increased behavioral despair, anhedonia, and anxiety-related behavior in the novelty-induced hypophagia test. They also present psychomotor retardation as well as increased emotional response to stressful events. Crtc1(-/-) mice have a blunted response to the antidepressant fluoxetine in behavioral despair paradigms, whereas fluoxetine normalizes their aggressiveness and their behavioral response in the novelty-induced hypophagia test. Crtc1(-/-) mice strikingly show, in addition to a reduced dopamine and serotonin turnover in the prefrontal cortex, a concomitant decreased expression of several susceptibility genes involved in neuroplasticity, including Bdnf, its receptor TrkB, the nuclear receptors Nr4a1-3, and several other CREB-regulated genes. Collectively, these findings support a role for the CRTC1-CREB pathway in mood disorders etiology and behavioral response to antidepressants and identify CRTC1 as an essential coactivator of genes involved in mood regulation.

Running‐induced anxiety is dependent on increases in hippocampal neurogenesis

Exercise, specifically voluntary wheel running, is a potent stimulator of hippocampal neurogenesis in adult mice. In addition, exercise induces behavioral changes in numerous measures of anxiety in rodents. However, the physiological underpinnings of these changes are poorly understood. To investigate the role of neurogenesis in exercise-mediated anxiety, we examined the cellular and behavioral effects of voluntary wheel running in mice with a reduction in hippocampal neurogenesis, achieved through conditional deletion of ataxia telangiectasia-mutated and rad-3-related protein (ATR), a cell cycle checkpoint kinase necessary for normal levels of neurogenesis. Following hippocampal microinjection of an adeno-associated virus expressing Cre recombinase to delete ATR, mice were exposed to 4 weeks of voluntary wheel running and subsequently evaluated for anxiety-like behavior. Wheel running resulted in increased cell proliferation and neurogenesis, as measured by bromodeoxyuridine and doublecortin, respectively. Wheel running also resulted in heightened anxiety in the novelty-induced hypophagia, open field and light-dark box tests. However, both the neurogenic and anxiogenic effects of wheel running were attenuated following hippocampal ATR deletion, suggesting that increased neurogenesis is an important mediator of exercise-induced anxiety.

RGS4 as a regulator of the antidepressant effects of SSRIs

Previously, we showed that RGS‐insensitive Gαi2G184S (Gαi2GS) mice exhibit basal and serotonin‐dependent antidepressant (AD) phenotypes. Here we show that acute (3‐day) administration of the serotonin selective reuptake inhibitor (SSRI) fluoxetine (FLX) produced AD‐like responses in Gαi2GS mice in the novelty‐induced hypophagia test, which requires chronic (21‐day) FLX to produce AD effects in wild‐type (WT) animals. In contrast, acute desipramine, a norepinephrine‐based antidepressant, had no effect. The AD efficacy of FLX in acutely treated Gαi2GS mice was twice that of chronically treated WT littermates. Also, Gαi2GS mice exhibited basal and selective 4‐fold upregulation of cortical RGS4 vs. WT mice. mRNA expression of eleven RGS proteins in the cortex and hippocampus by RT‐PCR showed chronic FLX selectively upregulated cortical RGS4 in WT mice. Notably, vehicle‐treated Gαi2GS mice showed similar regional and RGS‐selective upregulation of cortical RGS4 mRNA and protein. These are the first studies of which we are aware to show altered expression of RGS proteins in response to SSRIs. Overall, these data suggest RGS insensitivity improves the efficacy and onset of action of SSRIs in animal models of mood. Moreover, upregulation of cortical RGS4 may contribute to the AD phenotype of Gαi2GS animals and to the therapeutic effects of SSRIs. Supported by DA04087 and the Bower Bennett Bennett Endowment.

Acute Pain and a Motivational Pathway in Adult Rats: Influence of Early Life Pain Experience

BackgroundThe importance of neonatal experience upon behaviour in later life is increasingly recognised. The overlap between pain and reward pathways led us to hypothesise that neonatal pain experience influences reward-related pathways and behaviours in adulthood.Methodology/Principal FindingsRat pups received repeat plantar skin incisions (neonatal IN) or control procedures (neonatal anesthesia only, AN) at postnatal days (P)3, 10 and 17. When adult, rats with neonatal ‘pain history’ showed greater sensory sensitivity than control rats following acute plantar skin incision. Motivational behaviour in the two groups of rats was tested in a novelty-induced hypophagia (NIH) paradigm. The sensitivity of this paradigm to pain-induced changes in motivational behaviour was shown by significant increases in the time spent in the central zone of the arena (43.7±5.9% vs. 22.5±6.7%, p<0.05), close to centrally placed food treats, and decreased number of rears (9.5±1.4 vs. 19.2±2.3, p<0.001) in rats with acute plantar skin incision compared to naive, uninjured animals. Rats with a neonatal ‘pain history’ showed the same pain-induced behaviour in the novelty-induced hypophagia paradigm as controls. However, differences were observed in reward-related neural activity between the two groups. Two hours after behavioural testing, brains were harvested and neuronal activity mapped using c-Fos expression in lateral hypothalamic orexin neurons, part of a specific reward seeking pathway. Pain-induced activity in orexin neurons of control rats (18.4±2.8%) was the same as in uninjured naive animals (15.5±2.6%), but in those rats with a ‘pain history’, orexinergic activity was significantly increased (27.2±4.1%, p<0.01). Furthermore the extent of orexin neuron activation in individual rats with a ‘pain history’ was highly correlated with their motivational behaviour (r = −0.86, p = 0.01).Conclusions/SignificanceThese results show that acute pain alters motivational behaviour and that neonatal pain experience causes long-term changes in brain motivational orexinergic pathways, known to modulate mesolimbic dopaminergic reward circuitry.

Social isolation produces anxiety-like behaviors and changes PSD-95 levels in the forebrain

Isolation rearing induces profound behavioral and neurochemical abnormalities in rodents. However there have been many controversies with its anxiogenic-like effects using models like elevated-plus maze. In the current study we aimed to address this by using one novelty-based anxiety paradigm that has been largely overlooked in previous isolation rearing studies. We found that eight-week isolation rearing produced potent anxiogenic-like effects in novelty-induced hypophagia test in mice. We also demonstrated PSD-95 levels were elevated in the hippocampus and amygdala and reduced in the frontal cortex after social isolation. This study provides further behavioral and neurochemical evidence to support that isolation rearing can produce anxiogenic-like effects in rodents.

Further characterization of the prototypical nociceptin/orphanin FQ peptide receptor agonist Ro 64-6198 in rodent models of conflict anxiety and despair

Ro 64-6198, the prototypical non-peptide nociceptin/orphanin FQ peptide (NOP) receptor agonist, has potent anxiolytic-like effects in several preclinical models and species. However the effects of Ro 64-6198 on distinctive anxiety-provoking conditions related to unconditioned conflict behavior as well as its role in despair-like behavior remain to be addressed. Here we examined the effects of Ro 64-6198 on unconditioned conflict anxiety using stimuli with different salience and on regulation of autonomic reactivity and compared these to the effects of benzodiazepine receptor agonists. We also addressed the potential effects of Ro 64-6198 on despair-like behavior. Ro 64-6198 (0.1 to 10 mg/kg i.p.) and either diazepam or chlordiazepoxide were tested in the Vogel conflict punished drinking test (VCT) in Sprague Dawley rats, in the social approach-avoidance (SAA) test in Lewis rats, in the novelty-induced hypophagia (NIH) in C57BL/6J mice, and in stress-induced hyperthermia in NMRI mice, as well as in the forced swim test (FST) in Sprague Dawley rats and the tail suspension test (TST) in C57BL/6J mice. Ro 64-6198 (0.3 to 3 mg/kg) dose-dependently produced anxiolytic-like effects in the VCT, SAA, NIH, and SIH, similar to benzodiazepine receptor agonists. Ro 64-6198 did not alter immobility time in the FST and TST. Ro 64-6198 produced marked anxiolytic-like effects in response to a variety of mild to strong anxiogenic stimuli, whereas it did not facilitate depression-related behaviors. This data extend previous literature suggesting that NOP receptors are a viable target for the treatment of anxiety disorders.

Genetic, pharmacological and lesion analyses reveal a selective role for corticohippocampal GLUN2B in a novel repeated swim stress paradigm

Glutamate and N-methyl-d-aspartate receptor (NMDAR) dysfunction is strongly implicated in the pathophysiology of mood and anxiety disorders. Treatment with NMDAR antagonists has antidepressant efficacy in treatment-resistant depressives. In preclinical rodent models, NMDAR antagonist administration reduces anxiety- and stress-related behaviors in concert with increases in prefrontal cortical (PFC) dendritic spinogenesis and synaptic proteins. While these effects have been attributed to actions at the NMDAR GluN2B subunit, the precise role of cortical GluN2B in mediating emotional behaviors and stress-responsivity is not fully understood. Here, we employed a novel mutant model in which the GluN2B subunit is postnatally deleted in principal neurons in the cortex and the dorsal CA1 subregion of the hippocampus. GluN2BKO mice were phenotyped on a battery of tests for anxiety-related (light/dark exploration, stress-induced hyperthermia) and antidepressant-sensitive (sucrose preference, novelty-induced hypophagia, single-trial forced swim) behaviors. A novel repeated inescapable forced swim paradigm (riFS) was developed to assess behavioral responses to repeated stress in the GluN2BKO mice. For comparison, non-mutant C57BL/6J mice were tested for single-trial forced swim behavior after systemic Ro 25-6981 treatment and for riFS behavior after lesions of the ventromedial prefrontal cortex. riFS-induced alterations in corticolimbic GluN2B expression were also examined in C57BL/6J mice. We found that GluN2BKO mice reduced "despair-like" behavior in the riFS procedure, as compared to GluN2BFLOX controls. By contrast, GluN2BKO mice showed minimal alterations on anxiety-like or antidepressant-sensitive assays, including the single-trial forced swim test. In C57BL/6J mice, induction of "despair-like" responses in the riFS test was attenuated by vmPFC lesions, and was associated with changes in limbic GluN2B expression. Collectively, these data suggest that cortical GluN2B plays a major role in modulating adaptive responses to stress. Current findings provide further support for GluN2B as a key mechanism underlying stress responsivity, and a novel pharmacotherapeutic target for stress-related neuropsychiatric disorders.

Strain Differences Determine the Response to Citalopram on Hippocampal Neurogenesis, Neurotrophin Mobilization and Behavior

The objective of this study is to examine strain differences on measures of antidepressant‐related behavior and hippocampal neurogenesis in response to chronic treatment with the selective serotonin reuptake inhibitor citalopram. MRL/MpJ mice, known for superior wound healing and resilience to stress, were compared with C57Bl/6J mice on responses to chronic infusion of the selective serotonin reuptake inhibitor citalopram (5 mg/kg/day for 21 days). The animals were then evaluated in the novelty‐induced hypophagia (NIH) test and examined for increased hippocampal cell proliferation after BrdU labeling by flow cytometry. Exposure to chronic citalopram significantly reduced the latency to approach food in a novel environment in the NIH paradigm in the MRL/MpJ mouse strain but had no effect on approach latency in C57Bl/6J mice. MRL/MpJ mice also showed increased cell proliferation and increased BDNF levels in response to citalopram treatment, while C57Bl/6J mice showed no significant change in cell proliferation or BDNF levels. Overall, MRL/MpJ mice showed a significant behavioral and neurobiological response to citalopram, in contrast to the C57Bl/6J strain. These results indicate that strain differences strongly impact responses to chronic citalopram. Future studies will determine the mechanisms of antidepressant action in these mice.This research was supported by USPHS T32 MH14654 and R01 MH72832.

Selective Deletion of a Cell Cycle Checkpoint Kinase (ATR) Reduces Neurogenesis and Alters Responses in Rodent Models of Behavioral Affect

Hippocampal function has been implicated in mood and anxiety disorders, as well as in the response to antidepressant (AD) treatment. However, the significance of new neurons in the therapeutic mechanism of ADs remains unclear. In this study, the proliferation of new neurons was inhibited through conditional deletion of ataxia telangeictasia-mutated and rad-3 related (ATR), a cell cycle checkpoint kinase, and cellular and behavioral outcomes following AD exposure were evaluated. ATR was conditionally deleted by microinjecting a Cre recombinase-expressing virus into the hippocampus of floxed-ATR mice. Behavioral assessment in multiple rodent models of affective state revealed anxiolytic-like behavior in the elevated zero maze, marble burying test, and novelty-induced hypophagia (NIH) test. The efficacy of chronic desipramine (DMI) treatment was evaluated in the NIH test, as this paradigm is thought to be sensitive to increases in neurogenesis by chronic AD exposure. Chronic exposure to DMI reduced hyponeophagia in the NIH test in control mice, whereas DMI had no behavioral effect in ATR-deleted mice. Although DMI did not alter cell proliferation in either group, it did produce a robust increase in dendritic spine density in control mice, indicative of enhanced neuronal plasticity. This effect of DMI on spine density was severely attenuated following ATR deletion. These findings demonstrate that reductions in basal neurogenesis produce an anxiolytic phenotype and reduce AD efficacy in behaviors requiring chronic exposure. Furthermore, attenuated capacity for synaptic remodeling may underlie these behaviors. ATR deletion may serve as a valuable model to study the various proposed roles of newborn neurons in the hippocampus.

Inactivation of fibroblast growth factor binding protein 3 causes anxiety-related behaviors

The neurobiological mechanisms of emotional modulation and the molecular pathophysiology of anxiety disorders are largely unknown. The fibroblast growth factor (FGF) family has been implicated in the regulation of many physiological and pathological processes, which include the control of emotional behaviors. The present study examined mice with a targeted deletion of the fgf-bp3 gene, which encodes a novel FGF-binding protein, in animal models relevant to anxiety. To define the behavioral consequences of FGF-BP3 deficiency, we evaluated fgf-bp3-deficient mice using anxiety-related behavioral paradigms that provide a conflict between the desire to explore an unknown area or objects and the aversion to a brightly lit open space. The fgf-bp3-deficient mice exhibited alterations in time spent in the central area of the open-field arena, were less active in the lit areas of a light/dark transition test, and had a prolonged latency to feed during a novelty-induced hypophagia test. These changes were associated with alterations in light-induced orbitofrontal cortex (OFC) activation in an extracellular signal-regulated kinase (ERK) pathway-dependent manner. These results demonstrate that FGF-BP3 is a potent mediator of anxiety-related behaviors in mice and suggest that distinct pathways regulate emotional behaviors. Therefore, FGF-BP3 plays a critical role in the regulation of emotional states and in the development of anxiety disorders and should be investigated as a therapeutic target for anxiety disease in humans.

Fluoxetine treatment induces dose dependent alterations in depression associated behavior and neural plasticity in female mice

Antidepressant-induced increases in neurogenesis and neurotrophin mobilization in rodents and primates are proposed to be necessary for behavioral efficacy. The current study examines the relationship between the effects of fluoxetine treatment on behavior, cell proliferation and the neurotrophin BDNF in females. Female MRL/MpJ mice were treated acutely (5 and 10 mg/kg) or chronically (2.5, 5 and 10 mg/kg b.i.d.) with fluoxetine and tested in the tail suspension test (TST) and or novelty-induced hypophagia test (NIH), respectively. Mice treated chronically with fluoxetine received 4 (100 mg/kg) injections of 5-bromo-2′-deoxyuridine (BrdU) on the last 4 days of treatment to measure DNA synthesis. The other half of the hippocampus and the frontal cortex was removed and examined for BDNF levels. Fluoxetine treatment decreased immobility in the TST and latency to eat in the NIH test, but only the highest dose of fluoxetine significantly altered behavior in both tests. Chronic treatment with 5 and 10 mg/kg of fluoxetine significantly increased cell proliferation and BDNF levels in the hippocampus. Only chronic treatment with the highest of fluoxetine increased BDNF levels in the frontal cortex. Behavioral measures in the NIH test correlated with BDNF levels in the frontal cortex but not in the hippocampus or with cell proliferation in the hippocampus. These data suggest that females require high doses of fluoxetine for behavioral efficacy regardless of elevations of neurogenesis and BDNF mobilization in the hippocampus. Elevations in BDNF levels in the frontal cortex are related to the behavioral efficacy of fluoxetine.

Peripheral BDNF Produces Antidepressant-Like Effects in Cellular and Behavioral Models

Recent clinical studies demonstrate that serum levels of brain-derived neurotrophic factor (BDNF) are significantly decreased in patients with major depressive disorder (MDD) and that antidepressant treatments reverse this effect, indicating that serum BDNF is a biomarker of MDD. These findings raise the possibility that serum BDNF may also have effects on neuronal activity and behavior, but the functional significance of altered serum BDNF is unknown. To address this issue, we determined the influence of peripheral BDNF administration on depression- and anxiety-like behavior, including the forced swim test (FST), chronic unpredictable stress (CUS)/anhedonia, novelty-induced hypophagia (NIH) test, and elevated-plus maze (EPM). Furthermore, we examined adult hippocampal neurogenesis as well as hippocampal and striatal expression of BDNF, extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB), in order to determine whether peripherally administered BDNF produces antidepressant-like cellular responses in the brain. Peripheral BDNF administration increased mobility in the FST, attenuated the effects of CUS on sucrose consumption, decreased latency in the NIH test, and increased time spent in the open arms of an EPM. Moreover, adult hippocampal neurogenesis was increased after chronic, peripheral BDNF administration. We also found that BDNF levels as well as expression of pCREB and pERK were elevated in the hippocampus of adult mice receiving peripheral BDNF. Taken together, these results indicate that peripheral/serum BDNF may not only represent a biomarker of MDD, but also have functional consequences on molecular signaling substrates, neurogenesis, and behavior.

The Neuropeptide VGF Is Reduced in Human Bipolar Postmortem Brain and Contributes to Some of the Behavioral and Molecular Effects of Lithium

Recent studies demonstrate that the neuropeptide VGF (nonacronymic) is regulated in the hippocampus by antidepressant therapies and animal models of depression and that acute VGF treatment has antidepressant-like activity in animal paradigms. However, the role of VGF in human psychiatric disorders is unknown. We now demonstrate using in situ hybridization that VGF is downregulated in bipolar disorder in the CA region of the hippocampus and Brodmann's area 9 of the prefrontal cortex. The mechanism of VGF in relation to LiCl was explored. Both LiCl intraperitoneally and VGF intracerebroventricularly reduced latency to drink in novelty-induced hypophagia, and LiCl was not effective in VGF(+/-) mice, suggesting that VGF may contribute to the effects of LiCl in this behavioral procedure that responds to chronic antidepressant treatment. VGF by intrahippocampal injection also had novel activity in an amphetamine-induced hyperlocomotion assay, thus mimicking the actions of LiCl injected intraperitoneally in a system that phenocopies manic-like behavior. Moreover, VGF(+/-) mice exhibited increased locomotion after amphetamine treatment and did not respond to LiCl, suggesting that VGF is required for the effects of LiCl in curbing the response to amphetamine. Finally, VGF delivered intracerebroventricularly in vivo activated the same signaling pathways as LiCl and is necessary for the induction of mitogen-activated protein kinase and Akt by LiCl, thus lending insight into the molecular mechanisms underlying the actions of VGF. The dysregulation of VGF in bipolar disorder as well as the behavioral effects of the neuropeptide similar to LiCl suggests that VGF may underlie the pathophysiology of bipolar disorder.