Porsolt Forced Swim Test Research Articles

The behavioral and biochemical effects of BDNF containing polymers implanted in the hippocampus of rats

Brain-derived neurotrophic factor (BDNF) is closely linked with neuronal survival and plasticity in psychiatric disorders. In this work, we engineered degradable, injectable alginate microspheres and non-degradable, implantable poly(ethylene vinyl acetate) matrices to continuously deliver BDNF to the dorsal hippocampus of rats for two days or more than a week, respectively. The antidepressant-like behavioral effects of BDNF delivery were examined in the Porsolt forced swim test. Rats were sacrificed 10 days after surgery and tissue samples were analyzed by western blot. A small dose of BDNF delivered in a single infusion, or from a two-day sustained-release alginate implant, produced an antidepressant-like behavior, whereas the same dose delivered over a longer period of time to a larger tissue region did not produce antidepressant-like effects. Prolonged delivery of BDNF resulted in a dysregulation of plasticity-related functions: increased dose and duration of BDNF delivery produced increased levels of TrkB, ERK, CREB, and phosphorylated ERK, while also producing decreased phosphorylated CREB. It is evident from this work that both duration and magnitude of BDNF dosing are of critical importance in achieving functional outcome.

Knockout mice in understanding the mechanism of action of lithium

Lithium inhibits IMPase (inositol monophosphatase) activity, as well as inositol transporter function. To determine whether one or more of these mechanisms might underlie lithium's behavioural effects, we studied Impa1 (encoding IMPase) and Smit1 (sodium-myo-inositol transporter 1)-knockout mice. In brains of adult homozygous Impa1-knockout mice, IMPase activity was found to be decreased; however, inositol levels were not found to be altered. Behavioural analysis indicated decreased immobility in the forced-swim test as well as a strongly increased sensitivity to pilocarpine-induced seizures. These are behaviours robustly induced by lithium. In homozygous Smit1-knockout mice, free inositol levels were decreased in the frontal cortex and hippocampus. These animals behave like lithium-treated animals in the model of pilocarpine seizures and in the Porsolt forced-swim test model of depression. In contrast with O'Brien et al. [O'Brien, Harper, Jove, Woodgett, Maretto, Piccolo and Klein (2004) J. Neurosci. 24, 6791-6798], we could not confirm that heterozygous Gsk3b (glycogen synthase kinase 3beta)-knockout mice exhibit decreased immobility in the Porsolt forced-swim test or decreased amphetamine-induced hyperactivity in a manner mimicking lithium's behavioural effects. These data support the role of inositol-related processes rather than GSK3beta in the mechanism of the therapeutic action of lithium.

Direct and dam-mediated effects of prenatal dexamethasone on emotionality, cognition and HPA axis in adult Wistar rats

Prenatal stress can affect foetal neurodevelopment and result in increased risk of depression in adulthood. It promotes increased maternal hypothalamo–pituitary–adrenal gland (HPA) secretion of glucocorticoid (GC), leading to increased foetal and maternal GC receptor activity. Prenatal GC receptor activity is also increased during prenatal treatment with dexamethasone (DEX), which is commonly prescribed as a prophylactic treatment of preterm delivery associated morbid symptoms. Here, we exposed pregnant Wistar rats to 0.1 mg/kg/d DEX during the last week of pregnancy and performed cross-fostering at birth. In the adult offspring we then studied the effects of prenatal DEX exposure per se and the effects of rearing by a dam exposed to prenatal DEX. Offspring were assessed in the following paradigms testing biobehavioural processes that are altered in depression: progressive ratio schedule of reinforcement (anhedonia), Porsolt forced swim test (behavioural despair), US pre-exposure active avoidance (learned helplessness), Morris water maze (spatial memory) and HPA axis activity (altered HPA function). Responsiveness to a physical stressor in terms of HPA activity was increased in male offspring exposed prenatally to DEX. Despite this increased HPA axis reactivity, we observed no alteration of the assessed behaviours in offspring exposed prenatally to DEX. We observed impairment in spatial memory in offspring reared by DEX exposed dams, independently of prenatal treatment. This study does not support the hypothesis that prenatal DEX exposure leads to depression-like symptoms in rats, despite the observed sex-specific programming effect on HPA axis. It does however emphasise the importance of rearing environment on adult cognitive performances.

Melatonin Modulates Cell Survival of New Neurons in the Hippocampus of Adult Mice

Regulation of adult hippocampal neurogenesis is influenced by circadian rhythm, affected by the manipulation of sleep, and is disturbed in animal models of affective disorders. These observations and the link between dysregulation of the circadian production of melatonin and neuropsychiatric disorders prompted us to investigate the potential role of melatonin in controlling adult hippocampal neurogenesis. In vitro, melatonin increased the number of new neurons derived from adult hippocampal neural precursor cells in vitro by promoting cell survival. This effect was partially dependent on the activation of melatonin receptors as it could be blocked by the application of receptor antagonist luzindole. There was no effect of melatonin on cell proliferation. Similarly, in the dentate gyrus of adult C57BL/6 mice in vivo, exogenous melatonin (8 mg/kg) also increased the survival of neuronal progenitor cells and post-mitotic immature neurons. Melatonin did not affect precursor cell proliferation in vivo and also did not influence neuronal and glial cell maturation. Moreover, melatonin showed antidepressant-like effects in the Porsolt forced swim test. These results indicate that melatonin through its receptor can modulate the survival of newborn neurons in the adult hippocampus, making it the first known exogenously applicable substance with such specificity.

Prenatal Equol Treatment: Does Not Alter Newborn Genital Development but Alters Depressive‐like Behaviors in Pre‐pubertal Offspring.

In this study we examined equol, the intestinal metabolite of daidzein, and its effects on genital morphology and subsequent postnatal behavior. Pregnant rats were divided into six treatment groups before subcutaneous injection treatments: 1) Non‐injected Controls, 2) dimethyl sulfoxide (DMSO)‐injected controls, 3) Equol at 10.5 mg/Kg (in DMSO), 4) Equol at 21.0 mg/Kg (in DMSO), 5) Equol at 63.0 mg/Kg (in DMSO), and 6) Flutamide (90 mg/Kg, androgen‐receptor blocker). The mothers received daily treatment injections from gestational days 14‐20. After birth, body weight and anogenital distance (AGD) were measured and sex determined. Some of the pups and mothers (a subset at birth) were sacrificed and trunk blood collected for determining isoflavone and 5alpha‐dihydrotestosterone (5alpha‐DHT) levels. The remainder of the pups developed postnatally until day 29 where animals underwent analysis via the Porsolt forced swim test to determine depressive‐like behaviors. In summary, equol exposure during late pregnancy 1) does not alter 5alpha‐DHT levels in the males or females or alter male external genital development, 2) the high equol dosed mothers weighed the least before and after birth and their offspring also weighed the least at birth, and 3) after birth the high dosed equol treated animals that gained the most weight postnatally displayed the least depressive‐like behaviors. (USDA 2004‐01811)

Differential behavioral and neurochemical effects of exercise, reboxetine and citalopram with the forced swim test

Aims In this study, we investigated whether short-term exercise, known to promote hippocampal brain-derived neurotrophic factor (BDNF) expression, would also enhance activity in the Porsolt forced swim test (FST), a model for assessing antidepressant efficacy. We also wished to determine whether exercise combined with antidepressants would be more effective at modifying behavior in the FST than either intervention alone. In parallel with this, we also expected that these interventions would preserve post-stress levels of BDNF, and that antidepressants designed to selectively enhance noradrenergic or serotonergic neurotransmission (reboxetine or citalopram, respectively) would have differential effects on behavior and BDNF expression. Main methods Male Sprague-Dawley rats were treated with exercise (voluntary wheel running), reboxetine, citalopram, or the combination of exercise and each antidepressant, for 1 week. At the end of this period, a subset of animals from each treatment group underwent the FST. Post-stress levels of hippocampal BDNF mRNA were then quantified via in situ hybridization. Key findings Our results indicate that while both exercise and antidepressant treatment preserved post-stress levels of hippocampal BDNF mRNA, each intervention led to a unique behavioral profile in the FST. We found that antidepressant treatment increased swimming time in the FST, but that exercise decreased swimming time. While the combination of reboxetine-plus-exercise led to an increase in climbing and diving, citalopram-plus-exercise reduced these behaviors. Significance It is possible that active behaviors during the FST, though specific to antidepressant medications, may not reflect increased hippocampal BDNF expression or other survival- associated benefits.

Nortriptyline mediates behavioral effects without affecting hippocampal cytogenesis in a genetic rat depression model

A prevailing hypothesis is that neurogenesis is reduced in depression and that the common mechanism for antidepressant treatments is to increase it in adult hippocampus. Reduced neurogenesis has been shown in healthy rats exposed to stress, but it has not yet been demonstrated in depressed patients. Emerging studies now indicate that selective serotonin reuptake inhibitors can, exert behavioral effects without affecting neurogenesis in mice. Here we extend our previous findings demonstrating that the number of BrdU positive cells in hippocampus was significantly higher in a rat model of depression, the Flinders Sensitive Line (FSL) compared to the control strain the Flinders Resistant Line (FRL). We also show that chronic treatment with the tricyclic antidepressant nortriptyline exerts behavioral effects in the Porsolt forced swim test without affecting hippocampal cell proliferation in the FSL model. These results strengthen the arguments against hypothesis of neurogenesis being necessary in etiology of depression and as requisite for effects of antidepressants, and illustrate the importance of using a disease model and not healthy animals to assess effects of potential therapies for major depressive disorder.

Affective and cognitive effects of global deletion of α3-containing gamma-aminobutyric acid-A receptors

Gamma-aminobutyric acid (GABA)A receptors characterized by the presence of the alpha3 subunit are the major GABAA receptor subtype expressed in brain stem monoaminergic nuclei. These alpha3-GABAA receptors are therefore in a unique position to regulate monoaminergic functions. To characterize the functional properties of alpha3-GABAA receptors, we present a preliminary assessment of the expression of affective and cognitive behaviour in male mice with a targeted deletion of the Gabra3 gene encoding the alpha3 subunit [alpha3 knockout (KO) mice] on a C57BL/6Jx129X1/SvJ F1 hybrid genetic background. The alpha3 KO mice did not exhibit any gross change of anxiety-like behaviour or spontaneous locomotor behaviour. In the Porsolt forced swim test for potential antidepressant activity, alpha3 KO mice exhibited reduced floating and enhanced swimming behaviour relative to wild-type controls. Performance on a two-choice sucrose preference test, however, revealed no evidence for an increase in sucrose preference in the alpha3 KO mice that would have substantiated a potential phenotype for depression-related behaviour. In contrast, a suggestion of an enhanced negative contrast effect was revealed in a one-bottle sucrose consumption test across different sucrose concentrations. These affective phenotypes were accompanied by alterations in the balance between conditioned responding to the discrete conditioned stimulus and to the context, and a suggestion of faster extinction, in the Pavlovian conditioned freezing paradigm. Spatial learning in the water maze reference memory test, however, was largely unchanged in the alpha3 KO mice, except for a trend of preservation during reversal learning. The novel phenotypes following global deletion of the GABAA receptor alpha3 subunit identified here provided relevant insights, in addition to our earlier study, into the potential behavioural relevance of this specific receptor subtypes in the modulation of both affective and cognitive functions.

Risperidone, an atypical antipsychotic enhances the antidepressant-like effect of venlafaxine or fluoxetine: Possible involvement of alpha-2 adrenergic receptors

Clinical studies have reported the beneficial outcome of addition of lower doses of risperidone to antidepressant therapy specifically with selective serotonin reuptake inhibitors (SSRIs) in the treatment of major depression. The present study, therefore, examined the beneficial effect, if any, of addition of risperidone (an atypical antipsychotic) to the antidepressant-like effect of venlafaxine (dual reuptake inhibitors of both serotonin and norepinephrine, SNRI) or fluoxetine (SSRI) in Porsolt's Forced Swim Test (FST) using male laca mice. Attempts have been made to study the involvement of alpha-2 adrenergic receptors in the mechanism of action. Immobility period was recorded for a period of 6 min. Venlafaxine (4 and 8 mg/kg, i.p.) or fluoxetine (10 and 20 mg/kg, i.p.) inhibited the immobility period in mice. Addition of risperidone (0.1 mg/kg, i.p.) potentiated the anti-immobility effect of either venlafaxine (4 and 8 mg/kg, i.p.) or fluoxetine (10 and 20 mg/kg, i.p.) in mouse FST. Furthermore, the anti-immobility effect of combination of risperidone (0.1 mg/kg, i.p) plus venlafaxine (4 mg/kg, i.p.) or fluoxetine (10 mg/kg, i.p.) was potentiated by the addition of yohimbine (2 mg/kg, i.p.), an alpha-2 adrenoceptors antagonist. The results of the present study suggest that the beneficial consequences of addition of risperidone with venlafaxine or fluoxetine in mouse forced swim test may involve alpha-2 adrenergic receptors.

Prevention of depressive behaviour in the YAC128 mouse model of Huntington disease by mutation at residue 586 of huntingtin

Huntington disease is a neurodegenerative disorder caused by an expanded CAG repeat in the Huntington disease gene. The symptomatic phase of the disease is defined by the onset of motor symptoms. However, psychiatric disturbances, including depression, are common features of Huntington disease and recent studies indicate that depression can occur long before the manifestation of motor symptoms. The aetiology of depression in Huntington disease is not fully understood and psychosocial factors such as the knowledge of carrying a mutation for an incurable disease or adverse social circumstances may contribute to its presentation. Due to the difficulties in discriminating between social and biological factors as contributors to depression in clinical Huntington disease, we chose to assess whether a model for Huntington disease not subject to environmental stressors, namely the YAC mouse model of Huntington disease, displays a depressive phenotype. Indeed, the YAC transgenic mice recapitulate the early depressive phenotype of Huntington disease as assessed by the Porsolt forced swim test as well as the sucrose intake test as a measure of anhedonia. The YAC model mirrors clinical Huntington disease in that there were no effects of CAG repeat length or disease duration on the depressive phenotype. The depressive phenotype was completely rescued in YAC transgenic animals expressing a variant of mutant huntingtin that is resistant to cleavage at amino acid 586 suggesting that therapies aimed towards inhibition of huntingtin cleavage are also likely to have beneficial effects on this aspect of the disease. In conclusion, our study provides strong support for a primary neurobiological basis for depression in Huntington disease.

Fetal alcohol spectrum disorder-associated depression: Evidence for reductions in the levels of brain-derived neurotrophic factor in a mouse model

Prenatal ethanol exposure is associated with an increased incidence of depressive disorders in patient populations. However, the mechanisms that link prenatal ethanol exposure and depression are unknown. Several recent studies have implicated reduced brain-derived neurotrophic factor (BDNF) levels in the hippocampal formation and frontal cortex as important contributors to the etiology of depression. In the present studies, we sought to determine whether prenatal ethanol exposure is associated with behaviors that model depression, as well as with reduced BDNF levels in the hippocampal formation and/or medial frontal cortex, in a mouse model of fetal alcohol spectrum disorder (FASD). Compared to control adult mice, prenatal ethanol-exposed adult mice displayed increased learned helplessness behavior and increased immobility in the Porsolt forced swim test. Prenatal ethanol exposure was associated with decreased BDNF protein levels in the medial frontal cortex, but not the hippocampal formation, while total BDNF mRNA and BDNF transcripts containing exons III, IV or VI were reduced in both the medial frontal cortex and the hippocampal formation of prenatal ethanol-exposed mice. These results identify reduced BDNF levels in the medial frontal cortex and hippocampal formation as potential mediators of depressive disorders associated with FASD.

Glycogen synthase kinase-3β heterozygote knockout mice as a model of findings in postmortem schizophrenia brain or as a model of behaviors mimicking lithium action: negative results

In mice glycogen synthase kinase (GSK)-3beta heterozygote knockout status was reported to cause reduced immobility in the Porsolt forced swim test and reduced amphetamine-induced hyperactivity, behaviors that mimic the effects of lithium. GSK-3beta protein and mRNA level and activity have been reported to be reduced in the postmortem brain of schizophrenia patients and this could suggest the involvement of GSK-3beta in the etiology of schizophrenia. However, apomorphine-induced stereotyping was reported to be unchanged in GSK-3beta heterozygote (HZ) knockout (KO) mice. As such behaviors are not always robust, study in another laboratory seemed indicated. Motor activity and coordination were assessed in the rotarod test. Behavior was studied in the following tests: pilocarpine-induced seizures model for lithium action, Porsolt forced swim test, tail suspension test, elevated plus-maze, large open field, startle response and prepulse inhibition of acoustic startle response, amphetamine-induced hyperactivity, and apomorphine-induced stereotypic climbing. We could not confirm the report that GSK-3beta HZ KO mice exhibit reduced immobility in the Porsolt forced swim or reduced amphetamine-induced hyperactivity in a manner mimicking the behavioral effects of lithium. We did not find increased apomorphine-induced stereotypic climbing or disruption of prepulse inhibition, suggesting that human postmortem findings regarding GSK-3beta in schizophrenia are not mediated by changes in dopamine receptors and are not the cause of prepulse inhibition deficits in schizophrenia. These data do not support the role of GSK-3beta in schizophrenia or in the mechanism of therapeutic action of lithium. Although differences in the genetic background of the GSK-3beta HZ KOs used in the present study compared with that of the previous study could be responsible, such results could suggest that the previously reported effects of GSK-3beta knockout on behavior are not robust.

Homozygote inositol transporter knockout mice show a lithium‐like phenotype

Lithium inhibits inositol monophosphatase and also reduces inositol transporter function. To determine if one or more of these mechanisms might underlie the behavioral effects of lithium, we studied inositol transporter knockout mice. We previously reported that heterozygous knockout mice with reduction of 15-37% in brain inositol had no abnormalities of pilocarpine sensitivity or antidepressant-like behavior in the Porsolt forced swim test. We now report on studies of homozygous inositol transporter knockout mice. Homozygote knockout mice were rescued by 2% inositol supplementation to the drinking water of the dam mice through pregnancy and lactation. Genotyping was carried out by polymerase chain reaction followed by agarose electrophoresis. Brain free myo-inositol levels were determined gas-chromatographically. Motor activity and coordination were assessed by the rotarod test. Behavior of the mice was studied in lithium-pilocarpine seizure models for lithium action and in the Porsolt forced swim test model for depression. In homozygote knockout mice, free inositol levels were reduced by 55% in the frontal cortex and by 60% in the hippocampus. There were no differences in weight or motor coordination by the rotarod test. They behaved similarly to lithium-treated animals in the model of pilocarpine seizures and in the Porsolt forced swimming test model of depression. Reduction of brain inositol more than 15-37% may be required to elicit lithium-like neurobehavioral effects.

Regulation of Monoamine Oxidase A by Circadian-Clock Components Implies Clock Influence on Mood

The circadian clock has been implicated in addiction and several forms of depression [1, 2], indicating interactions between the circadian and the reward systems in the brain [3-5]. Rewards such as food, sex, and drugs influence this system in part by modulating dopamine neurotransmission in the mesolimbic dopamine reward circuit, including the ventral tegmental area (VTA) and the ventral striatum (NAc). Hence, changes in dopamine levels in these brain areas are proposed to influence mood in humans and mice [6-10]. To establish a molecular link between the circadian-clock mechanism and dopamine metabolism, we analyzed the murine promoters of genes encoding key enzymes important in dopamine metabolism. We find that transcription of the monoamine oxidase A (Maoa) promoter is regulated by the clock components BMAL1, NPAS2, and PER2. A mutation in the clock gene Per2 in mice leads to reduced expression and activity of MAOA in the mesolimbic dopaminergic system. Furthermore, we observe increased levels of dopamine and altered neuronal activity in the striatum, and these results probably lead to behavioral alterations observed in Per2 mutant mice in despair-based tests. These findings suggest a role of circadian-clock components in dopamine metabolism highlighting a role of the clock in regulating mood-related behaviors.

Involvement of alpha-melanocyte stimulating hormone (α-MSH) in differential ethanol exposure and withdrawal related depression in rat: Neuroanatomical–behavioral correlates

We investigated the involvement of alpha-melanocyte stimulating hormone (α-MSH) following acute, chronic and withdrawal treatments of ethanol with reference to depression. The degree of depression was evaluated using Porsolt's forced swim test. While intracerebroventricular (icv) α-MSH (100–400 ng/rat) dose-dependently increased the immobility, opposite response was observed following administration of selective MC4 receptor antagonist HS014 (0.01–0.07 ng/rat, icv). The anti-immobility effect of acute ethanol (1–2 g/kg), injected via intra-peritoneal route (ip), was suppressed by central administration of α-MSH (100 ng/rat, icv), but was enhanced following pretreatment with HS014 (0.01 ng/rat, icv). Chronic ethanol resulted in increased immobility time, while further augmentation in immobility was noticed following ethanol withdrawal. However, concomitant HS014 (0.01 ng/rat, icv) treatment prevented tolerance as well as attenuated enhanced immobility in ethanol-withdrawn rats. Acute administration of HS014 (0.01–0.03 ng/rat, icv), at 24h post-withdrawal time point, also antagonized the ethanol withdrawal immobility in rats. The profile of α-MSH-immunoreactivity in the paraventricular (PVN), arcuate (ARC), paraventricular thalamic (PVT), dorsomedial hypothalamic-dorsal (DMNd) and -ventral (DMNv) nuclei, lateral hypothalamus (LH) and central nucleus of amygdala (CeA) was investigated with immunocytochemistry. Acute ethanol significantly reduced the α-MSH-immunoreactivity in the cells and fibers of ARC, and fibers in the PVN, DMNd, DMNv and CeA. While chronic ethanol treatment significantly increased the α-MSH-immunoreactivity as compared to the pair-fed control group, further augmentation was noticed following 24 h ethanol withdrawal. However, the α-MSH-immunoreactive profile in the PVT and LH did not respond. α-MSH in discrete areas may play a role in ethanol-induced antidepressant-like response and withdrawal-induced depression.

Differential effects of caffeine on the antidepressant-like effect of amitriptyline in female rat subpopulations with low and high immobility in the forced swimming test

The interaction of caffeine (1 mg/kg) and amitriptyline (15 mg/kg) on the immobility time (IT) during Porsolt's forced swimming test (FST) was investigated in female Wistar rats. Akaike's Information Criterion indicated that the ITs recorded from 142 rats during the first day of the FST followed a bimodal distribution. Hence, the median (125.5 s) was used to classify the animals in subpopulations with low (< 125.5 s, LI-rats) or high (> 125.5 s, HI-rats) immobility. The paired t-test was used to compare the change of ITs between the first and second swimming sessions. Vehicle-treated animals had a significant increase of ITs during the second day of the test, either in LI-rats (77 ± 12 s vs. 196 ± 8 s, P < 0.0001, n = 6) or HI-rats (150 ± 8 s vs. 201 ± 10 s, P < 0.02, n = 6). In LI-rats amitriptyline only prevented the increase of ITs during the second session (74 ± 27 s vs. 97 ± 42 s, n = 12), whereas in HI-rats the antidepressant produced a significant decrease of ITs during the second session (161 ± 22 s vs. 118 ± 32 s, n = 7, P < 0.02). While caffeine alone prevented the increase of ITs in both groups, the methylxanthine abolished the effect of amitriptyline in HI-rats (165 ± 23 s vs. 165 ± 46 s, n = 9), leaving the antidepressant action unaffected in LI-rats (87 ± 23 s vs. 96 ± 58 s, n = 9). These results suggest that the anti-immobility effect of amitriptyline in HI-rats is mediated in part by endogenous adenosine.

Mice lacking the transcription factor Ikaros display behavioral alterations of an anti-depressive phenotype

The Ikaros (Ik) family of transcription factors has critical functions in immune regulation, lymphohematopoiesis and the hypothalamic-pituitary axis. Ik influences cell fate decisions through transcriptional activation of target genes and its interaction with chromatin remodeling complexes. While Ik is well-described in the lymphoid system and pituitary, its presence and function in the brain has received limited attention to date. This study describes the transient spatio-temporal expression of Ik in striatal medium spiny neurons of the developing murine CNS. To determine the impact of Ik deficiency, standardized behavioral tests were performed. In the elevated plus-maze and contextual fear conditioning tests, homozygous Ik-deficient mice performed similarly to wild-type or heterozygote mice. However, significant differences were observed in Ik-null mice in several behavioral tests. Pinch-induced catalepsy was markedly extended. In the Porsolt forced swim test, Ik-null mice showed reduced immobility, consistent with an anti-depressive effect. The acoustic startle response of Ik-null mice was also markedly diminished. Our findings extend the role of the Ikaros zinc-finger protein to the maturation and differentiation of striatal medium spiny neurons and indicate important actions for Ik in the development of neurocognitive functions and affecting depressive behaviors.

Antidepressant Secondary Metabolites from Three Florida Sponges

Depression is very common nervous system disorder and according to WHO it is the third most common illness in the world after infectious diseases and heart diseases [1]. All clinically used antidepressant drugs suffer from very serious side effect (e.g. suicidal thoughts) and require about six weeks before the full therapeutic effect occurs [2]. In our search for possible leads to control depression we have investigated three Florida sponges: Verongula rigida, Smenospongia aurea and S. cerebriformis. Several known compounds were isolated and evaluated in the porsolt forced swim test and chick anxiety-depression model. Among the examined metabolites, 5,6-dibromo-N,N-dimethyltryptamine (1) exhibited significant antidepressant action while 5-bromo-N,N-dimethyltryptamine (2) caused reduction in locomotor activity, which indicates potential sedative action. This study reveals the potential of marine natural products as leads to control depression. Acknowledgements: We are grateful to Mr. J. Diers for testing (1) in the forced swim test. This research was conducted pursuant to the Florida Fish and Wildlife Conservation Division of Marine Fisheries Management Special Activity License.

Secondary metabolites from three Florida sponges with antidepressant activity.

Brominated indole alkaloids are a common class of metabolites reported from sponges of the order Verongida. Herein we report the isolation, structure determination, and activity of metabolites from three Florida sponges, namely, Verongula rigida (order Verongida, family Aplysinidae), Smenospongia aurea, and S. cerebriformis (order Dictyoceratida, family Thorectidae). All three species were investigated chemically, revealing similarities in secondary metabolites. Brominated compounds, as well as sesquiterpene quinones and hydroquinones, were identified from both V. rigida and S. aurea despite their apparent taxonomic differences at the ordinal level. Similar metabolites found in these distinct sponge species of two different genera provide evidence for a microbial origin of the metabolites. Isolated compounds were evaluated in the Porsolt forced swim test (FST) and the chick anxiety-depression continuum model. Among the isolated compounds, 5,6-dibromo- N,N-dimethyltryptamine ( 1) exhibited significant antidepressant-like action in the rodent FST model, while 5-bromo- N,N-dimethyltryptamine ( 2) caused significant reduction of locomotor activity indicative of a potential sedative action. The current study provides ample evidence that marine natural products with the diversity of brominated marine alkaloids will provide potential leads for antidepressant and anxiolytic drugs.

Effect Of Buspirone On Inflammation, Pain And Gastric Injury In Mice

Buspirone, a 5HT1A receptor partial agonist, was evaluated in various acute nociceptive pain models, on the carrgaeenaninduced paw oedema, in Porsolt's forced-swimming test, on haloperidol-induced catalepsy, on the indomethacin-induced gastric mucosal damage and on gastric acid secretion in mice. Buspirone (2, 4 or 8 mg/kg, i.p.) significantly increased the response latency in the mouse hot plate test. The anti-nociceptive activity was observed with 2 mg/kg and a maximal increase in hot-plate latency by 41.3%. Buspirone in addition markedly increased the nociceptive thresholds in the acetic-acid-induced writhing assay, in the capsaicin-induced chemogenic pain and in electrically-induced pain in mice. It displayed no antidepressant activity in the Porsolt's forced-swimming test, but at doses of 8 or 16 mg/kg, buspirone decreased the duration of catalepsy induced by haloperidol by 28.1 and 58.3%, respectively. When given 30 min prior to subplantar carrageenan injection, the drug at 8, 16 mg/kg, inhibited paw oedema response 4 h post-carrageenan by 26.3, 41.6%, respectively. Buspirone (2, 4 or 8 mg/kg, i.p.) significantly inhibited the development of indomethacin gastric mucosal lesions and gastric acid secretion in a dose-dependent manner. In conclusion, Buspirone increased pain threshold in models of thermal, chemogenic, electrical and visceral pain and displayed anti-inflammatory and gastric protective properties. The drug might prove of value for the management of inflammatory painful conditions.