Effects Of Chronic Antidepressant Treatment Research Articles

Chronic SSRI Treatment, but Not Norepinephrine Reuptake Inhibitor Treatment, Increases Neurogenesis in Juvenile Rats

There has been growing recognition that major depressive disorder is a serious medical disorder that also affects children. This has been accompanied by an increased use of antidepressant drugs in adolescents; however, not all classes of antidepressants are effective in children and adolescents. There is an increasing need to understand the differences in antidepressant action in different developmental stages. There are some data indicating that the behavioral effect of chronic antidepressant treatment in adult rodents is dependent on hippocampal neurogenesis; however, it is not known which classes of antidepressant drugs induce hippocampal neurogenesis in adolescent rodents. Three classes of antidepressant drugs were tested in two age groups of Sprague Dawley rats, pre-adolescent (postnatal days 11–24) and adolescent (postnatal days 21–34): monoamine oxidase inhibitors (MAOIs); selective serotonin reuptake inhibitors (SSRIs); serotonin norepinephrine reuptake inhibitors (SNRIs); and tricyclic antidepressants (TCAs). To address which classes of antidepressant drugs might alter the rate of mitogenesis in neural progenitor cells in an adolescent rodent model, adolescent Sprague Dawley rats were treated with the thymidine analog 5-bromo-deoxy-2′-uridine (BrdU) on postnatal days 21 and 22 and antidepressant drugs or vehicle for 14 days (postnatal days 21–34). To address which classes of antidepressant drugs might alter the rate of neurogenesis, postnatal day-21 Sprague Dawley rats were treated with antidepressant drugs or vehicle for 14 days (postnatal days 21–34) and BrdU on postnatal days 33 and 34. In both experimental paradigms, BrdU-positive cells in the subgranular zone and the granule cell layer were counted. Newborn neurons were identified in the neurogenic paradigm by identifying cells expressing both the neuronal specific marker NeuN and BrdU using confocal microscopy. Only the SSRI fluoxetine significantly altered the basal mitogenic and neurogenic rates in adolescent rats. Treatment with the monoamine oxidase inhibitor (MAOI) tranylcypromine (TCP) and the TCA desipramine did not alter the rate of hippocampal neurogenesis in the adolescent rats. This is consistent with human clinical observations, where only SSRIs have efficacy for treatment of depression in patients under the age of 18. In pre-adolescent rats, postnatal days 11–24, none of the drugs tested significantly altered the basal mitogenic or neurogenic rates. All of the classes of antidepressant drugs are known to induce hippocampal neurogenesis in adult rats. The mechanisms of action underlying this developmental difference in antidepressant drug action between juveniles and adults are not known.

Failure to detect the action of antidepressants in the forced swim test in Swiss mice.

The aims of this study were to replicate previously published experiments and to modify the protocol to detect the effects of chronic antidepressant treatment in mice. Male Swiss mice (n=6-8/group) housed in reversed light/dark cycle were randomly assigned into receive vehicle (10% sucrose), sub-effective doses (1 and 3 mg/kg) or effective doses (10 and 30 mg/kg) of bupropion, desipramine, and fluoxetine and a candidate antidepressant, sodium butyrate (1-30 mg/kg) per gavage (p.o.) 1 h before the forced swim test (FST). Treatments continued daily for 7 and 14 days during retests 1 and 2, respectively. In an additional experiment, mice received fluoxetine (20 mg/kg) or vehicle (10% sucrose or 0.9% saline) p.o. or i.p. before the FST. Mice housed in reversed or standard light/dark cycles received fluoxetine (20 mg/kg) prior FST. Video recordings of behavioural testing were used for blind assessment of the outcomes. According to the expected, doses of antidepressants considered sub-effective failed to affect the immobility time of mice in the FST. Surprisingly, acute and chronic treatment with the high doses of bupropion, desipramine, and fluoxetine or sodium butyrate also failed to reduce the immobility time of mice in the FST. Fluoxetine 20 mg/kg was also ineffective in the FST when injected i.p. or in mice housed in normal light/dark cycle. Data suggest the lack of efficacy of orally administered bupropion, desipramine, fluoxetine in the FST in Swiss mice. High variability, due to high and low immobility mice, may explain the limited effects of the treatments.

Genetic background contributes to the co-morbidity of anxiety and depression with audiogenic seizure propensity and responses to fluoxetine treatment.

Anxiety and depression are the most frequent comorbidities of different types of convulsive and non-convulsive epilepsies. Increased anxiety and depression-like phenotype have been described in the genetic absence epilepsy models as well as in models of limbic epilepsy and acquired seizure models, suggesting a neurobiological connection. However, whether anxiety and/or depression are comorbid to audiogenic epilepsy remains unclear. The aim of this study was to investigate whether anxiety or depression-like behavior can be found in rat strains with different susceptibility to audiogenic seizures (AS) and whether chronic fluoxetine treatment affects this co-morbidity. Behavior in the elevated plus-maze and the forced swimming test was studied in four strains: Wistar rats non-susceptible to AS; Krushinsky-Molodkina (KM) strain, selectively bred for AS propensity from outbred Wistar rats; and a selection lines bred for maximal AS expression (strain "4") and for a lack of AS (strain "0") from KM×Wistar F2 hybrids. Effects of chronic antidepressant treatment on AS and behavior were also evaluated. Anxiety and depression levels were higher in KM rats (with AS) compared with Wistar rats (without AS), indicating the comorbidity with AS. However, in strains "4" and "0" with contrasting AS expression, but with a genetic background close to KM rats, anxiety and depression were not as divergent as in KMs versus Wistars. Fluoxetine treatment exerted an antidepressant effect in all rat strains irrespective of its effect on AS. Genetic background contributes substantively to the co-morbidity of anxiety and depression with AS propensity.

Effects of chronic antidepressant treatment under blockade of CB2 receptors on the level of endocannabinoids in rat brain structures

Effects of chronic antidepressant treatment under blockade of CB2 receptors on the level of endocannabinoids in rat brain structures

Sex-specific effects of chronic antidepressant treatment in middle-aged rats: impact of citalopram on cognition and depressive-like behaviors

Sex-specific effects of chronic antidepressant treatment in middle-aged rats: impact of citalopram on cognition and depressive-like behaviors

Functional dissociation of adult‐born neurons along the dorsoventral axis of the dentate gyrus

Adult-born granule cells in the mammalian dentate gyrus have long been implicated in hippocampal dependent spatial learning and behavioral effects of chronic antidepressant treatment. Although recent anatomical and functional evidence indicates a dissociation of the dorsal and ventral regions of the hippocampus, it is not known if adult neurogenesis within each region specifically contributes to distinct functions or whether adult-born cells along the entire dorsoventral axis are required for these behaviors. We examined the role of distinct subpopulations of adult-born hippocampal granule cells in learning- and anxiety-related behaviors using low-dose focal x-irradiation directed specifically to the dorsal or ventral dentate gyrus. Our findings indicate a functional dissociation between adult-born neurons along the longitudinal axis of the dentate gyrus wherein new neurons in the dorsal dentate gyrus are required for timely acquisition of contextual discrimination while immature neurons in the ventral dentate gyrus are necessary for anxiolytic/antidepressant-related effects of fluoxetine. Interestingly, when contexts are presented with altered temporal cues, or fluoxetine is administered alongside chronic glucocorticoid treatment, this dissociation is abrogated such that adult-born neurons across the entire dorsoventral extent of the dentate gyrus appear to contribute to these behaviors. Our results suggest that individual subpopulations of adult-born hippocampal neurons may be sufficient to mediate distinct behaviors in certain conditions, but are required to act in concert in more challenging situations.

Involvement of 5-HT2C and 5-HT1A receptors of the basolateral nucleus of the amygdala in the anxiolytic effect of chronic antidepressant treatment

Facilitation of serotonin 2C- and 1A-receptor (5-HT2C-R and 5-HT1A-R) mediated neurotransmission in the basolateral nucleus of the amygdala (BLA) has been associated with anxiogenic and anxiolytic effects, respectively. It has been also shown that stimulation of BLA 5-HT2C-Rs underlies the anxiogenic effect caused by acute systemic administration of the antidepressants imipramine or fluoxetine. Here we investigated whether chronic treatment with these two antidepressants, which causes anxiolytic effects, decreases the responsiveness of these receptors in the BLA. We also investigated whether the blockage of 5-HT1A-Rs in the same amygdala nucleus alters the anxiolytic effect of chronic imipramine treatment. The results showed that in male Wistar rats intra-BLA injection of the 5-HT2C-R agonist MK-212 facilitated inhibitory avoidance acquisition in the elevated T-maze and decreased the percentage of time spent by the animals in the lit compartment of the light–dark transition test, indicating an anxiogenic effect. Chronic (21 days) systemic treatment with imipramine (5 or 15 mg/kg) or fluoxetine (10 mg/kg) abolished these effects of MK-212. Acute administration of imipramine (5 mg/kg) failed to interfere with MK-212 effects in both tests. Intra-BLA injection of the 5-HT1A antagonist WAY-100635 blocked the anxiolytic, but not the panicolytic, effect of imipramine in the tests used. Our findings indicate that both a reduction in 5-HT2C-R- and a facilitation of 5-HT1A-R-mediated neurotransmission in the BLA are involved in the anxiolytic effect of antidepressant drugs.

Effects of chronic antidepressant treatments in a putative genetic model of vulnerability (Roman low-avoidance rats) and resistance (Roman high-avoidance rats) to stress-induced depression

The Roman low- (RLA) and high-avoidance (RHA) rats were selectively bred for, respectively, poor versus rapid acquisition of active avoidance in a shuttle box and, under aversive conditions, display reactive (RLA) versus proactive (RHA) coping behaviors. In the forced swim test (FST), RLA rats exhibit a depression-like behavior characterized by greater immobility and fewer climbing counts when compared with their RHA counterparts. Furthermore, subacute treatments with clinically effective antidepressant drugs decrease immobility and increase climbing or swimming in RLA rats but do not modify the performance of RHA rats. Because chronic treatment with antidepressants is usually required to produce clinical effects, the present study was designed to compare the behaviors of RLA and RHA rats in the FST after subacute (1day) and chronic (15days) administration of desipramine, fluoxetine, and chlorimipramine. In RLA rats, subacute treatments with low doses of desipramine, fluoxetine, and chlorimipramine (2.5-5mg/kg) were ineffective whereas chronic treatments with the same doses of all three antidepressants decreased immobility and also increased climbing (desipramine) or swimming (fluoxetine). By contrast, neither subacute nor chronic treatments with these antidepressants induced significant changes in the behavior of RHA rats in the FST. RLA and RHA rats represent two divergent phenotypes, respectively susceptible and resistant to develop depression-like behavior under aversive environmental conditions that may be used to identify genetically determined neural substrates and mechanisms underlying vulnerability and resistance to stress-induced depression.

Cannabinoids, Neurogenesis and Antidepressant Drugs: Is there a Link?

Similar to clinically used antidepressants, cannabinoids can also regulate anxiety and depressive symptoms. Although the mechanisms of these effects are not completely understood, recent evidence suggests that changes in endocannabinoid system could be involved in some actions of antidepressants. Chronic antidepressant treatment modifies the expression of CB1 receptors and endocannabinoid (EC) content in brain regions related to mood and anxiety control. Moreover, both antidepressant and cannabinoids activate mitogen-activated protein (MAP) kinase and phosphoinositide 3-kinase(PI3-K)/Akt or PKB signaling, intracellular pathways that regulate cell proliferation and neural cell survival. Facilitation of hippocampal neurogenesis is proposed as a common effect of chronic antidepressant treatment. Genetic or pharmacological manipulations of cannabinoid receptors (CB1 and CB2) or enzymes responsible for endocannabinoid-metabolism have also been shown to control proliferation and neurogenesis in the hippocampus. In the present paper we reviewed the studies that have investigated the potential contribution of cannabinoids and neurogenesisto antidepressant effects. Considering the widespread brain distribution of the EC system, a better understanding of this possible interaction could contribute to the development of therapeutic alternatives to mood and anxiety disorders.

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<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<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.

Analysis of Target Genes Regulated by Chronic Electroconvulsive Therapy Reveals Role for Fzd6 in Depression

Chronic electroconvulsive seizure (chr-ECS), one of the most efficacious treatments for depressed patients, increases the levels of transcription factor cyclic adenosine monophosphate response element binding protein (CREB) in rodent models and mediates the effects of chronic antidepressant treatment. The objective of this study was to determine the changes in CREB occupancy at gene promoters and subsequent gene expression changes induced by chr-ECS. We use chromatin immunoprecipitation followed by microarray analysis to identify CREB binding promoters that are influenced by chr-ECS (n = 6/group). Selected genes are confirmed by secondary validation techniques, and the functional significance of one target was tested in behavioral models (n = 8/group) by viral mediated inhibition of gene expression. The results demonstrate that chr-ECS enhances CREB binding and activity at a select population of genes in the hippocampus, effects that could contribute to the efficacy of chr-ECS. Viral vector-mediated inhibition of one of the CREB-target genes regulated by chr-ECS, Fzd6, produced anxiety and depressive-like effects in behavioral models of depression. The results identify multiple gene targets differentially regulated by CREB binding in the hippocampus after chr-ECS and demonstrate the role of Fzd6, a Wnt receptor in behavioral models of depression.

P.2.d.018 Analysis of the effects of chronic antidepressant treatment on neuronal plasticity in middle-aged rats

P.2.d.018 Analysis of the effects of chronic antidepressant treatment on neuronal plasticity in middle-aged rats

Chronic buspirone treatment decreases 5-HT 1B receptor densities and the serotonin transporter but increases the density of 5-HT 2A receptors in the bulbectomized rat model of depression: an autoradiographic study

The olfactory bulbectomized (OBX) rat model is an animal model of depression. The deregulation of the serotonergic (5-HT) system is implicated in the pathophysiology of depression. Buspirone is a partial agonist of 5-HT 1A receptors and is used in the treatment of depression and anxiety. The aim of this study was to assess, in OBX rats and sham operated controls, the effect of chronic buspirone treatment on the densities of 5-HT 2A and 5-HT 1B receptors, as well as the 5-HT transporter (5-HTT), which are all important mediators of 5-HT transmission. Male Sprague-Dawley rats (180-240 g) were used. Two weeks following the surgeries, the rats were assigned into the saline or treatment groups, receiving either saline, or 10 or 20 mg/kg day of buspirone, for 2 weeks by subcutaneous mini pump. Following the treatment, the rats were sacrificed. The autoradiographic experiments were performed ex vivo using [ 3H]5-HT for the 5-HT 1B receptors, [ 3H]-ketanserin for the 5-HT 2A receptors, and [ 3H]-paroxetine for the 5-HTT binding. The receptors and 5-HTT densities were quantified in 38 brain regions as well as the pineal body. Chronic treatment with buspirone produced the following: 1) a decrease in the 5-HT 1B densities, which was more pronounced in the Sham rats; 2) an increase in the 5-HT 2A receptor densities, which was more pronounced in the Sham rats; and 3) an decrease in 5-HTT densities in both groups. The results indicate differential effects of chronic antidepressant treatment on the 5-HT system regulation in the OBX model of depression and normal rats.

Regulation of brain-derived neurotrophic factor (BDNF) in the chronic unpredictable stress rat model and the effects of chronic antidepressant treatment

Chronic unpredictable stress (CUS) is a widely used animal model of depression. The present study was undertaken to investigate behavioral, physiological and molecular effects of CUS and/or chronic antidepressant treatment (venlafaxine or imipramine) in the same set of animals. Anhedonia, a core symptom of depression, was assessed by measuring consumption of a palatable solution. Exposure to CUS reduced intake of a palatable solution and this effect was prevented by chronic antidepressant treatment. Moreover, chronic antidepressant treatment decreased depressive-like behavior in a modified forced swim test in stressed rats. Present evidence suggests a role for brain-derived neurotrophic factor (BDNF) in depression. BDNF mRNA levels in the ventral and dorsal hippocampus were assessed by in situ hybridization. Exposure to CUS was not correlated with a decrease but rather with an increase in BDNF mRNA expression in both the dentate gyrus of the dorsal hippocampus and the CA3 region of the ventral hippocampus indicating that there is no simple link between depression-like behaviors per se and brain BDNF levels in rats. However, a significant increase in BDNF mRNA levels in the dentate gyrus of the dorsal hippocampus correlated with chronic antidepressant treatment emphasizing a role for BDNF in the mechanisms underlying antidepressant activity.

Antidepressant-like effects of 3,6′-disinapoyl sucrose on hippocampal neuronal plasticity and neurotrophic signal pathway in chronically mild stressed rats

Recent studies suggest that the behavioral effects of chronic antidepressant treatment are mediated by stimulation of hippocampal neuronal plasticity and neurogenesis. The present study was designed to examine the effects of 3,6'-disinapoyl sucrose (DISS), a bioactive component of Polygala tenuifolia Willd, on the expressions of four plasticity-associated genes: cell adhesion molecule L1 (CAM-L1), laminin, cAMP response element binding protein (CREB) and brain-derived neurotrophic factor (BDNF) in hippocampus, all of which are involved in neuronal plasticity and neurite outgrowth. We confirmed that chronic stress in rats caused a reduction in sensitivity to reward (sucrose consumption) and a decrease in mRNA levels of CAM-L1, laminin, and BDNF, together with a decrease in protein levels of phosphorylated CREB and BDNF. Repeated administration of DISS for 21 days at doses of 5, 10 and 20mg/kg reversed stress-induced alterations in sucrose consumption and these target mRNA and protein levels. In conclusion, increased expressions in the hippocampus of three noradrenergic-regulated plasticity genes and one neurotrophic factor may be one of the molecular and cellular mechanisms underlying the antidepressant action of DISS in chronic mild stress (CMS) rats.

Glucocorticoid status affects antidepressant regulation of locus coeruleus tyrosine hydroxylase and dorsal raphé tryptophan hydroxylase gene expression

Brainstem monoaminergic nuclei express glucocorticoid receptors ( GR), and glucocorticoids have been shown to inhibit expression of enzymes involved in monoamine synthesis. Monoamine deficits have been implicated in depression pathology. However, it is unknown if antidepressants regulate brainstem GR, and if glucocorticoids might influence antidepressant effects on monoamine-synthesizing enzymes. Our lab has found opposing effects of the monoamine oxidase inhibitor phenelzine and the tricyclic antidepressant imipramine on HPA activity and forebrain GR gene expression. We therefore hypothesized that phenelzine and imipramine would also affect brainstem GR gene expression differentially, and that antidepressant-induced changes in GR expression would correlate with effects on monoamine-synthesizing enzyme expression. Using in situ hybridization, we measured effects of chronic antidepressant treatment on brainstem GR, locus coeruleus and ventral tegmental area (VTA) tyrosine hydroxylase ( TH), and dorsal raphé tryptophan hydroxylase ( TPH2) gene expression in male C57BL/6 mice that were adrenalectomized and replaced with defined levels of corticosterone. GR expression was decreased by phenelzine in the locus coeruleus and decreased by imipramine in the dorsal raphé. Phenelzine increased locus coeruleus TH and imipramine increased dorsal raphé TPH2 gene expression in a glucocorticoid-dependent manner, suggesting that increases in these enzymes were due to relief of inhibitory glucocorticoid signaling. We did not find antidepressant effects on GR or TH expression in the VTA or on mineralocorticoid receptor ( MR) expression in any of the nuclei examined. Our findings represent a potential mechanism through which antidepressants and glucocorticoids could alter both HPA activity and mood via effects on brainstem GR, norepinephrine, and serotonin.

Alterations in β‐adrenergic receptors in frontal cortex and amygdala in rats with heart failure: Effects of chronic antidepressant treatment

Chronic treatment with the serotonin reuptake inhibitor, fluoxetine (FLX), decreases cardiac sensitivity to β‐adrenergic receptor stimulation in rats with congestive heart failure (CHF). To determine if β‐adrenergic receptors are altered in brain regions important in anxiety, frontal cortex and amygdale were dissected and β‐adrenergic receptors were determined at a single concentration of 0.2 nM 125Iodocyanopindolol in 4 groups of rats (CHF‐vehicle, n=8‐9; CHF‐FLX, n=6‐8; Sham‐Vehicle, n=5; Sham‐FLX, n=6) in the absence and presence of propranolol (100 µM) to determine specific binding. 10 µM serotonin was included to preclude binding of 5‐HT receptors. β‐adrenergic receptors in the frontal cortex were significantly decreased in rats with CHF (19.3%, P<0.05) while FLX had no effect. In contrast, β‐adrenergic receptors were increased in the amygdala of rats with CHF (27.3%, P<0.05), while FLX caused an overall reduction in binding (13.2%, P<0.05). Thus, alterations in β‐adrenergic receptor binding develop in brain regions involved in behavioral and autonomic responses to stress during CHF and chronic antidepressant treatment. Supported by Loyola University.

Enhanced Sensitivity of the MRL/MpJ Mouse to the Neuroplastic and Behavioral Effects of Chronic Antidepressant Treatments

Chronic administration of antidepressant drugs produce changes in neuroplasticity and behavior in rodents, effects that may be associated with the slow emergence of clinical therapeutic effects. Because of uncertainty over the effects of chronic antidepressant treatments in mice, these experiments compared the regulation of neurogenesis, mobilization of neurotrophins, and behavior produced by chronic antidepressant treatments between two inbred mouse strains, MRL/MpJ and C57BL/6J. The MRL/MpJ strain is associated with enhanced wound healing and tissue regeneration, whereas C57BL/6J mice are commonly used for behavioral studies. Proliferation and survival of hippocampal progenitor cells were measured using flow cytometry, a new platform that rapidly quantifies BrdU incorporation. Hippocampal cell proliferation was significantly increased following chronic administration of fluoxetine (5, 10 mg/kg; i.p. b.i.d.) or desipramine (5, 10 mg/kg; i.p. b.i.d.) for 21 days in MRL/MpJ mice, but not in C57BL/6J mice. Hippocampal progenitor cells born prior to chronic antidepressant treatments were not affected in either mouse strain. Protein levels of brain-derived neurotrophic factor (BDNF) in MRL/MpJ mice were elevated significantly in the frontal cortex, hippocampus, and amygdala following chronic fluoxetine treatment, but increased only in the frontal cortex by chronic desipramine. In contrast, BDNF levels in C57BL/6J mice were decreased in all regions except for the amygdala after chronic fluoxetine, and were decreased in the brain stem after chronic desipramine. Novelty-induced hypophagia was used to examine a behavioral effect produced by chronic antidepressant treatment. MRL/MpJ mice chronically administered fluoxetine or desipramine had significantly shorter latencies to consume food when exposed to a novel environment than untreated mice, whereas there were no effects on the behavior of C57BL/6J mice. In conclusion, robust effects of chronic antidepressant treatments on hippocampal cell proliferation and BDNF levels paralleled the ability of these drugs to produce changes in NIH behavior in MRL/MpJ, but none of these effects were produced in C57BL/6J mice. The greater responsiveness of MRL/MpJ mice may be important for drug discovery, for genetic studies and for understanding the neural mechanisms underlying the physiological and behavioral effects of chronic antidepressant treatments.

CTN-986, a compound extracted from cottonseeds, increases cell proliferation in hippocampus in vivo and in cultured neural progenitor cells in vitro

We have previously reported that Quercetin 3-O-b- d-apiofuranosyl-(1→2)-[a- l-rhamnopyranosyl-(1→6)]-b- d-glucopyranoside (CTN-986), a potential antidepressant extracted from glandless cottonseeds, exerted a notable antidepressant-like effect in experimental animal models. Recent evidence suggested, at least in some animal models, that the behavioral effects of chronic antidepressant treatment were mediated by the stimulation of hippocampal neurogenesis. To explore possible mechanisms of CTN-986′s antidepressant-like effect, CTN-986 (10 mg/kg, i.g) or imipramine (IMI, 10 mg/kg, i.g) was administered once per day to the chronically stressed mice over 21 days. Immunohistochemical analysis revealed that chronic CTN-986 treatment increased bromodeoxyuridine (BrdU; thymidine analog as a marker for dividing cells)-positive cells in the hippocampal dentate gyrus in stressed mice, as was the case with chronic IMI treatment. Moreover, using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide (MTT) assay and [ 3H] thymidine incorporation assay, it was found that exposure to CTN-986 for 4 days dose-dependently increased the proliferation of the cultured hippocampal neural progenitor cells (NPCs). This effect was significantly reversed by co-incubation with serotonin 1A (5-HT 1A) receptor antagonist WAY100635. These results indicate that CTN-986 increase hippocampal NPCs proliferation which might be closely related to the activation of the 5-HT 1A receptor. This finding can shed light on the mechanisms for its antidepressant-like effects.

Animal models of depression in dopamine, serotonin, and norepinephrine transporter knockout mice: prominent effects of dopamine transporter deletions

Antidepressant drugs produce therapeutic actions and many of their side effects via blockade of the plasma membrane transporters for serotonin (SERT/SLC6A2), norepinephrine (NET/SLC6A1), and dopamine (DAT/SLC6A3). Many antidepressants block several of these transporters; some are more selective. Mouse gene knockouts of these transporters provide interesting models for possible effects of chronic antidepressant treatments. To examine the role of monoamine transporters in models of depression DAT, NET, and SERT knockout (KO) mice and wild-type littermates were studied in the forced swim test (FST), the tail suspension test, and for sucrose consumption. To dissociate general activity from potential antidepressant effects three types of behavior were assessed in the FST: immobility, climbing, and swimming. In confirmation of earlier reports, both DAT KO and NET KO mice exhibited less immobility than wild-type littermates whereas SERT KO mice did not. Effects of DAT deletion were not simply because of hyperactivity, as decreased immobility was observed in DAT+/- mice that were not hyperactive as well as in DAT-/- mice that displayed profound hyperactivity. Climbing was increased, whereas swimming was almost eliminated in DAT-/- mice, and a modest but similar effect was seen in NET KO mice, which showed a modest decrease in locomotor activity. Combined increases in climbing and decreases in immobility are characteristic of FST results in antidepressant animal models, whereas selective effects on swimming are associated with the effects of stimulant drugs. Therefore, an effect on climbing is thought to more specifically reflect antidepressant effects, as has been observed in several other proposed animal models of reduced depressive phenotypes. A similar profile was observed in the tail suspension test, where DAT, NET, and SERT knockouts were all found to reduce immobility, but much greater effects were observed in DAT KO mice. However, to further determine whether these effects of DAT KO in animal models of depression may be because of the confounding effects of hyperactivity, mice were also assessed in a sucrose consumption test. Sucrose consumption was increased in DAT KO mice consistent with reduced anhedonia, and inconsistent with competitive hyperactivity; no increases were observed in SERT KO or NET KO mice. In summary, the effects of DAT KO in animal models of depression are larger than those produced by NET or SERT KO, and unlikely to be simply the result of the confounding effects of locomotor hyperactivity; thus, these data support reevaluation of the role that DAT expression could play in depression and the potential antidepressant effects of DAT blockade.