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A high proportion of depressed patients fail to respond to antidepressant drug treatment. Treatment-resistant depression (TRD) is a major challenge for the psychopharmacology of mood disorders. Only in the past decade have novel treatments, including deep brain stimulation (DBS) and ketamine, been discovered that provide rapid and sometimes prolonged relief to a high proportion of TRD sufferers. In this review, we consider the current status of TRD from four perspectives: the challenge of developing an appropriate regulatory framework for novel rapidly acting antidepressants; the efficacy of non-pharmacological somatic therapies; the development of an animal model of TRD and its use to understand the neural basis of antidepressant non-response; and the potential for rapid antidepressant action from targets (such as 5-HT1A receptors) beyond the glutamate receptor.

Background: The chronic mild stress (CMS) procedure is a widely used animal model of depression, and its application in Wistar–Kyoto (WKY) rats has been validated as a model of antidepressant-refractory depression. While not responding to chronic treatment with antidepressant drugs, WKY rats do respond to acute deep brain stimulation (DBS) of the medial prefrontal cortex (mPFC). In antidepressant-responsive strains there is evidence suggesting a role for AMPA subtype of glutamate receptor in the action mechanism of both antidepressants and DBS. Methods: Animals were subjected to CMS for 6 to 8 weeks; sucrose intake was monitored weekly and novel object recognition (NOR) test was conducted following recovery from CMS. Wistars were treated chronically with venlafaxine (VEN), while WKY were treated acutely with either DBS, optogenetic stimulation (OGS) of virally-transduced (AAV5-hSyn-ChR2-EYFP) mPFC or ventral hippocampus, or acute intra-mPFC injection of the AMPA receptor positive allosteric modulator CX-516. The AMPA receptor antagonist NBQX was administered, at identical sites in mPFC, immediately following the exposure trial in the NOR. Results: Sucrose intake and NOR were suppressed by CMS, and restored by VEN in Wistars and by DBS, OGS, or CX-516 in WKY. However, OGS of the ventral hippocampal afferents to mPFC was ineffective. A low dose of NBQX selectively blocked the procognitive effect of VEN, DBS and OGS. Conclusions: These results suggest that activation of AMPA receptors in the mPFC represents a common pathway for the antidepressant effects of both conventional (VEN) and novel (DBS, OGS) antidepressant modalities, in both antidepressant responsive (Wistar) and antidepressant-resistant (WKY) rats.

A growing body of evidence suggests that depression may be associated with impairment of the tryptophan catabolites (TRYCATs) pathway. The present study investigated the effects of the chronic administration of venlafaxine on the expression and methylation status of Katl, Tph1/2, Ido1, Kmo and Kynu in the brain and blood of rats exposed to the CMS model of depression. The rats were subjected to the CMS procedure for 2 or 7 weeks and administered venlafaxine (10 mg/kg/day, IP) for 5 weeks. mRNA and protein expression and the methylation status of gene promoters in PBMCs and six brain structures were evaluated and analysed using the TaqMan Gene Expression Assay and Western blotting, and methylation-sensitive high-resolution melting (MS-HRM), respectively. We found that the CMS procedure increased KatI expression in the midbrain and KatII expression in the midbrain and the amygdala, while venlafaxine administration decreased KatII expression in the hypothalamus and the cerebral cortex. The methylation status of the Tph1 and Kmo promoters in peripheral blood mononuclear cells (PBMCs) was significantly increased in the stressed group after antidepressant therapy. The protein levels of Tph1 and Ido1 were decreased following venlafaxine administration. Our results confirmed that CMS and venlafaxine modulate the expression levels and methylation status of genes involved in the TRYCATs pathway.

Background: Stress represents one of the main precipitating factors for psychiatric diseases, characterised by an altered function of glucocorticoid receptors (GR), known to play a role in mood and cognitive function. We investigated the ability of the antipsychotic lurasidone to modulate the involvement of genomic and non-genomic GR signalling in the behavioural alterations due to chronic stress exposure Methods: Male Wistar rats were exposed to seven weeks of chronic mild stress (CMS) and treated with lurasidone (3 mg/kg/day) starting from the second week of stress for more five weeks. Gene expression and protein analyses were conducted in dorsal hippocampus. Results: Seven weeks of CMS induced anhedonia and cognitive impairment, which were normalised by lurasidone. At molecular level, CMS rats showed an increase of GR protein levels by 60% ( pConclusion: Our results further support the role of glucocorticoid signalling in the dysfunction associated with stress exposure. We provide novel insights on the mechanism of lurasidone, suggesting its effectiveness on different domains associated with psychiatric disorders.

Stress, a major precipitant of depression, and antidepressants have major impact on synaptic integrity and plasticity in brain areas, such as hippocampus (HPC) and prefrontal cortex (PFC). We have recently shown that, unlike Wistar rats, rats of the Wistar-Kyoto (WKY) strain fail to respond to chronic antidepressant treatment after exposure to chronic mild stress (CMS) procedure. However, deep brain stimulation (DBS) of PFC was effective in both strains. We aimed to identify genes that were affected by CMS, to determine whether their expression was normalized by DBS, and to establish whether common changes could be identified in antidepressant responsive (Wistar) and antidepressant-resistant (WKY) strains. Male Wistar and WKY rats were exposed chronically to CMS then treated acutely with DBS. A battery of behavioural tests was used to monitor recovery, followed by TaqMan screening of a panel of genes known to be involved in stress and antidepressant action. WKY showed over-expression of five genes in dorsal HPC and under-expression of seven genes in ventral HPC. Expression of three genes, Egr1, Htr7 and Mmp9 was decreased by CMS and normalized by DBS in the ventral HPC of Wistar rats. Some other changes in gene expression were identified in dorsal HPC and PFC, particularly in Wistars, that were not normalized by DBS. No effects were identified that were common to both Wistars and WKY. The difference between Wistars and WKY in the balance of overall gene expression in HPC may be relevant to the resistance of WKY rats to antidepressant drug treatment.

There is increasing evidence of functional lateralization within the rat brain. Here, we have examined the lateralization of dopamine (DA) function in the medial prefrontal cortex (PFC) in relation to memory consolidation in the novel object recognition test (NOR). Male Wistar rats received single bilateral or unilateral injections into prelimbic-PFC of agonists (SKF81297; 0.2 µg, quinpirole; 1 µg, SB277,011; 0.5 µg) and antagonists (SCH23390; 3 µg, L-741,626; 1 µg, 7-OH-DPAT; 3 µg) at DA D1, D2, or D3 receptors, immediately following the exposure trial in the NOR, and were tested either 1 or 24 h later for discrimination between a novel and a familiar object. As previously reported, bilateral injection of a D1 antagonist (SCH23390, 3 µg/side), a D2 antagonist (L-741,626, 1 µg/side) or a D3 agonist (7-OH-DPAT, 3 µg/side) impaired NOR at 1 h, while a D1 agonist (SKF81297, 0.2 µg/side), a D2 agonist (quinpirole, 1 µg/side) or a D3 antagonist (SB277,011, 0.5 µg/side) improved NOR at 24 h. The same effects were seen with left-sided unilateral injections. No effects were seen with right-sided unilateral injections. Endogenous DA release in the prelimbic-PFC promotes memory consolidation in the NOR, but only on the left side of the brain.

Preclinical studies conducted to date suggest that depression could be elicited by the elevated expression of proinflammatory molecules: these play a key role in the mediation of neurochemical, neuroendocrine and behavioral changes. Thus, this study investigates the effect of chronic mild stress (CMS) and administration of venlafaxine (SSRI) on the expression and methylation status of new target inflammatory genes: TGFA, TGFB, IRF1, PTGS2 and IKBKB, in peripheral blood mononuclear cells (PMBCs) and in selected brain structures of rats. Adult male Wistar rats were subjected to the CMS and further divided into matched subgroups to receive vehicle or venlafaxine. TaqMan gene expression assay and methylation-sensitive high-resolution melting (MS-HRM) were used to evaluate the expression of the genes and the methylation status of their promoters, respectively. Our results indicate that both CMS and chronic treatment with venlafaxine were associated with changes in expression of the studied genes and their promoter methylation status in PMBCs and the brain. Moreover, the effect of antidepressant administration clearly differed between brain structures. Summarizing, our results confirm at least a partial association between TGFA, TGFB, IRF1, PTGS2 and IKBKB and depressive disorders.

Background: There is extensive evidence that antidepressant drugs restore normal brain function by repairing damage to ventral hippocampus (vHPC) and medial prefrontal cortex (mPFC). While the damage is more extensive in hippocampus, the evidence of treatments, such as deep brain stimulation, suggests that functional changes in prefrontal cortex may be more critical. We hypothesized that antidepressant non-response may result from an insufficiency of transmission from vHPC to mPFC. Method: Antidepressant non-responsive Wistar Kyoto (WKY) rats were subjected to chronic mild stress (CMS), then treated with chronic daily administration of the antidepressant drug venlafaxine (VEN) and/or repeated weekly optogenetic stimulation (OGS) of afferents to mPFC originating from vHPC or dorsal HPC (dHPC). Results: As in many previous studies, CMS decreased sucrose intake, open-arm entries on the elevated plus maze (EPM), and novel object recognition (NOR). Neither VEN nor vHPC–mPFC OGS alone was effective in reversing the effects of CMS, but the combination of chronic VEN and repeated OGS restored normal behaviour on all three measures. dHPC–mPFC OGS restored normal behaviour in the EPM and NOR test irrespective of concomitant VEN treatment, and had no effect on sucrose intake. Conclusions: The synergism between VEN and vHPC–mPFC OGS supports the hypothesis that the antidepressant non-responsiveness of WKY rats results from a failure of antidepressant treatment fully to restore transmission in the vHPC–mPFC pathway.

Preclinical studies conducted so far suggest that oxidative stress processes may be associated with the mechanism of depression development. This study shows the effects of chronic administration of agomelatine on expression and the methylation status of Sod1, Sod2, Gpx1, Gpx4, Cat, Nos1, and Nos2 in the brain stricture and blood in the chronic mild stress (CMS) animal model of depression. The animals were exposed to the CMS procedure and treatment with agomelatine (10 mg/kg/day, IP) for five weeks and then were sacrificed. TaqMan Gene Expression Assay, Western blot, and methylation-sensitive high-resolution melting techniques were used to evaluate mRNA and protein expression of the genes, and the methylation status of their promoters. Gpx1, Gpx4, and Sod2 expression in the PBMCs and Sod1 and Sod2 expression in the brain were reduced in the stressed group after agomelatine administration. CMS caused an increase in the methylation of the third Gpx4 promoter in peripheral blood mononuclear cells and Gpx1 promoter in the cerebral cortex. Additionally, stressed rats treated with agomelatine displayed a significantly lower Gpx4 level in the hypothalamus. The results confirm the hypothesis that the CMS procedure and agomelatine administration change the expression level and methylation status of the promoter region of genes involved in oxidative and nitrosative stress.

Background: A significant proportion of depressed patients fail to respond to treatment with antidepressant drugs. Such patients might nonetheless respond to deep brain stimulation of the prefrontal cortex. Deep brain stimulation has also been shown to normalize behaviour in the chronic mild stress (CMS) model of depression. However, these studies have involved animals that are in general treatment responsive. Thus, this is not the ideal situation in which to investigate how deep brain stimulation is effective where antidepressant drugs are not. Aims: Here, we studied the behavioural effects of deep brain stimulation in treatment-resistant animals. Methods: Wistar rats were exposed to chronic mild stress and concurrent treatment with saline or one of three antidepressant drugs, imipramine, citalopram and venlafaxine. Individuals were selected from the CMS-exposed drug-treated groups that had failed to increase their sucrose intake by week 5 of drug treatment. All animals were then implanted with deep brain stimulation electrodes in the ventro-medial prefrontal cortex, and tested for sucrose intake and in the elevated plus maze and novel object recognition test, following 2 × 2 h of deep brain stimulation. Results: The selected drug-treated animals were found to be antidepressant-resistant in all three tests. With a single exception (sucrose intake in imipramine-treated animals), deep brain stimulation reversed the anhedonic, anxiogenic and dyscognitive effects of CMS in all four conditions, with no significant differences between saline- and drug-treated animals. Conclusions: These data provide a proof of principle that deep brain stimulation of the prefrontal cortex can be effective in a rat model of resistance to chronic antidepressant treatment, replicating the clinical effect of deep brain stimulation in treatment-resistant depression.

We have previously reported the effects of intracranial injections of dopamine D1, D2 and D3 ligands in animals subjected to the Novel Object Recognition (NOR) test following exposure to chronic mild stress (CMS) and chronic treatment with risperidone (RSP). Here, we present some molecular biological data from the same animals. It was predicted that brain-derived neurotrophic factor (BDNF) signalling in the prefrontal cortex (PFC) would reflect behavioural performance, implying an increase following acute administration of a D2 agonist or a D3 antagonist, blockade of this effect by CMS and its restoration by chronic RSP. In separate cohorts, animals were injected within the PFC or the hippocampus (HPC) with either the D1 agonist SKF-81297, the D2 agonist quinpirole or the D3 antagonist SB-277,011, following exposure to control conditions or CMS and chronic treatment with saline or RSP. Intracranial injections followed an exposure trial in the NOR test, with a retention trial 24 h later. Immediately afterwards, the animals were killed and expression of BDNF and TRKβ protein, and their respective mRNAs, was measured in PFC and HPC samples. CMS decreased the expression of TRKβ in both PFC and HPC. Several effects associated with intracranial injection were noted, but they were inconsistent and unrelated to CMS exposure. The effects of CMS on TRKβ are consistent with a decrease in BDNF signalling, albeit that expression of BDNF itself did not change significantly. There was no evidence for an involvement of the BDNF-TRKβ system in responses to RSP or dopamine ligands in animals exposed to CMS. However, there was a 24 h delay between the intracranial injection and tissue harvesting, meaning that brief early drug effects could have been missed.

Emerging data continues to point towards a relationship between neuroinflammation and neuropsychiatric disorders. ATP-induced activation of P2X7 results in IL-1β release causing neuroinflammation and microglial activation. This study describes the in-vitro and in-vivo neuropharmacology of a novel brain-penetrant P2X7 antagonist, JNJ-55308942, currently in clinical development. JNJ-55308942 is a high-affinity, selective, brain-penetrant (brain/plasma of 1) P2X7 functional antagonist. In human blood and in mouse blood and microglia, JNJ-55308942 attenuated IL-1β release in a potent and concentration-dependent manner. After oral dosing, the compound exhibited both dose and concentration-dependent occupancy of rat brain P2X7 with an ED(50) of 0.07 mg/kg. The P2X7 antagonist (3 mg/kg, oral) blocked Bz-ATP-induced brain IL-1β release in conscious rats, demonstrating functional effects of target engagement in the brain. JNJ-55308942 (30 mg/kg, oral) attenuated LPS-induced microglial activation in mice, assessed at day 2 after a single systemic LPS injection (0.8 mg/kg, i.p.), suggesting a role for P2X7 in microglial activation. In a model of BCG-induced depression, JNJ-55308942 dosed orally (30 mg/kg), reversed the BCG-induced deficits of sucrose preference and social interaction, indicating for the first time a role of P2X7 in the BCG model of depression, probably due to the neuroinflammatory component induced by BCG inoculation. Finally, in a rat model of chronic stress induced sucrose intake deficit, JNJ-55308942 reversed the deficit with concurrent high P2X7 brain occupancy as measured by autoradiography. This body of data demonstrates that JNJ-55308942 is a potent P2X7 antagonist, engages the target in brain, modulates IL-1β release and microglial activation leading to efficacy in two models of anhedonia in rodents.

The effect of antidepressant drugs on tumor progress is very poorly recognized. The aim of the present study was to examine the effect of individual reactivity to stress and 24-day desipramine (DES) administration on the metastatic colonization of adenocarcinoma MADB 106 cells in the lungs of Wistar rats. Wistar rats were subjected to stress procedure according to the chronic mild stress (CMS) model of depression for two weeks and stress highly-sensitive (SHS) and stress non-reactive (SNR) rats were selected. SHS rats were more prone to cancer metastasis than SNR ones and chronic DES treatment further increased the number of lung metastases by 59% and 50% in comparison to vehicle-treated appropriate control rats. The increase in lung metastases was connected with DES-induced skew macrophage activity towards M2 functional phenotype in SHS and SNR rats. Moreover, during 24h after DES injection in healthy rats, the decreased number of TCD8+ and B cells in SHS and SNR rats as well as NK cell cytotoxic activity in SNR rats could be attributed to the lowered capacity to defend against cancer metastasis observed in chronic DES treated and tumor injected rats.

Ketamine is the prototype of a new generation of antidepressant drugs, which is reported in clinical studies to be effective in treatment-resistant patients, with an effect that appears within hours and lasts for a few days. Chronic mild stress (CMS) is a well-established and widely used animal model of depression, in which anhedonia, anxiogenesis and cognitive dysfunction can be observed reliably. Studies using acute or brief ketamine treatment following withdrawal from CMS have replicated the clinical finding of a rapid onset of antidepressant action. However, there have been no CMS studies of chronic daily ketamine treatment or continued stress following ketamine treatment, which would have greater translational potential in relation to the long-term maintenance of antidepressant effects. Wistar rats were drug treated following an initial 2 weeks of CMS exposure, which continued alongside daily drug treatment. A first experiment tested a range of chronic (5 weeks) ketamine doses (5-30 mg/kg); a second compared the effects of subacute (3-5 days) and chronic (5 weeks) treatment. CMS-induced anhedonic, anxiogenic and dyscognitive effects, as measured, respectively, by decreased sucrose intake, avoidance of open arms in the elevated plus maze and loss of discrimination in the novel object recognition test. A sustained antidepressant-like effect of ketamine in the sucrose intake test was observed in both experiments, with an onset at around 1 week, faster than imipramine, and an optimum dose of 10 mg/kg. Anxiogenic and dyscognitive effects of CMS, in the elevated plus maze and novel object recognition test, respectively, were fully reversed by both subacute and chronic ketamine treatment. Daily treatment with ketamine in the CMS model causes sustained long-term antidepressant, anxiolytic and procognitive effects. The demonstration of a procognitive effect of ketamine may have particular translational value.

BACKGROUND: Psychiatric diseases are characterized by an altered function of the hypothalamic-pituitary-adrenal axis. The activation of this system is also involved in learning and memory processes and its dysregulation may therefore contribute to different psychopathologic domains, including cognitive deficits. On these bases, the aim of this study was to investigate the potential involvement of genomic and non-genomic glucocorticoid receptor (GR) signaling in the behavioral alterations induced by the chronic mild stress (CMS) paradigm in rats. Under this scenario, we also investigated the ability of the novel antipsychotic lurasidone in normalizing the behavioral and molecular changes produced by CMS. METHODS: Adult male Wistar rats were exposed to CMS for 2 weeks and sucrose consumption was used to identify the rats susceptible to the stress protocol. Animals were then randomized to receive vehicle or lurasidone for 5 weeks while continuing the stress procedure. During the 7 weeks of stress protocol rats were tested for anhedonia and at the end of the CMS, animals were exposed to the novel object recognition test (NOR), before being sacrificed for the dissection of the brain regions to be investigated at molecular level. RESULTS: Exposure to 7 weeks of CMS produced an anhedonic phenotype as well as cognitive impairment in the NOR test and these abnormalities were normalized by chronic lurasidone treatment. At molecular level, CMS rats show an increase of GR protein levels in the membrane compartment of the dorsal hippocampus, which was paralleled by an up-regulation of the phosphorylation in Ser603 of SINAPSYN Ia/b, a protein enriched in the presynaptic compartment, and by an increase of the mitochondrial marker Cox3. Moreover, exposure to the NOR test induced nuclear translocation of GRs in control (non-stressed) rats, which was associated with an upregulation of GR-transcriptional activity, as demonstrated by increased mRNA levels for Gadd45β, Sgk-1 and Nr4a1 mRNA. Interestingly such mechanisms were impaired in CMS rats, but they were completely normalized following prolonged lurasidone treatment. DISCUSSION: In summary, our results suggest that exposure to CMS produces complex changes in GR function and signaling, which may contribute to the behavioral abnormalities (anhedonia and cognitive impairment) found in stressed rats. The ability of chronic lurasidone to normalize such alterations provides further support on the potential of this novel antipsychotic to counteract molecular and functional changes that contribute to different domains of psychiatric disorders.

Aims: The Wistar-Kyoto rat has been validated as an animal model of treatment-resistant depression. Here we investigated a role of dopamine D2 and D3 receptors in the ventro-medial prefrontal cortex in the mechanism of action of deep brain stimulation in Wistar-Kyoto rats and venlafaxine in Wistar rats. Methods: Wistar or Wistar-Kyoto rats were exposed chronically to chronic mild stress. Wistar rats were treated chronically with venlafaxine (10 mg/kg) beginning after two weeks of chronic mild stress; Wistar-Kyoto rats received two sessions of deep brain stimulation before behavioural tests. L-742,626 (1 µg), a D2 receptor agonist, or 7-OH DPAT (3 µg), a D3 receptor antagonist, were infused into the ventro-medial prefrontal cortex immediately following the exposure trial in the Novel Object Recognition Test, and discrimination between novel and familiar object was tested one hour later. Results: Chronic mild stress decreased sucrose intake and impaired memory consolidation; these effects were reversed by venlafaxine in Wistar rats and deep brain stimulation in Wistar-Kyoto rats. In control animals, L-742,626 and 7-OH DPAT also impaired memory consolidation. In Wistar rats, venlafaxine reversed the effect of L-742,626 in controls, but not in the chronic mild stress group, and venlafaxine did not reverse the effect of 7-OH DPAT in either group. In Wistar-Kyoto rats, deep brain stimulation reversed the effect of both L-742,626 and 7-OH DPAT in both control and chronic mild stress groups. Conclusions: We conclude that the action of venlafaxine to reverse the impairment of memory consolidation caused by chronic mild stress in Wistar rats involves D2 receptors in the ventro-medial prefrontal cortex; but the effect of deep brain stimulation to reverse the same effect in Wistar-Kyoto rats does not.

A recent review proposed four criteria for an animal model of treatment-resistant depression (TRD): a phenotypic resemblance to a risk factor for depression; enhanced response to stress; nonresponse to antidepressant drugs and response to treatments effective in TRD, such as deep brain stimulation (DBS) of the prefrontal cortex or ketamine. Chronic mild stress (CMS) provides a valid model of depression; the Wistar-Kyoto (WKY) rat is considered to be nonresponsive to antidepressant drugs. Here, we applied CMS to WKY rats. WKY and Wistar rats were exposed to CMS, then treated with saline, imipramine, citalopram or venlafaxine. After 5 weeks of CMS and 3 weeks of drug treatment, all WKY groups were implanted unilaterally with DBS electrodes in the prefrontal cortex, and examined in sucrose intake, elevated plus maze (EPM; decreased entries and time in the open arms) and novel object recognition (decreased exploration) tests, following 2×2 h of DBS. CMS decreased sucrose intake, open arm entries on the EPM, and object recognition. Relative to Wistars, WKY rats showed evidence of increased emotionality in the EPM and novel object recognition tests, and a greater impact of CMS on body weight gain and open arm entries. Wistars responded to drug treatment with an increase in sucrose intake but WKY were nonresponsive to drug treatment on all three behavioural tests. With one exception, DBS reversed the anhedonic, anxiogenic and dyscognitive effects of CMS in all groups of WKY rats. In a further experiment, subacute ketamine (10 mg/kg) also normalized behaviour on all three tests. We conclude that WKY rats subjected to CMS meet all four criteria for a valid model of TRD, and provide a basis for studying the mechanism of action of DBS.

The effect of two second-generation antidepressants escitalopram and venlafaxine on the activity of brain and liver cytochrome P450 2D (CYP2D) involved in the metabolism of psychotropics and neurotransmitters was determined in the chronic mild stress (CMS) model of depression. Escitalopram or venlafaxine (10 mg/kg ip/day each) were administered to control and CMS rats for 5 weeks. The activity of CYP2D was studied by measurement of the rate of bufuralol 1′-hydroxylation in microsomes derived from the liver or different brain structures. The obtained results indicate that CMS and the studied antidepressants had different effects on the CYP2D activity depending on the location of the enzyme. In the brain, CMS produced an increase in the CYP2D activity in the hippocampus. Chronic escitalopram or venlafaxine had no effect on the CYP2D activity in the brain of nonstressed rats, however, the antidepressants increased the enzyme activity in the frontal cortex, hypothalamus and cerebellum of stressed animals. In the liver, CMS did not affect the CYP2D activity, while chronic escitalopram or venlafaxine significantly decreased the CYP2D activity and protein level in nonstressed and stressed rats. We conclude that: 1) CMS stimulates the CYP2D activity in the hippocampus and triggers the stimulatory effect of antidepressants on CYP2D in other brain structures; 2) the local brain metabolism of CYP2D substrates (neurosteroids, neurotransmitters, psychotropics) may be enhanced by CMS and/or antidepressants; 3) in contrast to the brain, the liver metabolism of CYP2D substrates may be slower during long-term treatment with escitalopram or venlafaxine.

The kynurenine pathway (KP), a major route of tryptophan catabolism, may be associated with the pathophysiology of depressive disorders. KP is responsible for ca. 99% of brain tryptophan metabolism via its degradation to kynurenine (KYN) catalyzed by indoleamine 2,3-dioxygenase (IDO). Some cytokines, such as interferon-γ (IFN-γ) and interleukin (IL)-6 are potent inducers of IDO. KYN is further converted by kynurenine aminotransferase (KAT) to the more neuroprotective kynurenic acid or by kynurenine 3-monooxygenase (KMO) to neurotoxic 3-hydroxykynurenine. The aim of the present study was to delineate whether the administration of imipramine (IMI) to rats subjected to chronic mild stress (CMS) may reverse behavioral changes induced by CMS in association with changes in immune-inflammatory markers and KP. We confirmed that the CMS procedure modeled one of the main symptoms of depression, i.e. anhedonia, and administration of IMI for 5 weeks resulted in a significant reduction in anhedonia in a majority of animals (CMS IMI-R animals), whereas 20% of animals did not respond to IMI treatment (CMS IMI-NR animals). We established that CMS procedure increased IFN-γ and IDO mRNA and decreased KAT II mRNA expression in the rat cortex. In the cortex and hippocampus, IMI treatment and non-responsiveness to IMI (in CMS IMI-NR animals) were associated with increased IL-6 mRNA expression. In the spleen, CMS increased production of IFN-γ and IL-6 proteins, while these cytokines were decreased by IMI in CMS IMI-R animals. Chronic IMI administration to CMS rats decreased IDO and KMO mRNA and protein expression and increased KAT II/KMO mRNA and protein ratio in IMI responders (CMS IMI-R) in comparison to CMS rats. In CMS IMI-NR rats, a significant increase in IDO mRNA expression and protein level in comparison with IMI responders was observed. Our findings indicate that resistance to therapeutic action of IMI could be explained by a deficiency of the inhibitory properties of IMI on IDO, KMO and KYN synthesis in the cortex. We conclude that the antidepressant activity of IMI may, at least in part, be explained by modulatory activities on the KAT II/KMO ratio in brain areas.

Rationale The role of somatostatin and its receptors for the stress-related neuropsychiatric disorders has been widely raised. Recently, we have also demonstrated the involvement of somatostatin receptor type 2-sst2R and dopamine receptor type 2-D2R in stress. Objective In this context, we decided to find if these receptors are involved in response to antidepressant treatment in animal model of depression—chronic mild stress (CMS). Methods Here, we report data obtained following 7-week CMS procedure. The specific binding of [125I]Tyr3-Octreotide to sst2R and [3H]Domperidone to D2R was measured in the rat brain, using autoradiography. Additionally, the level of dopamine and metabolites was measured in the rat brain. Results In the final baseline test after 7 weeks of stress, the reduced consumption of sucrose solution was observed (controls vs the stressed animals (6.25 0.16 vs. 10.39 0.41; p

Recent studies indicated an important role of the monoaminergic nervous systems (dopaminergic, noradrenergic, and serotonergic systems) and stress in the regulation of cytochrome P450 (CYP) expression and activity in the liver. The aim of our present research was to determine the effect of the novel atypical neuroleptic drug with antidepressant properties lurasidone, on the expression (mRNA and protein level) and activity of liver CYP isoforms involved in the metabolism of drugs and endogenous steroids, in the chronic mild stress (CMS) model of depression. Male Wistar rats were subjected to CMS for 7 weeks. Lurasidone (3 mg/kg per os per day) was administered to nonstressed or stressed animals for 5 weeks (weeks 3-7 of CMS). It has been found that 1) CMS moderately affects CYP (CYP2B, CYP2C11, and CYP3A), and its effects are different from those observed after other kinds of psychologic stress, such as repeated restraint stress or early-life maternal deprivation; 2) chronic lurasidone influences the expression and/or activity of CYP2B, CYP2C11, and CYP3A isoforms; and 3) CMS modifies the action of lurasidone on CYP expression and function, leading to different effects of the neuroleptic in nonstressed and stressed rats. Based on the obtained results, it can be suggested that the metabolism of endogenous substrates (e.g., steroids) and drugs, catalyzed by the isoforms CYP2B, CYP2C11, or CYP3A, may proceed at a different rate in the two groups of animals (nonstressed and stressed) in the rat CMS model.

Glutamatergic dysfunctions are observed in the pathophysiology of depression. The glutamatergic synapse as well as the AMPA receptor’s (AMPAR) activation may represent new potential targets for therapeutic intervention in the context of major depressive disorders. S 47445 is a novel AMPARs positive allosteric modulator (AMPA-PAM) possessing procognitive, neurotrophic properties and enhancing synaptic plasticity. Here, we investigated the antidepressant/anxiolytic-like effects of S 47445 in a mouse model of anxiety/depression based on chronic corticosterone administration (CORT) and in the Chronic Mild Stress (CMS) model in rats. Four doses of S 47445 (0.3 to 10 mg/kg, oral route, 4 and 5 weeks, respectively) were assessed in both models. In mouse, behavioral effects were tested in various anxiety-and depression-related behaviors : the elevated plus maze (EPM), open field (OF), splash test (ST), forced swim test (FST), tail suspension test (TST), fur coat state and novelty suppressed feeding (NSF) as well as on hippocampal neurogenesis and dendritic arborization in comparison to chronic fluoxetine treatment (18 mg/kg, p.o.). In rats, behavioral effects of S 47445 were monitored using sucrose consumption and compared to those of imipramine or venlafaxine (10 mg/kg, i.p.) during the whole treatment period and after withdrawal of treatments. In a mouse model of genetic ablation of hippocampal neurogenesis (GFAP-Tk model), neurogenesis dependent/independent effects of chronic S 47445 treatment were tested, as well as BDNF hippocampal expression. S 47445 reversed CORT-induced depressive-like state by increasing grooming duration and reversing coat state’s deterioration. S 47445 also decreased the immobility duration in TST and FST. The highest doses (3 and 10 mg/kg) seem the most effective for antidepressant-like activity in CORT mice. Furthermore, S 47445 significantly reversed the anxiety phenotype observed in OF (at 1 mg/kg) and EPM (from 1 mg/kg). In the CMS rat model, S 47445 (from 1 mg/kg) demonstrated a rapid onset of effect on anhedonia compared to venlafaxine and imipramine. In the CORT model, S 47445 demonstrated significant neurogenic effects on proliferation, survival and maturation of hippocampal newborn neurons at doses inducing an antidepressant-like effect. It also corrected CORT-induced deficits of growth and arborization of dendrites. Finally, the antidepressant/anxiolytic-like activities of S 47445 required adult hippocampal neurogenesis in the novelty suppressed feeding test contrary to OF, EPM and ST. The observed increase in hippocampal BDNF levels could be one of the mechanisms of S 47445 responsible for the adult hippocampal neurogenesis increase. Altogether, S 47445 displays robust antidepressant-anxiolytic-like properties after chronic administration through neurogenesis dependent/independent mechanisms and neuroplastic activities. The AMPA-PAM S 47445 could have promising therapeutic potential for the treatment of major depressive disorders or generalized anxiety disorders.

BACKGROUND: Under physiological conditions, the melanocortin system is a crucial part of the complex network regulating food intake and energy expenditure. In pathological states, like cachexia, these two parameters are deregulated, i.e., food intake is decreased and energy expenditure is increased-a vicious combination leading to catabolism. Agouti-related protein (AgRP), the endogenous antagonist at the melanocortin-4 receptor (MC-4R), was found to increase food intake and to reduce energy expenditure. This qualifies MC-4R blockade as an attractive mode of action for the treatment of cachexia. Based on this rationale, a novel series of small-molecule MC-4R antagonists was designed, from which the orally active compound BL-6020/979 (formerly known as SNT207979) emerged as the first promising development candidate showing encouraging pre-clinical efficacy and safety properties which are presented here. METHODS AND RESULTS: BL-6020/979 is an orally available, selective and potent MC-4R antagonist with a drug-like profile. It increased food intake and decreased energy expenditure in healthy wild-type but not in MC-4R deficient mice. More importantly, it ameliorated cachexia-like symptoms in the murine C26 adenocarcinoma model; with an effect on body mass and body composition and on the expression of catabolic genes. Moreover, BL-6020/979 showed antidepressant-like properties in the chronic mild stress model in rats and exhibits a favorable safety profile. CONCLUSION: The properties of BL-6020/979 demonstrated in animal models and presented here make it a promising candidate suitable for further development towards a first-in-class treatment option for cachexia that potentially opens up the opportunity to treat two hallmarks of the disease, i.e., decreased food intake and increased energy expenditure, with one drug.

The present study uses a proteomic approach to examine possible alterations of protein expression in the hippocampus of rats that are subjected to chronic mild stress (CMS). These rats serve as an animal model that was developed to mimic anhedonia, which is one of the core symptoms of depression. As antidepressant treatment is effective after a few weeks of administration, we also aimed to identify changes that were linked to chronic (once daily for 4 weeks) and 'pulse' (once a week) administration of imipramine. Fifteen differential proteins were identified with 2D electrophoresis followed by mass spectrometry. Although both methods of imipramine administration restored normal sucrose consumption in rats that were subjected to CMS, the molecular mechanisms of these two therapies were different. CMS-induced changes in the levels of dynactin 2, Ash 2, non-neuronal SNAP25 and alpha-enolase were reversed by chronic imipramine, but 'pulse' treatment was not that effective.

Background Exposure of rodents to chronic stress is able to recapitulate a number of functional alterations that are associated with psychiatric disorders, including anhedonia and cognitive impairment. Stress-based experimental models are also useful to investigate the ability of pharmacological intervention in normalizing such defects as well as the molecular alterations associated with the behavioral phenotype. On these bases, the aim of the present study was to investigate the ability of a chronic treatment with the multi-receptor modulator lurasidone in normalizing behavioral changes produced by chronic mild stress (CMS) in rats. Moreover, we investigated the potential contribution of parvalbumin expression and of redox mechanisms in the alterations brought about by CMS exposure. Methods Adult male Wistar rats were exposed to CMS for 2 weeks and sucrose consumption was used to identify rats that were susceptible to the stressful manipulation. Control and CMS-susceptible rats were then randomized to receive chronic vehicle or the multi-receptor modulator lurasidone (3 mg/kg/day) for 5 more weeks, while continuing the stress procedure. Animals were tested for anhedonia, using the sucrose intake test, and for cognitive impairment, using the novel object recognition (NOR) test. Rats were sacrificed at the end of the procedures and the brain regions of interest were dissected and used for the molecular analyses. Results Exposure to CMS produced a persistent anhedonic phenotype as well as a significant deficit in the NOR test. Both behavioral abnormalities were normalized by chronic lurasidone treatment. Rats exposed to CMS display a marked and selective reduction in the expression of parvalbumin, which identifies a subpopulation of GABAergic interneurons, in dorsal (but not ventral) hippocampus, an effect that was normalized by chronic lurasidone administration. CMS rats also show a significant up-regulation of (NADPH) oxidase 2 (NOX2), which is critically involved in oxidative stress, as well as a down-regulation of Nrf-2, a master regulator of antioxidant defense. These alterations in dorsal hippocampus were normalized in animals that received chronic lurasidone treatment that was also capable of reducing the levels of Keap-1, an important player that exerts a repressive control over Nrf-2. Discussion Our results demonstrate the ability of lurasidone in normalizing anhedonia and cognitive deficits associated with CMS exposure, suggesting its effectiveness on different ‘domains’ (RDoC) that characterize psychiatric disorders. Lurasidone was also able to normalize the effects produced by CMS exposure on parvalbumin expression, possibly through its ability in promoting anti-oxidative mechanisms within the dorsal hippocampus. All in all, these effects may promote resilience toward the alterations produced by adverse environmental conditions, such as stress, which represents a major vulnerability element in the etiology of psychiatric disorders.

Melanin-concentrating hormone (MCH) is an orexigenic and dipsogenic neuropeptide that has been reported to mediate acute behavioral and neuroendocrine stress-related responses via MCH 1 receptor activation in rodents. The purpose of the present investigation was to use the MCH 1 receptor antagonist SNAP 94847 ( N -(3-{1-[4-(3,4-difluoro-phenoxy)-benzyl]-piperidin-4-yl}-4-methyl-phenyl)-isobutyramide) to determine the effects of MCH 1 receptor blockade on MCH-evoked adrenocorticotropic hormone (ACTH) release, chronic mild stress-induced anhedonia, stress-induced hyperthermia and forced swim stress-induced immobility. The appropriate dose range for testing SNAP 94847 was determined by measuring MCH-evoked water drinking. The corresponding occupancy of MCH 1 receptors in rat striatum was also measured across a broad dose range. Orally administered (p.o.) SNAP 94847 (1–10 mg/kg) corresponds to 30–60% occupancy at MCH 1 receptors and significantly blocks water drinking induced by the intracerebroventricular (i.c.v.) injection of MCH. MCH (i.c.v.) significantly elevates plasma levels of ACTH in rats, and SNAP 94847 (2.5 mg/kg, p.o.) blocks MCH-evoked ACTH release. Using the chronic mild stress paradigm, we show that repeated daily exposure to environmental stressors for 5 weeks significantly suppresses sucrose intake in rats, and that SNAP 94847 (1 mg/kg, BID) for 1–5 weeks restores baseline sucrose intake. Moreover, a single administration of SNAP 94847 attenuates stress-induced hyperthermia and the behavioral effects of forced swim stress with minimal effective doses of 2.5 and 30 mg/kg (p.o.), respectively. The regulation of ACTH release and reversal of the effects of chronic and acute stress by SNAP 94847 are suggestive of a role for MCH 1 receptor blockade in the treatment of disorders characterized by high allostatic load.

This chapter describes the role of the endocannabinoid system (ECBS) in processes associated with cocaine addiction and relapse. Modification of the ECBS activity by blockade of cannabinoid type 1 receptors (CB1R) as well as by fatty acid amide hydrolase inhibitors does not affect cocaine self-administration but potently attenuates the reinstatement of cocaine- and cue-induced seeking behavior, the procedure believed to simulate cocaine craving and relapse in humans. These data are consistent with findings showing that several other behavioral effects of cocaine are inhibited or reversed by ligands of cannabinoid receptors. Repeated cocaine administration also causes upregulation of the CB1Rs in a number of brain areas known to be involved in motivational and cognitive processes associated with cocaine addiction. We conclude that CB1Rs are directly involved in pharmacological and motivational aspects of cocaine addiction, and therefore, can be a potential target for development of new and effective treatment of cocaine abuse and dependence.

Background The treatment of depression in old age is complicated by frequent co-morbidity with cognitive impairment. Anti-dementia drugs have some efficacy to improve cognitive performance and there is an inconsistent literature regarding the effect of such drugs on depressive symptoms. Here, we have investigated whether anti-dementia drugs would have antidepressant-like and pro-cognitive effects in a well-validated animal model of depression and cognitive impairment, chronic mild stress (CMS). Methods Rats were subjected to CMS for a total of 8 weeks. After 2 weeks, subgroups of stressed and non-stressed animals were treated daily, for 5 weeks followed by 1 week of drug withdrawal, with vehicle, imipramine (10 mg/kg), rivastigmine (2 mg/kg), donepezil (0.3 mg/kg) or memantine (5 mg/kg). Sucrose intake was tested weekly, and animals were also tested in the elevated plus maze (at week 7) and in an object recognition task (at weeks 7 and 8). Results CMS decreased sucrose intake, had an anxiogenic effect in the elevated plus maze, and impaired performance in the object recognition test. Imipramine, rivastigmine and donepezil normalized performance in all three tests. Memantine had anxiolytic and pro-cognitive effects, but did not reverse CMS-induced anhedonia. Discussion The fact that all three anti-dementia drugs reversed CMS-induced cognitive impairment and that cholinesterase inhibitors, but not memantine, have antidepressant-like effects in this model suggest that different mechanisms may underlie CMS-induced anhedonia and cognitive impairment. We discuss the clinical implications of these findings.

Major depression is a complex disease that originates from the interaction between a genetic background of susceptibility and environmental factors such as stress. At molecular level, it is characterized by dysfunctions of multiple systems including neurotransmitters, hormones, signalling pathways, neurotrophic and neuroplastic molecules and - more recently - inflammatory mediators. Accordingly, in the present study we used the chronic mild stress (CMS) paradigm in the rat to elucidate to what extent brain inflammation may contribute to the development and/or the maintenance of an anhedonic phenotype and how pharmacological intervention may interfere with such behavioral and molecular stress-induced alterations. To this aim, adult male rats were exposed to CMS for 2 weeks and the cerebral expression of several mediators of the inflammatory system was evaluated in the hippocampus and prefrontal cortex of both stressed and control animals in parallel with the sucrose intake. Next, the animals that showed a decreased sucrose consumption were exposed to five further weeks of CMS and treated with the antidepressants imipramine or agomelatine, or the antipsychotic lurasidone. Our results demonstrate that only the stressed animals that were characterized by a deficit in sucrose intake showed increased expression of the pro-inflammatory cytokines IL-1β, IL-6 and up-regulation of markers and mediators of microglia activation such as CD11b, CX3CL1 and its receptor CX3CR1 in comparison with stress-resilient animals. Some of these molecular alterations persisted also after longer stress exposure and were modulated, similarly to the behavioral effects of CMS, by chronic pharmacological treatment. These data suggest that neuroinflammation may have a key role in the pathological consequences of stress exposure, thus contributing to the subject's vulnerability for depression.

The dopamine D2/D3 receptor agonist and alpha2 adrenergic receptor antagonist, piribedil, is used clinically as monotherapy and as an adjunct to L-3,4-dihydroxyphenylalanine in the treatment of Parkinson's disease. As it appears to improve mood, we examined its actions in rodent models of antidepressant properties, in comparison with the prototypical anti-Parkinson agent, apomorphine, the D2/D3 receptor agonist, quinpirole, and the antidepressants, imipramine and fluvoxamine. In the mouse forced-swim test, acute administration of imipramine, fluvoxamine, apomorphine or quinpirole decreased immobility time, actions dose dependently mimicked by piribedil (2.5-10.0 mg/kg, subcutaneously). In rats, acute and subchronic administration of piribedil similarly reduced immobility (0.63-10.0 mg/kg, subcutaneously) and apomorphine, quinpirole and imipramine were also active in this test, whereas fluvoxamine was inactive. Both in mice and in rats, the D2/D3 receptor antagonist, raclopride, and the D2 receptor antagonist, L741,626, dose dependently blocked the antidepressant properties of piribedil, whereas the selective D3 receptor antagonists, S33084 and SB277,011, were ineffective. In a chronic mild stress model in rats, piribedil (2.5-40.0 mg/kg, subcutaneously) restored sucrose intake in stressed animals exerting its actions more rapidly (by week 1) than imipramine. Imipramine, fluvoxamine, apomorphine, quinpirole and piribedil dose dependently (0.63-10.0 mg/kg, subcutaneously) suppressed aggressive and marble-burying behaviour in mice. In the latter procedure, raclopride and L741,626, but not S33084, attenuated the actions of piribedil. Over a dose range (0.63-10.0 mg/kg, subcutaneously) equivalent to those active in models of antidepressant activity, piribedil did not stimulate locomotor behaviour. In conclusion, principally via recruitment of D2 receptors, piribedil exerts robust and specific antidepressant-like actions in diverse rodent models.

Background and purpose: A crucial role for the GABAB receptor in depression was proposed several years ago, but there are limited data to support this proposition. Therefore we decided to investigate the antidepressant-like activity of the selective GABAB receptor antagonists CGP 36742 and CGP 51176, and a selective agonist CGP 44532 in models of depression in rats and mice. Experimental approach: Effects of CGP 36742 and CGP 51176 as well as the agonist CGP 44532 were assessed in the forced swim test in mice. Both antagonists were also investigated in an olfactory bulbectomy (OB) model of depression in rats, while CGP 51176 was also investigated in the chronic mild stress (CMS) rat model of depression. The density of GABAB receptors in the mouse hippocampus after chronic administration of CGP 51176 was also investigated. Key results: The GABAB receptor antagonists CGP 36742 and CGP 51176 exhibited antidepressant-like activity in the forced swim test in mice. The GABAB receptor agonist CGP 44532 was not effective in this test, however, it counteracted the antidepressant-like effects of CGP 51176. The antagonists CGP 36742 and CGP 51176 were effective in an OB model of depression in rats. CGP 51176 was also effective in the CMS rat model of depression. Administration of CGP 51176 increased the density of GABAB receptors in the mouse hippocampus. Conclusions and Implications: These data suggest that selective GABAB receptor antagonists may be useful in treatment of depression, and support an important role for GABA-ergic transmission in this disorder. British Journal of Pharmacology (2006) 149, 581–590. doi:10.1038/sj.bjp.0706845

Considering that ligands of metabotropic glutamate and GABA receptors may exert beneficial effects on schizophrenia, we assessed the actions of the first mGlu>4-selective orthosteric agonist, LSP4-2022, in several tests reflecting positive, negative, and cognitive symptoms of schizophrenia. Moreover, we investigated the possible involvement of GABAB receptors in LSP4-2022-induced actions. Hyperactivity induced by MK-801 or amphetamine and DOI-induced head twitches in mice were used as the models of positive symptoms. The social interaction test, modified forced swim test (FST), and novel object recognition (NOR) test were used as the models of negative and cognitive symptoms of schizophrenia. LSP4-2022 inhibited hyperactivity (in a dose-dependent manner, 0.5-2 mg/kg) induced by MK-801 or amphetamine and DOI-induced head twitches. In mGlu4 receptor knockout mice, LSP4-2022 was not effective. However, it reversed MK-801-induced impairment in the social interaction test and the MK-801-induced increase of immobility in the modified FST. In the NOR test, LSP4-2022 was active at a dose of 2 mg/kg. GABAB receptor antagonist, CGP55845 (10 mg/kg), reversed LSP4-2022-induced effects in hyperactivity and head twitch tests. At the same time, the simultaneous administration of subeffective doses of LSP4-2022 (0.1 mg/kg) and a positive allosteric modulator of GABAB receptor PAM, GS39783 (0.1 mg/kg), induced clear antipsychotic-like effects in those two tests. Such an interaction between mGlu4 and GABAB receptors was not observed in the social interaction and NOR tests. Therefore, we suggest that the activation of the mGlu4 receptor is a promising approach facilitating the discovery of novel antipsychotic drugs, and that the interplay between mGlu4 and GABAB receptors may become the basis for a novel therapy for schizophrenic patients with predomination of positive symptoms.

Chronic mild stress (CMS), a well-validated model of depression, was used to study the effects of the melatonin agonist and selective 5-HT2C antagonist agomelatine (S 20098) in comparison with melatonin, imipramine, and fluoxetine. All drugs were administered either 2 h before (evening treatment) or 2 h after (morning treatment) the dark phase of the 12-h light/dark cycle. Chronic (5 weeks) evening treatment with agomelatine or melatonin (both at 10 and 50 mg/kg i.p.) dose-dependently reversed the CMS-induced reduction in sucrose consumption. The magnitude and time course of the action of both drugs was comparable to that of imipramine and fluoxetine (both at 10 mg/kg i.p.); however, melatonin was less active than agomelatine at this dose. The effect of evening administration of agomelatine and melatonin was completely inhibited by an acute injection of the MT1/MT2 antagonist, S 22153 (20 mg/kg i.p.), while the antagonist had no effect in animals receiving fluoxetine or imipramine. When the drugs were administered in the morning, agomelatine caused effects similar to those observed after evening treatment (with onset of action faster than imipramine) but melatonin was ineffective. Moreover, melatonin antagonist, S 22153, did not modify the intakes in stressed animals receiving morning administration of agomelatine and in any other control and stressed groups tested in this study. These data demonstrate antidepressant-like activity of agomelatine in the rat CMS model of depression, which was independent of the time of drug administration. The efficacy of agomelatine is comparable to that of imipramine and fluoxetine, but greater than that of melatonin, which had no antidepressant-like activity after morning administration. While the evening efficacy of agomelatine can be related to its melatonin receptors agonistic properties, its morning activity, which was not inhibited by a melatonin antagonist, indicates that these receptors are certainly required, but not sufficient to sustain the agomelatine efficacy. It is therefore suggested that the antidepressant-like activity of agomelatine depends on some combination of its melatonin agonist and 5-HT2C antagonist properties. Neuropsychopharmacology (2003) 28, 694–703. doi:10.1038/sj.npp.1300091

The aim of this study was to evaluate whether chronic treatment with cariprazine, a dopamine D2 and D3 receptor partial agonist with preferential binding to D3 receptors, shows antidepressant-like effects in the chronic mild stress (CMS)-induced anhedonia model. Male Wistar rats were subjected to the CMS procedure for 7 weeks; nonstressed animals served as controls. For the last 5 weeks of the CMS procedure, rats were injected once daily with vehicle, imipramine (10 mg/kg), aripiprazole (1 and 5 mg/kg), or cariprazine (0.01, 0.03, 0.065, 0.25, and 1.0 mg/kg). Activity in reversing CMS-induced decreases in consumption of 1% solution of sucrose was measured. CMS significantly reduced sucrose intake. Imipramine, and both doses of aripiprazole and cariprazine 0.03, 0.065, and 0.25 mg/kg significantly attenuated CMS-induced reductions in sucrose intake; the lowest and highest cariprazine doses (0.01 and 1 mg/kg) did not have this effect. Cariprazine showed greater potency (ED50=0.052) relative to aripiprazole (ED50=4.4) in this model. Thus, in the rat CMS model, cariprazine showed antidepressant-like action with greater potency than aripiprazole. These results suggest that cariprazine may have clinical utility in the treatment of depression and the negative symptoms of schizophrenia.

The chronic mild stress (CMS) model of depression was used to study the potential antidepressant-like activity of NKP608, a non-peptidic, specific, potent and orally active NK1 receptor antagonist. In this model, a substantial decrease in consumption of a 1% sucrose solution is observed in rats continously subjected to a variety of mild stressors. This effect can be reversed by chronic administration of various classes of antidepressant drugs. Chronic, oral treatment with NKP608 (once daily for 5 weeks) gradually reversed CMS-induced reductions in sucrose consumption and, the magnitude of this effect was comparable to that observed following administration of imipramine (10 mg/kg). The time-course of action of NKP608 in the CMS model was dose-dependent. At the dose of 0.03 mg/kg, NKP608 caused a full reversal of the CMS-induced deficit in sucrose consumption after 4 weeks of treatment (comparable to 5 weeks required for imipramine), while only 1 week of treatment was required in the group receiving the dose of 0.1 mg/kg NKP608. Lower (0.003 mg/kg) and higher (1.0 mg/kg) doses of the compound were ineffective. These results suggest that NKP608 has antidepressant-like properties in the CMS model in rats; the effect was comparable to conventional drugs, but the onset of action was faster than with the representative tricyclic antidepressant imipramine.

A chronic mild stress (CMS) model of depression was used to study an antidepressant-like activity of alnespirone (S 20499), a selective agonist of 5-HT1A receptors. In this model, a substantial decrease in consumption of a palatable sucrose solution over time is observed in rats subjected to a variety of mild stressors. This effect can be reversed by chronic administration of various classes of antidepressant drugs. Chronic (5 weeks) treatment with alnespirone, in a dose range between 1-5 mg/kg/day, gradually and dose dependently reversed the CMS-induced reductions in sucrose consumption without any significant effects in the non-stressed control animals. The onset of action of the most active doses (2.5 and 5 mg/kg/day) and the overall efficacy of alnespirone in the CMS model were comparable to those observed following similar administration of imipramine (10 mg/kg/ day). At the lower (0.5 mg/kg/day) and higher (10 and 20 mg/kg/day) doses, alnespirone was ineffective against the CMS-induced deficit in sucrose consumption. These data provide further support for previous suggestions, based on both the clinical observations and animal data, that agonism at 5-HT1A receptors may result in antidepressant action.