Discriminative stimulus properties in rats of the novel antipsychotic quetiapine

Rats discriminated the novel antipsychotic quetiapine (Seroquel). Full generalization was seen with the novel ("atypical") antipsychotics, clozapine, olanzapine, and risperidone. Generalization was not seen with the older "typical" antipsychotics, haloperidol, chlorpromazine, and loxapine, or with the novel atypical antipsychotic, amisulpride. The pattern of generalization resembled that seen in rats trained to discriminate a low dose (1.25 mg/kg) of clozapine, which dissociates most novel antipsychotics from typical antipsychotics. However, the failure of the novel antipsychotic amisulpride to generalize demonstrates that this bioassay does not detect all novel antipsychotics. These data suggest that the discrimination of antipsychotics such as quetiapine may be of value in the development of novel antipsychotics, although the relationship between the discriminative properties of such drugs and their clinical actions is unclear.     

Effects of amisulpride and aripiprazole on progressive-ratio schedule performance: comparison with clozapine and haloperidol

Clozapine and some other atypical antipsychotics (e.g. quetiapine, olanzapine) have been found to exert a characteristic profile of action on operant behaviour maintained by progressive-ratio schedules, as revealed by Killeen's Mathematical Principles of Reinforcement model of schedule-controlled behaviour. These drugs increase the value of a parameter that expresses the 'incentive value' of the reinforcer (a) and a parameter that is inversely related to the organism's 'motor capacity' (δ). This experiment examined the effects of two further atypical antipsychotics, aripiprazole and amisulpride, on progressive-ratio schedule performance in rats; the effects of clozapine and a conventional antipsychotic, haloperidol, were also examined. In agreement with previous findings, clozapine (4, 8?mg kg(-1)) increased a and δ, whereas haloperidol (0.05, 0.1?mg kg(-1)) reduced a and increased δ. Aripiprazole (3,30?mg kg(-1)) increased δ but did not affect a. Amisulpride (5, 50?mg kg(-1)) had a delayed and protracted effect: δ was increased 3-6 hours after treatment; a was increased 1.5 hours, and reduced 12-24 hours after treatment. Interpretation based on Killeen's model suggests that aripiprazole does not share clozapine's ability to enhance reinforcer value. Amisulpride produced a short-lived enhancement, followed by a long-lasting reduction, of reinforcer value. Both drugs impaired motor performance.     

Nicotine and nicotinic receptor antagonists potentiate the antidepressant-like effects of imipramine and citalopram

1. Epidemiological and clinical observations suggest the involvement of nicotinic acetylcholine receptors (nAChRs) in depressive illness. Nonetheless, there is no clearcut evidence that nicotine and/or nAChR antagonists produce an antidepressant effect. 2. In the tail-suspension test (C57/Bl male mice), nicotine (0.8-1.2 mg kg(-1) s.c. or i.p.) given 15-60 min before the measurement exerted no effect on immobility. 3. Given 30 min before the measurement, citalopram (2 mg kg(-1)) produced a slight decrease in immobility; coadministration of nicotine (0.8 mg kg(-1), 15 but not 40 min before the test) to citalopram-treated mice resulted in a robust decrease in immobility. Imipramine (4 mg kg(-1)) did not affect immobility, but given in combination with 0.8 mg kg(-1) of nicotine (15 but not 40 min before the test), a decrease in immobility was observed. Nicotine (0.8 and 1.2 mg kg(-1)) also produced an enhancement in the anti-immobility effect of imipramine (20 mg kg(-1)). 4. We further investigated if nAChR antagonists would influence the antidepressant-like effects of imipramine and citalopram. Unexpectedly, mecamylamine (1-2.5 mg kg(-1)) and dihydro-beta-erythroidine (2 mg kg(-1)) potentiated the antidepressant-like effect of imipramine (4-20 mg kg(-1)). Mecamylamine (2.5 mg kg(-1)) but not dihydro-beta-erythroidine also increased the antidepressant-like effect produced by 2 mg kg(-1) of citalopram. 5. The interaction between nAChR antagonists and antidepressants appeared synergistic. 6. Neither nAChR ligands, antidepressants nor combinations of the two, affected locomotor activity. 7. The present results demonstrate an unexpected interaction between nAChR ligands and imipramine and citalopram in the tail-suspension test.     

Therapeutic monitoring of new antipsychotic drugs

Typical antipsychotic drugs qualify for therapeutic drug monitoring (TDM) primarily for the following reasons: control of compliance and avoidance of extrapyramidal side effects by keeping chronic exposure to minimal effective blood levels. For the atypical antipsychotic clozapine, drug safety is another reason to use TDM. With regard to the new antipsychotics risperidone, olanzapine, quetiapine, amisulpride, ziprasidone, and aripiprazole, which have been introduced in the clinic during the last few years, the rationale to use TDM is a matter of debate. Positron emission tomography (PET), which enables measurement of the occupancy of dopamine D2 receptors, revealed that receptor occupancy correlated better with plasma concentrations than with doses of the antipsychotics. Regarding plasma levels related to therapeutic effects, optimal concentrations have been established for clozapine (350-600 ng/mL), risperidone (20-60 ng/mL), and olanzapine (20-80 ng/mL) but not for the other new antipsychotics. Studies that included analyses of drug levels in blood reported mean concentrations of 68 ng/mL for quetiapine and 317 ng/mL for amisulpride under therapeutic doses of the antipsychotic drugs. For ziprasidone or aripriprazole, data on therapeutic drug concentrations are so far lacking. In conclusion, evidence is growing that TDM may improve efficacy and safety in patients treated with the new antipsychotic drugs, especially when patients do not respond or develop side effects under therapeutic doses. The few reported investigations, however, need to be confirmed and extended.     

Atypical antipsychotic drugs: current issues of safety and efficacy in the management of schizophrenia

This review focuses on the comparative safety and efficacy profile of nine atypical antipsychotic drugs (amisulpride, aripiprazole, clozapine, olanzapine, quetiapine, risperidone, sertindole, ziprasidone and zotepine), which may ultimately affect the therapeutic options available for patients with schizophrenia. These antipsychotic compounds differ markedly in their potential to impact a number of quality-of-life measures. Furthermore, their differential effects on anxiety disorders, treatment-resistant depressive illness, cognitive functions and manic disorders may influence the selection of atypical antipsychotics for conditions associated with schizophrenia. The possible relevance of these parameters in evaluating the risk/benefit equation and probable involvement of varying receptor mechanisms is also discussed.     

Antidepressant-like activity of amisulpride in two animal models of depression

Clinical reports suggest that amisulpride, in addition to its antipsychotic efficacy, may also have antidepressant properties. The present study was designed to evaluate potential antidepressant-like activity of amisulpride in two behavioural procedures: the forced swim test (FST) and the chronic mild stress (CMS) model. The duration of immobility time in FST was reduced by subchronic (three injections over a 24 h period) administration of imipramine (10 mg/kg) and amisulpride (1 and 3 mg/kg), although the effect of imipramine was more potent. The 5 mg/kg dose of amisulpride was marginally effective and higher doses of 10 and 30 mg/kg were inactive. In CMS, the stress-induced decrease in the consumption of 1% sucrose solution was gradually reversed by chronic treatment with imipramine (10 mg/kg) and amisulpride (5 and 10 mg/kg). Lower (1 or 3 mg/kg) or higher (30 mg/kg) doses of amisulpride were inactive. The magnitude of the effect of active doses of amisulpride in the CMS model was comparable to that of imipramine but its onset of action was faster; at the most active dose of 10 mg/kg, amisulpride significantly increased the sucrose intake in stressed animals within 2 weeks of treatment while imipramine required 4 weeks before first effects on the stress-induced deficit in sucrose consumption could be observed. These results provide further support for clinical observations that amisulpride may possess potent and rapid antidepressant activity.     

Effects of antipsychotics and reference monoaminergic ligands on marble burying behavior in mice

Antipsychotics constitute efficacious augmenting agents in the treatment of anxiety disorders, including refractory obsessive-compulsive disorder. We examined the effects of 36 compounds, including typical, atypical and novel antipsychotics with dual dopamine D2/5-hydroxytryptamine 1A (D2/5-HT1A) actions on marble burying behavior in mice, a putative preclinical test for anxiety disorders. One hour after drug administration, male NMRI mice were placed individually in cages containing 20 marbles, and the total number of marbles buried after 30 min was counted. The selective serotonin reuptake inhibitors, citalopram (2.5-40 mg/kg), fluoxetine (2.5-10 mg/kg) and the benzodiazepine diazepam (2.5-10 mg/kg), reduced the number of buried marbles. The atypical antipsychotic, clozapine (0.16-10 mg/kg), but not its congener olanzapine, was effective in this test. Haloperidol, a typical antipsychotic, also reduced the number of buried marbles, albeit not in a dose-dependent manner. The atypical risperidone was partially active (0.16-0.63 mg/kg), as was the benzamide derivative, amisulpride, albeit at high (10-40 mg/kg) doses. Among the 'third-generation' antipsychotics possessing combined D2/5-HT1A properties, bifeprunox was active at 0.0025 mg/kg, whereas SLV313 and aripiprazole were active only at the highest doses (2.5 and 10 mg/kg, respectively). SSR181507, F15063 and the antidyskinetic agent, sarizotan, were without any effect. Among a series of receptor subtype-selective ligands, only the 5-HT1A agonist, (+)-8-OH-DPAT (0.63-2.5 mg/kg) and the 5-HT2A/2B/2C antagonist, ritanserin (0.63-2.5 mg/kg) were active. Among novel antipsychotics with dual D2/5-HT1A properties, only bifeprunox was able to potently reduce the number of buried marbles. Inhibition of marble burying behavior may result from the interplay of several receptor systems, including 5-HT2 receptor blockade, dopamine D2 partial agonism and serotonin 5-HT1A agonism.     

The antidepressant-like effects of neurokinin NK1 receptor antagonists in a gerbil tail suspension test

Recent clinical evidence supports the potential of neurokinin NK1 receptor antagonists as novel antidepressant drugs. A number of NK1 antagonists have reduced affinity for rat and mouse NK1 receptors compared to human, making it difficult to test for efficacy in traditional animal models. NK1 antagonists, in general, have similar affinity at gerbil and human NK1 receptors. The aims of these studies were first, to validate the gerbil tail suspension test, a test used frequently to demonstrate antidepressant drug efficacy in mice, and second, to determine whether the test could be used to demonstrate the antidepressant potential of NK1 antagonists. Immobility time was reduced by oral administration of the antidepressants imipramine (3-30 mg/kg), desipramine (1-30 mg/kg), amitriptyline (30 mg/kg), fluoxetine (1-30 mg/kg), paroxetine (3-10 mg/kg), citalopram (0.1-3 mg/kg), sertraline (1-30 mg/kg), venlafaxine (1-30 mg/kg) and nefazodone (100 mg/kg). Furthermore, oral administration of the NK1 antagonists MK-869 (10 mg/kg), L-742694 (10 mg/kg), L-733060 (10 mg/kg), CP-99994 (30 mg/kg), and CP-122721 (3-30 mg/kg) reduced immobility time. Diazepam (1-10 mg/kg), chlordiazepoxide (1-10 mg/kg), buspirone (3-30 mg/kg), FG-7142 (1-30 mg/kg), and haloperidol (1-10 mg/kg) did not reduce immobility. Amphetamine (0.3-10 mg/kg) and atropine (0.3-10 mg/kg) reduced immobility, suggesting susceptibility to false positives, e.g. compounds that affect locomotion. Compounds were therefore tested in a gerbil locomotor activity (LMA) test to ensure that the antidepressant-like effects were not secondary to effects on activity. Antidepressant drugs and NK1 antagonists had no effect on LMA at doses that reduced immobility, whereas amphetamine and atropine induced marked hyperactivity. These studies support both the utility of gerbils in behavioral pharmacology and the antidepressant potential of selective NK1 antagonists.     

Effect of the selective 5-HT7 receptor antagonist SB 269970 in animal models of anxiety and depression

The aim of the present study was to examine the effect of the selective 5-HT7 receptor antagonist SB 269970 (0.25-20 mg/kg) in the behavioral tests commonly used for predicting anxiolytic- and antidepressant-like activity. Diazepam and imipramine were used as standard drugs. SB 269970 (in one medium dose of 0.5 or 1 mg/kg) exerted a specific antianxiety-like effect in the Vogel drinking test in rats, in the elevated plus-maze test in rats and in the four-plate test in mice. Moreover, SB 269970 (in one medium dose of 5 or 10 mg/kg) showed antidepressant-like activity in the forced swimming and the tail suspension tests in mice. At the same time, the tested compound at doses of 1-20 mg/kg did not change the spontaneous locomotor activity of mice. The potential anxiolytic and antidepressant effects produced by SB 269970 were weaker than those of the reference drugs employed. It is noteworthy that the active doses of SB 269970 were devoid of any visible motor side-effects. In conclusion, the results of our studies indicate that 5-HT7 receptor antagonists may play a role in the therapy of both anxiety and depression.     

Current therapy issues and unmet clinical needs in the treatment of schizophrenia: a review of the new generation antipsychotics

This review discusses the atypical antipsychotics, focusing on the possibility of symptom reduction with a minimum of side-effects. A selective review of clinically relevant reports, studies and meta-analyses is presented. The results from clinical trials suggest that atypical agents improve negative and affective symptoms, and cognitive functioning more than typical antipsychotics, but that the pattern of effects on these domains, as well as on suicidality, appears to differ. In clinical trials, the newer drugs generally have less extrapyramidal side-effects (EPS) than typical antipsychotics. However, amisulpride, risperidone, olanzapine and ziprasidone still show evidence of a dose-related increase in EPS, whereas clozapine, quetiapine, sertindole and aripiprazole do not. Weight gain, increased blood lipids/cholesterol, and insulin resistance/type 2 diabetes are emerging as significant treatment-associated concerns, particularly for clozapine and olanzapine. Sedation has been reported for all the newer compounds except sertindole. The considerable variation in benefit/risk profiles of the atypical compounds can help the clinician to select the most appropriate treatment for individual patients.     

Antidepressant-like effects of Albizzia julibrissin in mice: involvement of the 5-HT1A receptor system

The present study was undertaken to investigate the antidepressant-like effects of the methylene chloride fraction of Albizzia julibrissin (MCAJ) using a tail suspension test in mice. MCAJ was orally administered at 50, 100, or 200 mg/kg to mice, 1 h before the tail suspension test. Acute treatment with MCAJ at 200 mg/kg significantly reduced the immobility time compared with the control group, and thus showed an antidepressant-like effect. This effect was comparable to that of imipramine at 10 mg/kg. This antidepressant-like effect was reversed by treatment with WAY-100635 (a 5-HT1A receptor antagonist) or pindolol (a 5-HT1A/1B receptor antagonist). However, the antidepressant effect of MCAJ was not effected by treatment with GR55562 (a 5-HT1B receptor antagonist) or ketanserin (a 5-HT2A receptor antagonist). Therefore, our findings suggest that MCAJ exerts its antidepressant-like effect via the 5-HT1A receptor system.     

Antidepressant-like effect of rutin isolated from the ethanolic extract from Schinus molle L. in mice: evidence for the involvement of the serotonergic and noradrenergic systems

We have recently shown that the hexanic extract from leaves of Schinus molle produces antidepressant-like effects in the tail suspension test in mice. This study investigated the antidepressant-like effect of the ethanolic extract from aerial part of S. molle in the forced swimming test and tail suspension test in mice, two predictive models of depression. Moreover, we investigated the antidepressant potential of rutin, a flavonoid isolated from the ethanolic extract of this plant and the influence of the pretreatment with the inhibitors of serotonin or noradrenaline synthesis, p-chlorophenylalanine methyl ester (PCPA) and alpha-methyl-p-tyrosine (AMPT), respectively in the antidepressant-like effect of this flavonoid. The administration of the ethanolic extract produced a reduction in the immobility time in the tail suspension test (dose range 600-1000 mg/kg, p.o.), but not in the forced swimming test. It also produced a reduction in the ambulation in the open-field test in mice not previously habituated to the arena, but no effect in the locomotor activity in mice previously habituated to the open-field. The administration of rutin reduced the immobility time in the tail suspension test (0.3-3 mg/kg, p.o.), but not in the forced swimming test, without producing alteration in the locomotor activity. In addition, pretreatment of mice with PCPA (100 mg/kg, i.p., for 4 consecutive days) or AMPT (100 mg/kg, i.p.) prevented the anti-immobility effect of rutin (0.3 mg/kg, p.o.) in the tail suspension test. The results firstly indicated the antidepressant-like effect of the ethanolic extract of S. molle in the tail suspension test may be dependent on the presence of rutin that likely exerts its antidepressant-like effect by increasing the availability of serotonin and noradrenaline in the synaptic cleft.     

Evaluation of antidepressant like activity of curcumin and its combination with fluoxetine and imipramine: an acute and chronic study

Curcumin is the active ingredient of commonly used spice Curuma longa Linn. In the present study, the antidepressant like activity of curcumin and its combination with fluoxetine and imipramine was studied in acute model (three doses 24, 5 and 1 h before test) of forced swimming test (FST) in glass jar and tail suspension test (TST) in mice and in chronic model (14 day study) of FST with water wheel in rats. All the tests were carried out in the following seven groups (n = 6 in each group), drugs being given orally (doses for mice): Group 1 (vehicle), group 2 (curcumin 50 mg/kg), group 3 (curcumin 100 mg/kg), group 4 (fluoxetine 20 mg/kg), group 5 (imipramine 15 mg/kg), group 6 (curcumin 100 mg/kg plus fluoxetine 20 mg/kg) and group 7 (curcumin 100 mg/kg plus imipramine 15 mg/kg). Equivalent doses for rats were used. Both the acute model of FST and TST, and the chronic model of FST with water wheel showed significant antidepressant like activity of curcumin in 100 mg/kg dose as compared to vehicle control (p < 0.05). The effect of curcumin (100 mg/kg) was similar to that of fluoxetine and imipramine (p > 0.05) but its addition to fluoxetine and imipramine did not improve their antidepressant activity (p > 0.05). Curcumin increased both the swimming and climbing behavior in FST, thus its antidepressant like activity could be due to an increase in serotonin, norepinephrine and dopamine levels in the brain. Curcumin can be a useful antidepressant especially in cases which respond to drugs having mixed effects on serotonin and catecholamines levels in the brain.     

Combined treatment with atypical antipsychotics and antidepressants in treatment-resistant depression: preclinical and clinical efficacy

Several clinical reports have documented a beneficial effect of adding atypical antipsychotic drugs to ongoing treatments with antidepressants, particularly selective serotonin reuptake inhibitors, in ameliorating drug-resistant depression. The aim of this paper was to summarize some preclinical evidence describing the mechanism responsible for the therapeutic action of combined treatment with antidepressants and atypical antipsychotics and also some clinical data supporting the efficacy and safety of the augmentation strategy for improving antidepressant-resistant depression using atypical antipsychotics. This analysis is based on five microdialysis studies and nine behavioral studies assessing the impact of combined atypical antipsychotic and antidepressant treatments on extracellular levels of dopamine, serotonin and noradrenaline in the prefrontal cortex of freely moving rats and on antidepressant-induced effects, respectively. In addition, clinical data demonstrating the efficacy and safety of augmentation strategies for treatmentresistant depression using atypical antipsychotics were included. Combined treatment of rats with all studied atypical antipsychotics (olanzapine, risperidone, clozapine and quetiapine) and antidepressants (citalopram, fluoxetine and fluvoxamine) increased the extracellular level of dopamine in the prefrontal cortex compared to a respective drug given alone; in addition, a combination of olanzapine or quetiapine plus fluoxetine or fluvoxamine increased the levels of dopamine and noradrenaline. Moreover, atypical antipsychotics administered in a low dose enhanced the antidepressant-like activity of antidepressants, with (among other mechanisms) the serotonin 5-HT_1A, 5-HT_2A and adrenergic a₂ receptors likely playing an important role in their action. The results support the conclusion that atypical antipsychotics may be effective as adjunctive therapy in treatment-resistant depression; however, their adverse effect profile may be unfavorable in some patients.     

Enhancement of the anti-immobility action of antidepressants by a selective 5-HT7 receptor antagonist in the forced swimming test in mice

Using the forced swimming test in mice, we examined the effect of the following antidepressants: citalopram, imipramine, desipramine and moclobemide (which are characterized by different mechanisms of action), administered in combination with the selective 5-HT7 receptor antagonist (2R)-1-[(3-hydroxyphenyl)sulfonyl]-2-[2-(4-methyl-1-piperidinyl)ethyl]-pyrrolidine (SB 269970). All those drugs were given in doses which did not shorten the immobility time of mice. Citalopram (1.25 mg/kg), imipramine (10 mg/kg), desipramine (5 mg/kg) or moclobemide (10 mg/kg) administered jointly with SB 269970 (5 mg/kg), produced a significant antidepressant-like effect. None of the compounds studied, given alone or in combination, increased the spontaneous locomotor activity of mice. The obtained results indicate that blockade of 5-HT7 receptors may facilitate the anti-immobility effect of antidepressants in mice.     

Anxiolytic and antidepressant activities of methanol extract of Aegle marmelos leaves in mice

The objective of the present study was to evaluate the anxiolytic and antidepressant activities of methanol extract of Aegle marmelos (AM) leaves as well as its interaction with conventional anxiolytic and antidepressant drugs using elevated plus maze and tail suspension test in mice. Albino mice were treated with AM (75, 150 and 300 mg/kg, po), imipramine (20 mg/kg, po), fluoxetine (20 mg/kg, po), and combination of sub-effective dose of AM with imipramine or fluoxetine. Effects were observed on (a) time spent on (b) number of entries into (c) number of stretch attend postures (d) number of head dips in arms of elevated plus maze and on duration of immobility in tail suspension test. Effects of pretreatment with prazosin (0.062 mg/kg, po), haloperidol (0.1 mg/kg, po) and baclofen (10 mg/kg, po) were also studied on AM induced decrease in duration of immobility. Effects of AM (75, 150 and 300 mg/kg po) were observed on locomotor activity using photoactometer. Results showed that AM significantly (P<0.05) and dose dependently increased proportionate time spent on and number of entries into open arms while decreased number of stretch attend postures and head dips in closed arms. Dose dependent and significant (P<0.05) anti-immobility effect was found in mice treated with AM. Combination of AM (75 mg/kg, po) with imipramine (5 mg/ kg, po) or fluoxetine (5 mg/kg, po) also produced significant (P<0.05) anxiolytic and antidepressant activity. Antidepressant activity of AM (150 mg/kg, po) was significantly (P<0.05) decreased by prazosin, haloperidol and baclofen. Methanol extract showed insignificant (P>0.05) effect on locomotor activity of mice. It is concluded that AM possess potential anxiolytic and antidepressant activities and it enhances the anxiolytic and antidepressant activities of imipramine and fluoxetine.     

Anti-cataleptic effects of clozapine, but not olanzapine and quetiapine, on SCH 23390- or raclopride-induced catalepsy in rats.

The present study investigated potential anti-cataleptic properties of the prototype atypical antipsychotic clozapine and two newly developed atypical antipsychotics, olanzapine and quetiapine, which are structurally related and display similar pharmacological profiles to clozapine. Clozapine (2.5 mg kg(-1), s.c.), but not olanzapine (2.0 mg kg(-1), s.c.) and quetiapine (20.0 mg kg(-1), s.c.), blocked catalepsy induced either by the dopamine D(1/5) receptor antagonist SCH 23390 (50.0 microg kg(-1), s.c) or the selective dopamine D(2/3) receptor antagonist raclopride (4.0 mg kg(-1), s.c.). Such findings are consistent with the beneficial effects of clozapine in the management of drug-induced psychosis in parkinsonian patients, and suggest that neither olanzapine nor quetiapine may be a safe alternative to clozapine in this field. Furthermore, the results indicate that clozapine has a unique pharmacological profile that distinguishes it from olanzapine and quetiapine. The mechanisms underlying anti-cataleptic or anti-parkinsonian properties of clozapine are unclear but may be related to dopamine D(1) receptor agonism of clozapine.     

8-Cyclopentyl-1,3-dimethylxanthine enhances effectiveness of antidepressant in behavioral tests and modulates redox balance in the cerebral cortex of mice

The objective of our study was to investigate whether 8-cyclopentyl-1,3-dimethylxanthine (CPT), associated with the adenosine system, enhances the antidepressant efficacy of antidepressant. All experiments were carried out on Albino Swiss mice. Following drugs: CPT (3?mg/kg) and imipramine (15?mg/kg) were administered intraperitoneally (ip), 60?min before tests. Two behavioral tests on antidepressant capability – a forced swim test (FST) and a tail suspension test (TST) – were performed. To examine whether co-administration of CPT with antidepressants affects the redox balance, the lipid peroxidation products (LPO), glutathione (GSH), glutathione disulfide (GSSG), nicotinamide adenine dinucleotide phosphate (NADP+), and reduced nicotinamide adenine dinucleotide phosphate (NADPH) were determined in the cerebral cortex. The results have demonstrated a CPT-induced enhancement of the antidepressant-like effect of imipramine both in the FST and TST, which may indicate that the adenosine system may be involved in the increasing the effect of antidepressant. Co-administration of CPT with imipramine, such as imipramine alone, decreased the NADP+ and LPO concentrations and increased the GSH/GSSG ratio in comparison to the control, which may confirm beneficial – but comparable to imipramine – effect on redox balance under environmental stress conditions. An increase in the concentration of GSSG in the cortex of animals treated with imipramine in ineffective dose compared to control and no such changes after combined administration of both drugs may suggest a favorable oxidation-reduction potential resulting from their synergistic antidepressant effect.     

Experimental study of the effects of citalopram, olanzapine, and their combinations in tests for antipsychotic, antidepressant and anxiolytic activities of drugs

The effects of citalopram, olanzapine and their combinations were studied in tests on outbred SHR male mice. The locomotor activity was determined in the open field, the antidepressant effects - in the tail suspension test, the anxiety-like behavior- in the light-dark transition test; in addition, the antidopaminergic effects of drugs and their combination were evaluated using the apomorphine-induced stereotypy. The results indicate that olanzapine inhibits locomotor activity in all behavioral tests, whereas citalopram alone has no significant effect and does not modify the action of olanzapine. An antagonistic interaction between drugs was revealed in tests for the specific antidepressant-like and antidopaminergic activity when citalopram/olanzapine combinations were used. No significant drug influence was observed on the anxiety-related mice behavior in the light/dark test.     

Small-Molecule Inhibitors at the PSD-95/nNOS Interface have Antidepressant-Like Properties in Mice

Previous studies have demonstrated that nitric oxide (NO) synthase inhibitors are as efficacious as tricyclic antidepressants in preclinical antidepressant screening procedures and in attenuating behavioural deficits associated with animal models of depression. The N-methyl-𝒟-aspartate receptor (NMDA-R) complex gates Ca²⁺, which interacts with calmodulin to subsequently activate NO synthase. We hypothesised that uncoupling neuronal nitric oxide synthase (nNOS) from the NMDA-R through the scaffolding protein postsynaptic density protein 95 (PSD-95) would produce behavioural antidepressant effects similar to NO synthase inhibitors. Small-molecule inhibitors of the PSD-95/nNOS interaction, IC87201 (0.01–2 mg/kg) and ZL006 (10 mg/kg) were tested for antidepressant properties in tests of antidepressant activity namely the tail suspension and forced swim tests in mice. We now report that IC87201 and ZL006 produce antidepressant-like responses in the forced swimming test (FST) and tail suspension test (TST) following a single administration in mice. By contrast to the tricyclic antidepressant imipramine (25 mg/kg), the effects are not observed 1 h following drug administration but are apparent 24 and 72 h later. Furthermore prior exposure to the TST or FST is required in order to observe the antidepressant-related activity. Similar delayed and sustained antidepressant-like effects were observed following TRIM (50 mg/kg) and ketamine (30 mg/kg) in the TST. The antidepressant-like effects of ZL006 also generalise to IC87201 in the TST. IC87201 was devoid of effects on locomotor activity and step-through latency in the passive avoidance cognition test. These data support the hypothesis that targeting the PSD-95/nNOS interaction downstream of NMDA-R produces antidepressant effects and may represent a novel class of therapeutics for major depressive disorders.