Influence of antiepileptics on efficacy of antidepressant drugs in forced swimming test

Antidepressant medications are indicated in a variety of sustained mood disorders, including depression, and in epileptic patients. On the other hand, some antiepileptics are also used in the treatment of affective disorders. Therefore, some interactions may appear between antiepileptics and antidepressant drugs. The aim of the present study was to investigate the influence of the treatment with antiepileptic drugs on the antidepressants' activity in mice (forced swimming test or assessment of locomotor activity). The animals received intraperitoneally (ip) antiepileptics: phenytoin (PHT) at 6 or 12 mg/kg, valproate (VAL) at 50, 100, 200 or 300 mg/kg, carbamazepine (CBZ) at 4, 6 or 9 mg/kg, vigabatrin (VGB) at 50, 100, 200 or 300 mg/kg or lamotrigine (LTG) at 12.5 or 25 mg/kg, 30, 60 or 90 min before the injection of antidepressants: imipramine (IMI, 20 mg/kg) amitriptyline (AMI, 10 mg/kg), maprotiline (MAP, 10 mg/kg), mianserin (MIA, 15 mg/kg), fluoxetine (FLX, 40 mg/kg) or fluvoxamine (FLV, 20 mg/kg). It was shown that the acute administration of antidepressant drugs significantly reduced the immobility time in forced swimming test in mice. Antiepileptics, given in a single dose, caused did not change the behavior of mice in this test, however, they abolished the characteristic effect of antidepressant drugs. Each antidepressant, given at a single dose, shortening the immobility time in forced swimming test and reduced the locomotor activity of mice. This sedative effect of antidepressants was intensified by antiepileptics. The present results suggest that antiepileptics can reduce the activating effect of antidepressant drugs of different groups.     

Action of antidepressant drugs on maternal stress-induced hypoactivity in female rats.

It has been reported that rats forced to swim in a restricted space assume, after initial frenzied attempts to escape, an immobile posture. Porsolt et al. referred to this phenomenon as "behavioral despair", an animal model of depression. Prenatal stress induces an increase of behavioral depression in adult female offspring. This study presents new evidence supporting the hypothesis that maternal stress during gestation increases the risk of depression in the offspring since immobility time was modified by antidepressant drugs (tricyclics and an atypical antidepressant). In rats, amitriptyline (5 mg/kg), imipramine (5 mg/kg) and nomifensine (1 mg/kg) decreased the immobility time in Porsolt test in offspring of mothers stressed during gestation. Moreover, increasing doses of amitriptyline (1, 5, 25 and 40 mg/kg) reduced depression in the forced swimming test in dose-dependent manner.     

The 5-HT(1A) receptor agonist F 13640 attenuates mechanical allodynia in a rat model of trigeminal neuropathic pain

It has been reported that the treatment with a tricyclic antidepressant imipramine induces an increase in the sensitivity of 5-HT(1A) receptors and a decrease in the sensitivity of 5-HT(4) receptors in the rat hippocampus. 5-HT(1A) receptor agonists and neuroleptics also affect 5-HT(1A) receptors in different brain areas; therefore, it was of interest to compare their effects on hippocampal 5-HT receptors with the influence of the well-established antidepressant imipramine. We studied the effects of repeated treatment with imipramine, the 5-HT(1A) receptor agonists 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) and buspirone, and the neuroleptics haloperidol and clozapine on the sensitivity of rat hippocampal CA1 neurons to 5-HT(1A)- and 5-HT(4) receptor activation. Imipramine was administered for 21 days (10 mg/kg p.o., twice daily), 8-OH-DPAT for 7 days (1 mg/kg s.c., twice daily) and buspirone for 21 days (5 mg/kg s.c., twice daily). The rats received haloperidol (1 mg/kg) and clozapine (30 mg/kg) for 6 weeks in drinking water. Hippocampal slices were prepared 2 days after the last treatment with imipramine, 8-OH-DPAT or buspirone, and 5 days after the last treatment with the neuroleptics. Using an extracellular in vitro recording, we studied changes in the amplitude of stimulation-evoked population spikes, induced by 5-HT, 8-OH-DPAT and the 5-HT(4) receptor agonist zacopride. Activation of 5-HT(1A) receptors decreased, while activation of 5-HT(4) receptors increased the amplitude of population spikes. Imipramine significantly enhanced the inhibitory effects of 5-HT and 8-OH-DPAT, and attenuated the excitatory effect of zacopride. No other treatment used in the present study changed the sensitivity of hippocampal CA1 neurons to 5-HT(1A) and 5-HT(4) receptors activation. These findings indicate that adaptive changes in the sensitivity of hippocampal neurons to 5-HT(1A) and 5-HT(4) receptors agonists are specific to imipramine and may thus-at least partly-mediate its effects.     

A comparison of drug effects in latent inhibition and the forced swim test differentiates between the typical antipsychotic haloperidol,the atypical antipsychotics clozapine and olanzapine,and the antidepressants imipramine and paroxetine

Current animal models of antipsychotic activity that have the capacity to dissociate between typical and atypical antipsychotic drugs (APDs) have two drawbacks: they require previous administration of a psychotomimetic drug, and they achieve the dissociation by demonstrating effectiveness of atypical but not typical APDs, thus losing specificity and selectivity for APDs. The present experiments were designed to solve these problems by using two non-pharmacological tests: latent inhibition (LI), in which potentiation of the deleterious effects of non-reinforced stimulus pre-exposure on its subsequent conditioning served as a behavioral index for a common action of typical and atypical APDs (antipsychotic), and the forced swim test (FST), in which reduction of immobility served as a behavioral index for a dissimilar action of these drugs (antidepressant). The typical APD haloperidol (0.1 mg/kg), the atypical APDs clozapine (2.5 mg/kg) and olanzapine (0.6 mg/kg), and the antidepressants imipramine (10 mg/kg) and paroxetine (7.0 mg/kg), produced distinct patterns of action in the two tests: haloperidol potentiated LI and increased immobility in the FST, clozapine and olanzapine potentiated LI and decreased immobility in the FST, and imipramine and paroxetine decreased immobility in the FST and did not potentiate LI. Thus, the comparison of drug effects in LI and FST enabled a discrimination between typical and atypical APDs without losing selectivity for APDs.     

Effects of chronic oral administration of imipramine in the rat forced swimming test

Male Wistar rats were treated with imipramine hydrochloride (IMI) in a dose of 2 or 10 mg/kg/24 h in drinking water for 2 weeks, 1, 3 or 6 months. Two or 72 h after the final treatment forced swimming test was performed. It was shown that 2 h after the final dose of 10 mg/kg of IMI the immobility time was reduced following a period of 1-6 month treatment but not after 2 weeks of IMI administration. The dose of 2 mg/kg of IMI has not changed this type of behavior at any time after IMI treatment. After 24 h IMI (2 or 10 mg/kg) decreased the immobility of rats. This paper presents for the first time that also after long-term treatment with IMI the evident effect on the time of immobility in the rat forced swimming test occurs.     

Antidepressant-like effects of N-acetyl-L-cysteine in rats

Oxidative stress disturbances have been reported in depressed patients and in animals submitted to stress. Recent evidence suggests that antidepressants may have antioxidant properties. However, the therapeutic potential of antioxidants as antidepressant drugs has not been systematically investigated. Therefore, this study tested the hypothesis that N-acetyl-L-cysteine (NAC), a cysteine prodrug with powerful antioxidant activity, would possess antidepressant-like properties in the forced swimming test. Male Wistar rats were subjected to 15 min of forced swimming and immediately afterward, 5, and 23 h later received intraperitoneal injections of NAC (5, 15, 50, 150, and 250 mg/kg), imipramine, (15 mg/kg) or vehicle. One hour later they were submitted to the 5 min test swimming session, where immobility time was recorded. Independent groups of animals received the same treatments and their exploratory activity was measured in an open arena for 5 min. NAC (at the doses of 15, 50, and 150 mg/kg) and imipramine induced a significant decrease in immobility time without changing exploratory behavior measured in an open arena. These results suggest that antioxidants such as NAC may have antidepressant effects.     

A possible mechanism for anxiolytic and antidepressant effects of alpha- and beta-amyrin from Protium heptaphyllum (Aubl.) March

In the present study, we examined the anxiolytic and antidepressant effects of the mixture of alpha- and beta-amyrin (AMY), pentacyclic triterpenes isolated from the stem bark resin of Protium heptaphyllum. These effects of AMY were demonstrated by the open-field, elevated-plus-maze, rota rod, forced swimming, and pentobarbital-induced sleeping time tests, in mice. In the open-field test, AMY at the doses of 10, 25 and 50 mg/kg, after intraperitoneal or oral administrations, significantly decreased the number of crossings, grooming, and rearing. All these effects were reversed by the pre-treatment with flumazenil (2.5 mg/kg, i.p.), similarly to those observed with diazepam used as a positive standard. In the elevated-plus-maze test, AMY increased the time of permanence and the number of entrances in the open arms. On the contrary, the time of permanence and the number of entrances in the closed arms were decreased. All these effects were also completely reversed by flumazenil, an antagonist of benzodiazepine receptors. In the pentobarbital-induced sleeping time test, AMY at the same doses significantly increased the animals sleeping time duration. In the rota rod test, AMY did not alter motor coordination and, thus, was devoid of effects, as related to controls. Since AMY, at the doses of 10 and 25 mg/kg, showed a sedative effect in the open field test, lower doses (2.5 and 5.0 mg/kg) were used in the forced swimming test, producing a decrease in the immobility time, similarly to that of imipramine, the positive control. The effect of AMI was greater when it was administered 15 min after imipramine (10 mg/kg). However, the antidepressant AMY effects were not altered by the previous administration of paroxetine, a selective blocker of serotonin uptake. In addition, AMY effects in the forced swimming test were totally blocked by reserpine pretreatment, a drug known to induce depletion of biogenic amines. In conclusion, the present work evidenced sedative and anxiolytic effects of AMY that might involve an action on benzodiazepine-type receptors, and also an antidepressant effect where noradrenergic mechanisms will probably play a role.     

Antidepressant effects of apocynum venetum leaves in a forced swimming test.

An extract of the leaves of Apocynum venetum L. (Apocynaceae) markedly shortened the immobility time of male rats in a forced swimming test (FST) in a dose range of 30-125 mg/kg, indicating a possible antidepressant activity. This effect was comparable to that of the tricyclic antidepressant imipramine (20 mg/kg). Neither imipramine (20 mg/kg) nor the Apocynum extract in various doses (30, 60, 125 mg/kg) produced any overt behavioural change or motor dysfunction in the open field test. This result confirms the assumption that the antidepressant effect of an Apocynum extract in the FST is specific. Further, it can be speculated that this effect might be related to hyperoside and isoquercitrin which are major flavonoids in the extract.     

Antidepressant--like properties of ACEA (arachidonyl-2-chloroethylamide), the selective agonist of CB1 receptors

The antidepressant effect of ACEA (arachidonyl-2-chloroethylamide), a selective agonist of CB1 receptors, and its interaction with fluoxetine were studied in mice. ACEA (1.0 and 2.0 mg/kg i.p.) reduced the immobility time in the forced swimming test and attenuated the head - twitch response to L-5-HTP. The concomitant administration of ACEA (1.0 mg/kg i.p.) and fluoxetine (20 mg/kg i.p.) resulted in the strongest shortening of immobility time, significant in comparison with both ACEA and fluoxetine given alone. The obtained results indicate that ACEA may have antidepressant efficacy and shows a synergistic effect when given with fluoxetine in the forced swimming test.     

Neurochemical responses to antidepressants in the prefrontal cortex of mice and their efficacy in preclinical models of anxiety-like and depression-like behavior: a comparative and correlational study

Rational Marble burying and forced swimming behavior are widely used and sensitive tests for identifying clinically effective antidepressant drugs, although the underlying neurobiology of these behaviors is not fully elucidated. Objectives The objective of this study was to determine the relationship between the behavioral effects of antidepressant drugs and their ability to modulate extracellular neurotransmitter levels in the prefrontal cortex. Materials and methods The effects of fluoxetine, fluvoxamine, citalopram, imipramine, and desipramine (0 to 60 mg/kg by oral gavage, except fluoxetine at 0 to 40 mg/kg) were studied independently in CD-1 mice in the marble-burying task, forced swim task and on extracellular concentrations of serotonin, norepinephrine, and dopamine in the prefrontal cortex by freely moving microdialysis. Results Fluvoxamine, fluoxetine, and citalopram all suppressed marble-burying behavior, but produced no change in immobility time in the forced swim test. In contrast, imipramine and desipramine suppressed both marble-burying behavior and increased swimming time in the forced swim test, although desipramine mildly suppressed locomotor activity at the maximal dose. Fluvoxamine, fluoxetine, and citalopram all increased extracellular levels of cortical serotonin. Desipramine and imipramine increased extracellular dopamine levels. Fluoxetine, desipramine, and imipramine increased extracellular norepinephrine levels. Correlational analysis revealed a positive correlation between efficacy of drugs in the forced swim test and cortical extracellular dopamine levels, whereas a positive correlation was found between efficacy in the marble-burying test and extracellular serotonin levels. Conclusions Although marble burying and forced swimming behavior have strong predictive validity in tests of antidepressant action, each assay appears to be underpinned by entirely different neurochemical systems.     

Influence of ACTH on the effects of imipramine, desipramine and lithium on duration of immobility of rats in the forced swim test.

We examined the effects of adrenocorticotropic hormone (ACTH) on the immobilization of rats in the forced swim test with the administration of imipramine, desipramine, or lithium. A single administration of either imipramine (10-30 mg/kg, i.p.) or desipramine (30 mg/kg, i.p.) significantly decreased the duration of immobility in normal rats in a dose-dependent manner. Lithium (10-100 mg/kg, p.o.), however, had no affect on the performance of rats in the forced swim test. ACTH (100 microg/day), administered subcutaneously to rats for 1, 3, 7, and 14 days, had no apparent effect on the duration of immobility in this test. The immobility-decreasing effect induced by a single administration of either imipramine (10-30 mg/kg, i.p.) or desipramine (30 mg/kg, i.p.) was blocked by chronic administration of ACTH for 3-14 days. The reduction of immobility, induced by chronic administration of imipramine (10 mg/kg, i.p.) for 15 days, was blocked by treatment with ACTH for 14 days. When lithium (100 mg/kg, p.o.) was administered for 15 days concurrently with imipramine (10 mg/kg, i.p.), we observed a significant decrease in immobility in rats treated with ACTH for 14 days. We suggest that chronic treatment of rats with ACTH may prove to be an effective model of tricyclic antidepressants-treatment-resistant depression.     

N-palmitoylethanolamide, an endocannabinoid, exhibits antidepressant effects in the forced swim test and the tail suspension test in mice

The antidepressant-like effects of N-palmitoylethanolamide (PEA), a putative endocannabinoid, was investigated in mice using the tail suspension test (TST) and the forced swimming test (FST). In TST, PEA (10, 20, and 40 mg/kg) produced a statistically significant reduction in immobility (50, 32, and 34%, respectively, vs. the control group), whereas fluoxetine (20 mg/kg) reduced immobility by 38%. In FST, PEA (5, 10, and 20 mg/kg) produced a statistically significant reduction in immobility (15, 21, and 36%, respectively), whereas fluoxetine (20 mg/kg) reduced immobility by 18%. Moreover, PEA (20 mg/kg) did not significantly change motor activity in a spontaneous behavioral test. In conclusion, PEA (dose range of 5-40 mg/kg) administered orally reduced immobility in TST and FST, comparable to the antidepressant effect of fluoxetine, and had no effect on spontaneous activity in mice.     

Antidepressant-like effect of asiaticoside in mice

In the present study, the potential antidepressant properties of asiaticoside were investigated in male mice in three tests -- splash test in the unpredictable chronic mild stress (CMS) model, tail suspension test (TST), forced swimming test (FST) -- with clomipramine being a positive control. In the splash test, asiaticoside (10 mg/kg, PO) and clomipramine (50 mg/kg, PO) significantly augmented the frequency of grooming behavior in stressed mice. In the tail suspension test, asiaticoside (10, 20 mg/kg, PO) and clomipramine (50 mg/kg, PO) significantly decreased immobility time. In the forced swimming test, asiaticoside (10, 20 mg/kg, PO) and clomipramine (50 mg/kg, PO) significantly decreased immobility time. These results suggest that asiaticoside may have antidepressant-like action.     

Anti-depressant action of melatonin in chronic forced swimming-induced behavioral despair in mice, role of peripheral benzodiazepine receptor modulation

The possible antidepressant effect of physiological and pharmacological doses of melatonin was investigated in the Porsolt forced swimming-induced behavioral despair test. The duration of immobility period of BALB/c and C57BL/6J mice during a 6-min swim test was measured at noon (11:00–12:00 h), early dark (20:00–21:00 h) and at midnight (1:00–2:00 h), respectively. The circadian time cycle did not alter the duration of immobility in either strains of mice. Similarly, exogenously administered melatonin (10–1000 μg/kg50 nM to 5 μM/mouse), a dose that could act on high affinity melatonin receptors, did not modify the duration of immobility period at any of the time intervals studied in either strains of the mice. This suggested that neither circadian variation influenced the duration of immobility period of BALB/c and C57BL/6J mice nor at physiological doses melatonin showed any anti-depressant action. Acute administration of higher doses of melatonin (2.5–10 mg/kg) failed to induce any anti-depressant activity in mice which were subjected to forced swimming test for the first time. However, daily administration of melatonin (2.5–10 mg/kg) prior to swimming test significantly reversed the increase in immobility period that was observed on chronic exposure to swimming test. This effect was comparable with the effect of GABA-benzodiazepine (BZ) receptor agonists. Similarly, like GABAergic drugs, acute administration of melatonin also showed anti-depressant activity in a mice which were exposed to chronic forced swimming test. The anti-depressant action of melatonin was sensitive to reversal by peripheral BZ receptor antagonist, PK11195. Whereas, flumazenil failed to reverse the anti-depressant action of melatonin, thereby suggesting that central BZ receptor were not involved in its action. In conclusion the study showed that at pharmacological doses melatonin has anti-depressant action in chronic forced swimming-induced despair behavior by an action involving peripheral BZ receptors.     

Acute administration of clozapine, thioridazine and metoclopramide increases extracellular DOPAC and decreases extracellular 5-HIAA, measured in the nucleus accumbens and striatum of the rat using in vivo voltammetry

Changes in the extracellular levels of dihydroxyphenylacetic acid (DOPAC) and 5-hydroxy-indoleacetic acid (5-HIAA) after acute administration of clozapine (50 mg/kg s.c.), thioridazine (20 mg/kg s.c.) and metoclopramide (5 mg/kg s.c.), were monitored using in vivo voltammetry with micro-carbon electrodes implanted in the nucleus accumbens and striatum of the rat anaesthetised with halothane/N2O. Both clozapine and thioridazine increased extracellular levels of DOPAC in the striatum and the nucleus accumbens. The maximum increases with clozapine were 60% and 86% in the nucleus accumbens and striatum and 44% and 55% with thioridazine. Both neuroleptics also decreased the extracellular level of 5-HIAA in these regions of the brain. Metoclopramide increased the extracellular level of DOPAC in the nucleus accumbens (42%) and the striatum (57%) and significantly decreased the level of 5-HIAA in the nucleus accumbens. These results suggest that the two so-called atypical neuroleptics, clozapine and thioridazine, do not have selective effects on the metabolism of dopamine in vivo in the nucleus accumbens after acute administration. Furthermore, neuroleptic-induced increases in dopamine metabolism are accompanied by reciprocal decreases in 5-hydroxytryptamine metabolism in vivo.     

Synergistic effect of imipramine and amantadine in the forced swimming test in rats. Behavioral and pharmacokinetic studies

Our previous studies demonstrated that joint administration of a tricyclic antidepressant drug, imipramine (IMI) with the uncompetitive antagonist of NMDA receptor, amantadine (AMA), produced stronger "antidepressant" effect in the forced swimming test (Porsolt's test) than the treatment with either of drugs given alone. Since it has been suggested that, in addition to their other functions, dopamine and alpha(1)-adrenergic receptors may play a role in behavioral response in the forced swimming test, in the present study we examined the effect of sulpiride (dopamine D(2/3) receptor antagonist) and prazosin (alpha(1)-adrenergic receptor antagonist) on the effect of AMA given alone or in combination with IMI in the forced swimming test in rats. We also measured the level of IMI and its metabolite, desipramine, in the rat plasma and brain, 1 h after the forced swimming test. Joint treatment with IMI (5 or 10 mg/kg) and AMA (20 mg/kg) produced stronger antidepressant-like effect than either of agents given alone. Sulpiride (10 mg/kg) or prazosin (1 mg/kg) (ineffective in the forced swimming test) inhibited an antidepressant-like effect induced by co-administration of IMI and AMA. The active behaviors in that test did not reflect an increase in general activity, since combined administration of IMI and AMA failed to enhance the locomotor activity of rats, measured in the open field test. Also sulpiride and prazosin did not decrease the exploratory activity induced by co-administration of IMI and AMA. The above result suggests that the dopamine D(2/3) and alpha(1)-adrenergic receptors may contribute to the mechanism of synergistic action of IMI and AMA in the forced swimming test in rats. The pharmacokinetic interaction can be excluded, since AMA did not change significantly the antidepressant level in the rat plasma and brain, measured 1 h after exposure to the forced swimming test.     

Synergistic effect of uncompetitive NMDA receptor antagonists and antidepressant drugs in the forced swimming test in rats

In spite of intensive research, the problem of treating antidepressant-resistant depressive patients has not yet been solved. The authors previously reported that combined administration of imipramine and the uncompetitive NMDA receptor antagonist amantadine reduced immobility time in the forced swimming test in rats to a much greater extent than either treatment alone. The present paper investigates the possibility of synergistic interactions between three antidepressants (imipramine, venlafaxine, fluoxetine) with three uncompetitive NMDA receptor antagonists (amantadine, memantine and neramexane). Most combinations resulted in synergistic (hyperadditive) antidepressive-like effects in the forced swim test. Most interesting was the observation that fluoxetine, which was inactive when given alone, showed a positive effect when combined with amantadine (10 and 20 mg/kg), memantine (2.5 and 5 mg/kg) or neramexane (2.5 and 5 mg/kg). The specificity of these observations is supported by control open field studies, which demonstrated no significant increase, or even a decrease in general locomotion after coadministration of the compounds. The present results suggest that the combination of traditional antidepressant drugs and NMDA receptor antagonists may produce enhanced antidepressive effects, and this is of particular relevance for antidepressant-resistant patients.     

Role of emotionality on inter and intrastrain variations in imipramine response. a comparative study in Balb/c and Swiss mice

Association between emotionality and effect of imipramine on immobility time in forced swimming test was investigated in Swiss and Balb/c mice. Mice of both the strains were segregated into normal emotional (mean +/- 1SD), low emotional (> mean + 1SD) and high emotional (< mean - 1SD) based on their performance with respect to each indices of emotionality in novel arena and elevated plus maze. Baseline immobility and effect of imipramine (20 mg/kg, po) on immobility time was evaluated in these emotionally different groups of mice using forced swimming test model. Baseline immobility time of low emotional mice was found to be significantly less (P<0.01) and that of high emotional mice was found to be significantly more (P<0.01) when compared to normal emotional mice of both the strains. Immobility time after imipramine administration was found to be significantly less (P<0.05) with low emotional mice and significantly more (P<0.01) with high emotional mice when compared to normal emotional mice of both the strains.     

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.     

A comparison of the neurochemical and behavioral effects of clenbuterol and desipramine

Because both long-term adrenoceptor agonist administration and antidepressant treatment in animals down-regulate CNS beta-adrenoceptors and attenuate brain adenylate cyclase activity, beta-adrenoceptor agonists may also possess antidepressant properties. We compared the effects of the centrally acting beta-adrenoceptor agonist clenbuterol (5, 10 and 35 mg/kg per day), and the combination of propranolol (5 mg/kg per day) and clenbuterol (10 mg/kg per day), with desipramine (15 mg/kg per day) on forced swim test performance and on cortical beta-adrenoceptors in rats following 7 days of drug administration. Desipramine (15 mg/kg per day), and clenbuterol (10 and 35 mg/kg per day, but not 5 mg/kg per day) both significantly reduced immobility in the forced swim test. Frontal cortex beta-adrenoceptors were significantly down-regulated after desipramine and all 3 doses of clenbuterol. The co-administration of propranolol (5 mg/kg per day) blocked both the reduction in immobility and down-regulation of cortical beta-receptors induced by clenbuterol (10 mg/kg per day). Propranolol (5 mg/kg per day) alone up-regulated frontal cortex beta-adrenoceptors, but had no significant effect on swimming performance. These data suggest that the physiological consequences of beta-adrenoceptor down-regulation are important in the mechanism of action of antidepressants. The results also suggest that clenbuterol may be useful in the treatment of depression.