Effect of curcumin against pentylenetetrazol-induced seizure threshold in mice: possible involvement of adenosine A1 receptors.

Curcumin, obtained from Curcuma longa, has been in use for manifold human disorders. The present study explores the effect of curcumin against pentylenetetrazol (PTZ) seizure threshold in mice. The possible involvement of adenosine receptor(s) mechanism was also investigated. Minimal dose of PTZ (i.v., mg/kg) needed to induce different phases of convulsions were recorded as an index of seizure threshold. Curcumin (20-120 mg/kg, p.o.) produced an increase in seizure threshold for convulsions induced by PTZ i.v. infusion. The anticonvulsant effect of curcumin (80 mg/kg) was prevented by 8-phenyltheophylline (0.5 mg/kg, i.p., non-selective adenosine receptor antagonist) and 8-cyclopentyl-1,3-dipropylxanthine (5 mg/kg, i.p., adenosine A1 receptor antagonist) but not by 8-(3-cholorostryl)caffeine (4 mg/kg, i.p., adenosine A2A receptor antagonist). Further, 5'-N-ethylcarboxamidoadenosine (0.005 mg/kg, i.p., non-selective A1 /A2 receptor agonist), or N(6) -cyclohexyladenosine (0.2 mg/kg, i.p., adenosine A1 receptor agonist), was able to potentiate the anticonvulsant action of curcumin. In contrast, 5'-(N-cyclopropyl) carboxamidoadenosine (0.1 mg/kg, i.p., adenosine A2A receptor agonist) failed to potentiate the effect of curcumin. This study demonstrated the anticonvulsant effect of curcumin against PTZ i.v. seizure threshold via a direct or indirect activation of adenosine A1 but not A2A receptors in mice. Thus, curcumin may prove to be an effective adjunct in treatment of convulsions.

Development and Validation of HPTLC Method for Estimation of Tenoxicam and its Formulations.

A simple, precise, accurate and rapid high performance thin layer chromatographic method has been developed and validated for the estimation of tenoxicam in the microemulsion gels. Tenoxicam was chromatographed on silica gel 60 F(254) TLC plate, as a stationary phase. The mobile phase was toluene: ethyl acetate: formic acid (6:4:0.3 v/v/v), which gave a dense and compact spot of tenoxicam with a R(f) value of 0.38±0.03. The quantification was carried out at 379 nm. The method was validated in terms of linearity, accuracy, precision and specificity. To justify the suitability, accuracy and precision of the proposed method, recovery studies were performed at three concentration levels. Statistical analysis proved that the proposed method is accurate and reproducible with linearity in the range of 100 to 400 ng. The limit of detection and limit of quantification for tenoxicam were 25 and 50 µg/spot, respectively. The proposed method can be employed for the routine analysis of tenoxicam as well as in pharmaceutical formulations.

Evaluation of antidepressant-like activity of novel water-soluble curcumin formulations and St. John's wort in behavioral paradigms of despair.

BACKGROUND: Curcumin is the active principle of Curcuma longa, one of the widely used components in the traditional system of medicine in India. Despite its efficacy in experimental studies aiming at neuronal disorders like depression, curcu-min's poor water solubility challenges the production of therapeutic formulations. This study investigates the antidepressant-like activity of novel water-soluble curcumin formulations, dispensed in three different concentrations. Further, the study comparatively evaluates St. John's wort (SJW), another herbal preparation. METHODS: These compounds were evaluated in the forced swimming test in mice, and the corresponding changes in the neurotransmitter levels were measured. RESULTS: Three water-soluble curcumin formulations, C-5, C-20 and C-50 (50-200 mg/kg p.o.) decreased the immobility period, and increased serotonin and dopamine levels in the brain tissues. A subeffective dose (50 mg/kg) of these formulations enhanced the antidepressant-like effect of classical antidepressants with varied mechanisms of action. In addition, an SJW dose of 25 mg/kg showed a significant antidepressant-like effect in all the behavioral studies and also significantly increased brain neurotransmitter levels, especially that of serotonin. The effects produced by C-5 were comparable with those of SJW and fluoxetine, respectively. CONCLUSION: In all these observations, the water-soluble formulations showed a significant antidepressant-like effect, including enhancement of neurotransmitter levels as compared to the similar dose of a conventional curcumin preparation. Thus, these formulations may be used as a novel treatment option in the management of mental depression.

Antidepressant-like effect of 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-YL)-cyclohexanol, a putative trace amine receptor ligand involves l-arginine-nitric oxide-cyclic guanosine monophosphate pathway.

1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-YL)-cyclohexanol is a novel putative trace amine receptor modulator hypothesized to be useful for treatment-resistant depression. In our previous study, we have demonstrated the antidepressant-like effect of this molecule in mouse forced swim and tail suspension tests and shown to act via modulating the levels of norepinephrine, serotonin and dopamine. The present study attempts to explore the involvement of l-arginine-nitric oxide-cyclic guanosine monophosphate pathway in the antidepressant-like effect of 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-YL)-cyclohexanol in the mouse forced swim test. The antidepressant-like action of 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-YL)-cyclohexanol (8 mg/kg, i.p) was reversed by pretreatment with L-arginine (750 mg/kg, i.p.), a nitric oxide precursor. In contrast, pretreatment with methylene blue (a soluble guanlyate cyclase inhibitor and nitric oxide synthase (NOS) inhibitor) or 7-nitroindazole (a specific neuronal NOS inhibitor) potentiated the antidepressant-like effect of sub-effective dose of 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-YL)-cyclohexanol (2mg/kg, i.p.) in this test model. Furthermore, the antidepressant-like effect of this molecule (8 mg/kg, i.p.) was reversed by sildenafil (5mg/kg, i.p.), a phosphodiesterase inhibitor. In conclusion, the antidepressant-like action of 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-YL)-cyclohexanol involved L-arginine-nitric oxide-cyclic guanosine monophospate signaling pathway.

Nitric oxide and major depression.

Nitric oxide has been known to play a significant role in the pathophysiology of various disorders of the body. Despite its very short half-life, nitric oxide is known to modulate various neurotransmitter system(s) in the body and thus is speculated to play an imperative role in the pathogenesis of neurological disorders. This "wonder" molecule has been often found to possess a "dual role" in many neurological disorders of the body. Evidences have shown its prominent role in the pathogenesis of major depression. Nitric oxide modulates norepinephrine, serotonin, dopamine, glutamate, the major neurotransmitters involved in the neurobiology of major depression. The nitric oxide modulatory activity of various new generations of antidepressants has been demonstrated. Clinical studies have also confirmed the nitric oxide modulatory activity of various antidepressants particularly belonging to the class of selective serotonin reuptake inhibitors. The present review attempts to discuss the role of nitric oxide in the pathophysiology of major depression. Further, the involvement of nitric oxide system in the mechanism of various antidepressants has been discussed in detail. Nitric oxide based antidepressants can be the future drugs of choice for major depression, particularly in the treatment of pharmacoresistant depression.

Evaluation of antidepressant activity of 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-YL)-cyclohexanol, a ß-substituted phenylethylamine in mice.

The ß-phenylethylamines are known to act as ligands for the trace amine receptors, a novel family of G-protein-coupled receptors. The trace amines are stored and released along with various neurotransmitter agents such as norepinephrine, serotonin, and dopamine and thus work as neuromodulator or neurotransmitter agents. Trace amines are known to play an important role in the pathophysiology of major depression. In our earlier study, we have demonstrated the synthesis of various ß-substituted phenylethylamine molecules hypothesized to be effective in various central nervous system disorders. The present study is an attempt to evaluate one of such molecules, 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-cyclohexanol, in animal models of depression. Various behavioral paradigms of despair such as forced swim and tail-suspension tests were used to assess the antidepressant-like activity. Further, an alteration in the levels of various neurotransmitters (norepinephrine, serotonin, and dopamine) in the mouse brain following 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-cyclohexanol administration was evaluated. The molecule (4-16 mg/kg., i.p.) dose-dependently inhibited the immobility period in mouse forced swim test, the effect comparable to venlafaxine. The ED50 values of 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-cyclohexanol and venlafaxine in mouse forced swim test were found to be 5.27 [4.38-6.35] mg/kg., i.p and 4.66 [3.48-6.25] mg/kg., i.p., respectively. Further, 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-cyclohexanol at 4-16 mg/kg., i.p. reversed the immobility period in mouse tail-suspension test. Additionally, the molecule at 8 mg/kg., i.p. reversed reserpine-induced behavioral despair in mouse forced swim test. When administered simultaneously, it (4 and 8 mg/kg., i.p) enhanced the antidepressant activity of sub-effective doses of imipramine (2mg/kg., i.p.) or fluoxetine (2mg/kg., i.p.) in the mouse forced swim test. Neurochemical analysis revealed that the molecule at 8 mg/kg., i.p. increased the levels of norepinephrine (21% increase) without affecting serotonin in the mouse brain. However, at higher dose (16 mg/kg., i.p.), it increased the levels of norepinephrine (13% increase), serotonin (37% increase), and dopamine (42% increase). The molecule enhanced the locomotor activity in mice only at higher doses. The molecule, unlike venlafaxine, which potentiated barbiturate-induced hypnosis, was devoid of any sedative activity. In conclusion, 1-(7-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinolin-4-yl)-cyclohexanol, possess antidepressant-like activity in animal models of depression by modulating the neurotransmitter levels in the brain. Such an activity might be due to the modulating action of this novel molecule on trace amine receptors. Such a molecule may be the future drugs of choice for the treatment of major depression.

Targeting oxidative stress, mitochondrial dysfunction and neuroinflammatory signaling by selective cyclooxygenase (COX)-2 inhibitors mitigates MPTP-induced neurotoxicity in mice.

Several studies have pointed towards the role of oxidative stress, mitochondrial dysfunction and neuroinflammation in Parkinson's disease (PD). The present study was focused on the possible neuroprotective effect of selective cyclooxygenase (COX)-2-inhibitors: valdecoxib and NS-398 in 1-methyl-4-phenyl-1,2,3,6-tertahydropyridine (MPTP)-induced neurotoxicity in mice. MPTP administration in dose of 40 mg/kg, i.p (four injections of 10mg/kg, i.p. at an interval of 1h each) significantly induced the Parkinson-like symptoms in mice as indicated by change in locomotor activity, inability to correct posture (bar test), and oxidative stress (increased levels of lipid peroxidation, nitrite concentration, and depletion of antioxidant enzyme). MPTP administration significantly impaired mitochondrial complex-I activity and redox activity, upregulated the caspase-3 and NF-κB levels as compared to vehicle group. Treatment with valdecoxib (5 or 10 mg/kg, p.o.) or NS-398 (5 or 10mg/kg, p.o.) for 7 days significantly reversed behavioral, biochemical, mitochondrial complex alterations as well as attenuated the induction of proinflammatory mediators in MPTP-treated groups. The findings of the present study substantiate the neuroprotective role of selective COX-2 inhibitors in ameliorating MPTP-induced neurodegeneration in mice and suggest the possible therapeutic potential of these drugs in the management of PD.

Effect of preferential cyclooxygenase-2 (COX-2) inhibitor against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced striatal lesions in rats: behavioral, biochemical and histological evidences.

Cyclooxygenase (COX) isoenzyme is known to play an important role in the pathophysiology of Parkinson's disease. The present study evaluated the neuroprotective effect of nimesulide, a preferential COX-2-inhibitor against 1-methyl-4-phenyl-1,2,3,6-tertahydropyridine (MPTP)-model of Parkinson's disease. Intrastriatal administration of MPTP (32 micromol in 2 microl) produced a significant decrease in the locomotor activity. Biochemical investigation of striatal region revealed a significant enhancement in the oxidative stress as evidenced by increased lipid peroxidation levels, nitrite levels and myeloperoxidase activity along with depleted antioxidant pool (reduced glutathione and superoxide dismutase levels) and reduced redox (GSH/GSSG) ratio. MPTP administration also showed significant mitochondrial complex-I inhibition and reduction in the mitochondrial viability. Histological examination of the MPTP-treated brain sections revealed alteration in the histo-architecture as well as undifferentiated bodies of varying contour and lesions. Chronic administration of nimesulide (5 or 10 mg/kg, po) for 12 days, significantly reversed the behavioral, biochemical, mitochondrial and histological alterations induced by MPTP. In conclusion, the findings of the present study implicate the possible neuroprotective potential of nimesulide in MPTP-treated rats and thus highlight the therapeutic potential of COX-inhibitors in treatment of Parkinson's disease.

An overview of curcumin in neurological disorders.

Curcumin, the principal curcuminoid found in spice turmeric, has recently been studied for its active role in the treatment of various central nervous system disorders. Curcumin demonstrates neuroprotective action in Alzheimer's disease, tardive dyskinesia, major depression, epilepsy, and other related neurodegenerative and neuropsychiatric disorders. The mechanism of its neuroprotective action is not completely understood. However, it has been hypothesized to act majorly through its anti-inflammatory and antioxidant properties. Also, it is a potent inhibitor of reactive astrocyte expression and thus prevents cell death. Curcumin also modulates various neurotransmitter levels in the brain. The present review attempts to discuss some of the potential protective role of curcumin in animal models of major depression, tardive dyskinesia and diabetic neuropathy. These studies call for well planned clinical studies on curcumin for its potential use in neurological disorders.

Effect of Convolvulus pluricaulis Choisy and Asparagus racemosus Willd on learning and memory in young and old mice: a comparative evaluation.

A dose dependent enhancement of memory was observed with A. racemosus and C. pluricaulis treatment as compared to control group when tested on second day. A. racemosus and C. pluricaulis at the dose of 200 mg/kg, po showed significantly higher percent retentions, than piracetam. Multiple treatment with A. racemosus and C. pluricaulis for three days also demonstrated significant dose dependent increase in percent retentions as compared to control group. The effect was more prominent with C. pluricaulis as compared with piracetam and A. racemosus. A significantly lower percent retention in aged mice was observed as compared to young mice. Aged mice (18-20 months) showed higher transfer latency (TL) values on first and second day (after 24 h) as compared to young mice, indicating impairment in learning and memory. Pretreatment with A. racemosus and C. pluricaulis for 7 days enhanced memory in aged mice, as significant increase in percent retention was observed. Significantly higher retention was observed with C. pluricaulis (200 mg/kg; po) as compared with piracetam (10 mg/kg/; po). Post-trial administration of C. pluricaulis and A. racemosus extract demonstrated significant decrease in latency time during retention trials. Hippocampal regions associated with the learning and memory functions showed dose dependent increase in AChE activity in CA 1 with A. reacemosus and CA3 area with C. pluracaulis treatment. The underlying mechanism of these actions of A. racemosus and C. pluricaulis may be attributed to their antioxidant, neuroprotective and cholinergic properties.

Licofelone attenuates MPTP-induced neuronal toxicity: behavioral, biochemical and cellular evidence.

Neuroinflammation and oxidative stress play critical role in the pathophysiology of neurodegenerative diseases including Parkinson's disease (PD). Recent reports indicate the beneficial effect of anti-inflammatory drugs in attenuating the progression of PD. Therefore, the present study is aimed to evaluate the possible role of licofelone, a dual COX/LOX-inhibitor against MPTP-induced neurotoxicity in mice. Administration of MPTP (40 mg/kg in divided doses of four injections of 10 mg/kg, i.p. each at 1 h interval) significantly impaired locomotor activity and induced catatonia, oxidative damage (elevated levels of lipid peroxidation, superoxide anion and nitrite, and decreased levels of non-protein thiols) as compared with vehicle-treated animals. Biochemical studies revealed significant alterations in mitochondrial enzyme complex activities (decreased complex-I activity and mitochondrial viability) and increased levels of caspase-3 and NF-κB/p65 as compared to vehicle treated group. Licofelone (2.5, 5 or 10 mg/kg/day, p.o.) treatment for 7 days significantly improved locomotor activity, attenuated the severity of catatonia, oxidative damage and restored mitochondrial enzyme complex activity as compared to MPTP-treated group. Licofelone treatment also attenuated the expression of apoptotic factor (caspase-3) and transcription factor (NF-κB/p65) as compared to MPTP-treated group. The findings of the present study suggest that licofelone (dual inhibitor of COX and LOX) represents a new class of anti-inflammatory agent which may provide a novel therapeutic alternative for the treatment and management of PD.

Berberine: a plant alkaloid with therapeutic potential for central nervous system disorders.

Berberine, an isoquinoline alkaloid of the protoberberine type found in an array of plants, has been used in Indian and Chinese medicines as an antimicrobial, stomachic, bitter tonic and in the treatment of oriental sores. Although pharmacological investigations of berberine have been reported by many in the past, there is renewed interest in berberine because of its reported beneficial effect in various neurodegenerative and neuropsychiatric disorders. The alkaloid is reported to modulate neurotransmitters and their receptor systems in the brain. This review attempts to discuss the pharmacological basis of the use of berberine in various central nervous system and related disorders. Its protective effect in Alzheimer's, cerebral ischemia, mental depression, schizophrenia and anxiety are highlighted. However, more detailed clinical trials along with a safety assessment of berberine are warranted for positioning the alkaloid in the treatment of neurological disorders.

Effect of various antiepileptic drugs in a pentylenetetrazol-induced seizure model in mice.

The present study was undertaken to compare the anticonvulsant effect of various antiepileptic drugs on the intravenous pentylenetetrazol (PTZ)-induced seizure threshold in mice. Minimal doses of PTZ needed to induce different phases (myoclonic jerks, generalized clonus and tonic extensor) of convulsions were recorded as an index of seizure threshold. Furthermore, TID50 (the dose of an anticonvulsant drug required to increase the PTZ seizure threshold for tonic extensor by 50%) was calculated for all drugs, and from these values the potency ratio was determined. Pentobarbital (10-40 mg/kg i.p.), phenobarbital (5-20 mg/kg i.p.), phenytoin (20-40 mg/kg i.p.), carbamazepine (5-20 mg/kg i.p.), diazepam (0.5-2 mg/kg i.p.), chlordiazepoxide (1-4 mg/kg i.p.), triazolam (0.02-0.08 mg/kg i.p.), clonazepam (0.03125-0.25 mg/kg i.p.), GABA (25-100 mg/kg i.p.), ethanol (1000-4000 mg/kg of 10% v/v p.o.), ashwagandha (50-200 mg/kg p.o.), tiagabine (20 and 40 mg/kg i.p.), gabapentin (50-200 mg/kg i.p.), pregabalin (10-40 mg/kg i.p.), progesterone (20-80 mg/kg s.c.), adenosine (25-200 mg/kg i.p.) and rofecoxib (1-4 mg/kg i.p.) exhibited dose-dependent anticonvulsant effects. The TID50 of triazolam was found to be the lowest among all the drugs tested, indicating higher potency. The relative potency of standard drugs to increase the PTZ seizure threshold for tonic extensor was found to be: triazolam > clonazepam > diazepam > rofecoxib > chlordiazepoxide > phenobarbital > carbamazepine > pentobarbital > pregabalin > phenytoin > progesterone > tiagabine > GABA > adenosine > gabapentin > ashwagandha > ethanol. The results of the present study indicate that the intravenous PTZ seizure threshold may be useful for assessing the anticonvulsant effect of drugs effective against different stages of convulsions.

Protective effect of cyclooxygenase (COX)-inhibitors against drug-induced catatonia and MPTP-induced striatal lesions in rats.

The present study explored the involvement of cyclooxygenase (COX) in the pathophysiology of Parkinson's disease (PD). Further, the protective effect of COX-inhibitors against perphenazine-induced catatonia and 1-methyl-4-phenyl-1, 2, 3, 6-tertahydropyridine (MPTP)-induced striatal lesions in rats was evaluated. Administration of perphenazine (5 mg/kg., i.p.) produced severe catatonia (rigid behavior) in rats; the maximum score reached at 4 h (estimated as 100% AUC) and declined within 24 h. An intrastriatal injection of MPTP produced hypolocomotor activity in rats. Both perphenazine and MPTP produced oxidative stress as demonstrated by increased levels of lipid peroxides, nitrite and decreased antioxidant defense system in the whole brain and striatal region, in particular. Pretreatment with various COX-inhibitors viz. rofecoxib, celecoxib, nimesulide or naproxen offered protection against perphenazine-induced catatonia, the effect was more pronounced with rofecoxib. Rofecoxib and celecoxib (both selective COX-2 inhibitors) also reversed the perphenazine-induced oxidative stress. Further, prior treatment with rofecoxib (8 mg/kg, p.o.) reversed both the behavioral and biochemical changes induced by MPTP. These results suggest that COX-inhibitors particularly, rofecoxib offers protection against drug-induced catatonia and MPTP-induced striatal lesions possibly by modulating dopaminergic neurotransmission and/or oxidative stress.

Influence of biomass and gold salt concentration on nanoparticle synthesis by the tropical marine yeast Yarrowia lipolytica NCIM 3589.

Cell-associated gold nanoparticles and nanoplates were produced when varying number of Yarrowia lipolytica cells were incubated with different concentrations of chloroauric acid (HAuCl(4)) at pH 4.5. With 10(9)cells ml(-1) and 0.5 or 1.0 mM of the gold salt, the reaction mixtures developed a purple or golden red colour, respectively, and gold nanoparticles were synthesized. Nanoparticles of varying sizes were produced when 10(10)cells ml(-1) were incubated with 0.5, 1.0 or 2.0 mM chloroauric acid salt. With 3.0, 4.0 or 5.0 mM HAuCl(4), nanoplates were also observed. With 10(11)cells ml(-1) nanoparticles were synthesized with almost all the gold salt concentrations. The cell-associated particles were released outside when nanoparticle-loaded cells were incubated at low temperature (20 degrees C) for 48 h. With increasing salt concentrations and a fixed number of cells, the size of the nanoparticles progressively increased. On the other hand, with increasing cell numbers and a constant gold salt concentration, the size of nanoparticles decreased. These results indicate that by varying the number of cells and the gold salt concentration, a variety of nanoparticles and nanoplates can be synthesized. Fourier transform infrared (FTIR) spectroscopy revealed the possible involvement of carboxyl, hydroxyl and amide groups on the cell surfaces in nanoparticle synthesis.

Cyclooxygenase in epilepsy: from perception to application.

Cyclooxygenase (COX) catalyzes the first committed step in the synthesis of prostanoids, a large family of arachidonic acid metabolites comprising prostaglandins, prostacyclin and thromboxanes. The COX enzyme is a major target of nonsteroidal antiinflammatory drugs. Two isoforms of COX enzymes have been identified: the constitutively expressed COX-1 and the inducible, highly regulated COX-2. Recently, COX has been found to be expressed in different areas of the brain, and inhibitors of COX enzyme(s), particularly the COX-2 inhibitors, may attenuate inflammation associated with brain disorders. Although COX-1 is constitutively expressed in different areas of brain, there has been a conceptual neglect of the role of COX-1 inhibitors in various neurodegenerative and neuropsychiatric disorders. The present review summarizes the current understanding of COX expression in the central nervous system and the effects of COX inhibitors (both nonselective and selective COX-2 inhibitors) in epilepsy. It is speculated that COX inhibition will be a useful ameliorative adjunct in the management of epilepsy and related disorders.

Antidepressant-like effect of 17beta-estradiol: involvement of dopaminergic, serotonergic, and (or) sigma-1 receptor systems.

17beta-estradiol has been reported to possess antidepressant-like activity in animal models of depression, although the mechanism for its effect is not well understood. The present study is an effort in this direction to explore the mechanism of the antidepressant-like effect of 17beta-estradiol in a mouse model(s) of behavioral depression (despair behavior). Despair behavior, expressed as helplessness to escape from a situation (immobility period), as in a forced swim test in which the animals are forced to swim for a total of 6 min, was recorded. The antiimmobility effects (antidepressant-like) of 17beta-estradiol were compared with those of standard drugs like venlafaxine (16 mg/kg, i.p.). 17beta-estradiol produced a U-shaped effect in decreasing the immobility period. It had no effect on locomotor activity of the animal. The antidepressant-like effect was comparable to that of venlafaxine (16 mg/kg, i.p.). 17beta-estradiol also exhibited a similar profile of antidepressant action in the tail suspension test. When coadministered with other antidepressant drugs, 17beta-estradiol (5 microg/kg, i.p.) potentiated the antiimmobility effect of subeffective doses of fluoxetine (5 mg/kg, i.p.), venlafaxine (2 mg/kg, i.p.), or bupropion (10 mg/kg, i.p.), but not of desipramine (5 mg/kg, i.p.) or tranylcypromine (2 mg/kg, i.p.), in the forced swim test. The reduction in the immobility period elicited by 17beta-estradiol (20 microg/kg, i.p.) was reversed by haloperidol (0.5 mg/kg, i.p.; a D(2) dopamine receptor antagonist), SCH 23390 (0.5 mg/kg, i.p.; a D(1) dopamine receptor antagonist), and sulpiride (5 mg/kg, i.p.; a specific dopamine D(2) receptor antagonist). In mice pretreated with (+)-pentazocine (2.5 mg/kg, i.p.; a high-affinity sigma-1 receptor agonist), 17beta-estradiol (5 microg/kg, i.p.) produced a synergistic effect. In contrast, pretreatment with progesterone (10 mg/kg, s.c.; a sigma-1 receptor antagonist neurosteroid), rimcazole (5 mg/kg, i.p.; another sigma-1 receptor antagonist), or BD 1047 (1 mg/kg, i.p.; a novel sigma-1 receptor antagonist) reversed the antiimmobility effects of 17beta-estradiol (20 microg/kg, i.p.). Similarly, in mice pretreated with a subthreshold dose of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, a 5-HT1A serotonin receptor agonist), 17beta-estradiol (5 microg/kg, i.p.) produced an antidepressant-like effect. These findings demonstrate that 17beta-estradiol exerted an antidepressant-like effect preferentially through the modulation of dopaminergic and serotonergic receptors. This action may also involve the participation of sigma-1 receptors.