Antidepressant-like Effects In Rats Research Articles

The hydroalcoholic extract of Salvia elegans induces anxiolytic- and antidepressant-like effects in rats

Behavioral effects of a hydroalcoholic (60% ethanol) extract from the leaves of Salvia elegans Vahl (Lamiaceae) were studied in male Sprague–Dawley rats. The extract was administered intraperitoneally and its effects on spontaneous motor activity (total motility, locomotion, rearing and grooming behavior) were monitored. Putative anxiolytic and antidepressant properties of Salvia elegans were studied in the elevated plus-maze test (EPM) and in the forced swimming test (FST), respectively. Deleterious effects of Salvia elegans on learning and memory were also studied by using active and passive avoidance paradigms. The results revealed that all doses (3.12, 12.5, 25 and 50 mg/kg) of the extract caused a significant decrease in total motility, locomotion, rearing and grooming behavior. Only the dose of 12.5 mg/kg increased the exploration of the EPM open arms in a similar way to that of diazepam (1 mg/kg). In the FST, all doses of the extract induced a reduction of immobility, in a similar way to that of fluoxetine (10 mg/kg) and imipramine (12.5 mg/kg), along with a significant increase in the time spent in swimming behavior. Acquisition of active avoidance responses was disrupted by pre-treatment with the extract, but retention of a passive avoidance response was not significantly modified. These results suggest that some of the components of the hydroalcoholic extract of Salvia elegans have psychotropic properties, which deserve further investigation.

Differential effects of the novel kappa opioid receptor antagonist, JDTic, on reinstatement of cocaine-seeking induced by footshock stressors vs cocaine primes and its antidepressant-like effects in rats

Stress and depression have been linked to relapse of cocaine abuse. Antagonism of the kappa opioid receptor (KOR) has been reported to attenuate some effects of stressors, and antagonism of the KOR has been reported to have antidepressant-like properties. Our objective was to determine whether the potent and selective KOR antagonist, (3R)-7-hydroxy-N-{(1S)-1-{[(3R,4R)-4-(3-hydroxyphenyl)-3,4-dimethyl-1-piperidinyl]methyl}-2-methylpropyl}-1,2,3,4-tetrahydro-3-isoquinoline-carboxamide (JDTic), can reduce the ability of a stressor (intermittent footshock) to reinstate cocaine-seeking behavior and to have antidepressant-like effects in the forced swim test (FST). Male Long-Evans hooded rats were trained to lever-press, reinforced with 0.5 mg/kg i.v. infusion of cocaine, according to fixed ratio 1 reinforcement schedules during daily 2-h experimental sessions. After performance had stabilized, lever pressing was extinguished for 12 consecutive sessions, and doses of 0 (vehicle), 3, 10, and 30 mg/kg JDTic were then administered i.g. to separate groups of 12 rats. Twenty four hours later, the rats were given 15 min of intermittent footshock (0.87 mA, 0.5 s activation time, average inter-activation interval of 40 s) or a 17-mg/kg i.p. administration of cocaine prime followed by a 2-h reinstatement test session. JDTic was also evaluated for its ability to block diuresis induced by the KOR agonist, U50,488H (10 mg/kg, s.c.), during 5-h test sessions beginning 1 h after footshock reinstatement tests to verify its KOR antagonist activity. In the FST, male Sprague-Dawley rats were treated with either nor-binaltorphimine (nor-BNI) or JDTic (both at 0.3, 1, 3, or 10 mg/kg, injected s.c. 23 h before), or desipramine (5.6, 10, or 17 mg/kg, injected i.p. 23, 5, and 1 h before) and placed in a cylinder of water, during which the predominance of immobility, swimming, and climbing were scored during 5-s intervals for 5 min. The 10- and 30-mg/kg doses of JDTic significantly reduced footshock-induced reinstatement of responding previously reinforced by cocaine and significantly attenuated U50,488H-induced diuresis. In contrast, JDTic did not affect cocaine-prime-induced reinstatement. Both nor-BNI and JDTic decreased immobility and increased swimming time in the FST, similar to the antidepressant desipramine. Depression and stress are two states during cocaine abstinence which users identify as precipitating relapse, and JDTic may have properties which attenuate both.

Antidepressant-like effects of cranial stimulation within a low-energy magnetic field in rats

Evidence suggests that a novel type of magnetic resonance imaging (MRI) scan called echo planar magnetic resonance spectroscopic imaging (EP-MRSI) has mood-elevating actions in humans during the depressive phases of bipolar disorder. We examined whether a low-energy component of EP-MRSI (low-field magnetic stimulation [LFMS]) has antidepressant-like, locomotor-stimulating, or amnestic effects in rats. We examined the effects of LFMS on immobility in the forced swim test (FST) and activity within an open field in separate groups of rats. After exposure to forced swimming, rats received LFMS (three 20-min sessions at 1.5 G/cm and .75 V/m) before behavioral testing. We also examined the effects of LFMS on fear conditioning (FC), a learning paradigm that also involves exposure to stressful conditions. Low-field magnetic stimulation reduced immobility in the FST, an antidepressant-like effect qualitatively similar to that of standard antidepressants. Low-field magnetic stimulation did not alter locomotor activity or FC. Low-field magnetic stimulation has antidepressant-like effects in rats that seem unrelated to locomotor-activating or amnestic effects. These findings raise the possibility that electromagnetic fields can affect the brain biology and might have physiologic consequences that offer novel approaches to therapy for psychiatric disorders. These same consequences might render MRI-based scans more invasive than previously appreciated.

Antidepressant-like effects of uridine and omega-3 fatty acids are potentiated by combined treatment in rats

Brain phospholipid metabolism and membrane fluidity may be involved in the pathophysiology of mood disorders. We showed previously that cytidine, which increases phospholipid synthesis, has antidepressant-like effects in the forced swim test (FST) in rats, a model used in depression research. Because cytidine and uridine both stimulate synthesis of cytidine 5'-diphosphocholine (CDP-choline, a critical substrate for phospholipid synthesis), we examined whether uridine would also produce antidepressant-like effects in rats. We also examined the effects of omega-3 fatty acids (OMG), which increase membrane fluidity and reportedly have antidepressant effects in humans, alone and in combination with uridine. We first examined the effects of uridine injections alone and dietary supplementation with OMG alone in the FST. We then combined sub-effective treatment regimens of uridine and OMG to determine whether these agents would be more effective if administered together. Uridine dose-dependently reduced immobility in the FST, an antidepressant-like effect. Dietary supplementation with OMG reduced immobility when given for 30 days, but not for 3 or 10 days. A sub-effective dose of uridine reduced immobility in rats given sub-effective dietary supplementation with OMG. Uridine and OMG each have antidepressant-like effects in rats. Less of each agent is required for effectiveness when the treatments are administered together.

Effect of the antidepressant nefazodone on the density of cells expressing mu-opioid receptors in discrete brain areas processing sensory and affective dimensions of pain.

The principal use of antidepressants is in the treatment of depression and affective disorders. Antidepressants have also been used as an adjuvant to analgesics in pain treatment. However, in chronic treatment, their antinociceptive and antidepressive effects coexist simultaneously. Antidepressants can interact with the opioid system, which is also involved in regulating nociceptive processing and affective state. Chronic antidepressants could act by increasing mu-opioid receptor expression in many brain areas involved in the regulation of nociception and affective state. The aim of this study was to evaluate the antinociceptive and antidepressant-like effects and the possible variations in mu-opioid receptor expression induced by a chronic nefazodone treatment in brain areas related to pain and affective state. Wistar rats were chronically treated with nefazodone (10 and 25 mg/kg IP, twice a day, for 14 days). Twelve hours after the last day 14 dose of nefazodone, a tail-flick test was performed. After the administration of a daily dose of nefazodone, Porsolt's test was carried out 12 h after last dose. Two hours after completion of 14 days treatment, other animals were processed for mu-opioid receptor immunocytochemistry using polyclonal antisera raised in rabbits. Several brain regions were analyzed: the frontal and cingulate cortex, the dorsal raphe nucleus and the periaqueductal gray. Chronic nefazodone treatment induced a significant increase in tail-flick latency and a significant decrease in immobility time at total doses of 20 and 50 mg/kg per day ( P<0.05). In treated animals, the density of neural cells immunostained for mu-opioid receptor in the frontal and cingulate cortices, dorsal raphe nucleus and periaqueductal gray had increased after chronic nefazodone compared to controls. Therefore, chronic nefazodone induces antinociceptive and antidepressant-like effects in rats and increases mu-opioid receptor expression in brain areas related to pain and affective state. These results suggest that antidepressants could be effective on somatic and affective dimensions of pain and this action could be related to its influence on the opioid system.

Antidepressant-like effect of MPEP, a potent, selective and systemically active mGlu5 receptor antagonist in the olfactory bulbectomized rats.

Using the olfactory bulbectomy model of depression, we examined the antidepressant-like activity of 2-methyl-6-(phenylethynyl)-pyridine (MPEP) in rats. Bulbectomized rats required a significantly greater number of trials to acquire the response similar to sham-operated controls in the passive avoidance model. Both the prolonged (but not acute) treatment with MPEP and with antidepressant drug-desipramine restored the learning deficit. The results indicate that the prolonged blockade of mGlu5 receptors exerts antidepressant-like effects in rats.

Multiple MPEP administrations evoke anxiolytic- and antidepressant-like effects in rats

Several lines of evidence suggest a crucial involvement of glutamate in the mechanism of action of anxiolytic and antidepressant drugs. The involvement of group I mGlu receptors in anxiety and depression has also been proposed. In view of the recent discovery of anxiolytic- or antidepressant-like effects of acute injections of 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a selective and brain penetrable mGlu5 receptor antagonist, we designed the present study to examine anxiolytic- and/or antidepressant-like effects of multiple administrations of this drug. The anxiolytic-like effects of MPEP were evaluated in rats using the conflict drinking test. The antidepressant-like effect was estimated using the rat olfactory bulbectomy model of depression. Seven subsequent injections of MPEP (1 mg/kg) significantly (by 320%) increased the number of shocks accepted during the experimental session in the Vogel test. MPEP given once daily at a dose of 10 mg/kg, restored the learning deficit of bulbectomized rats after 14 days of treatment, remaining without any effect in the sham-operated animals. N-methyl- d-aspartic acid (NMDA)-induced convulsions in mice were not affected by a single injection of MPEP (30 mg/kg) indicating that at this dose MPEP did not block NMDA receptors. The results indicate that the prolonged blockade of mGlu5 receptors exerts anxiolytic- and antidepressant-like effects in rats. No tolerance to anxiolytic-like action occurs. The previously mentioned results further indicate that antagonists of group I mGlu receptors may play a role in the therapy of both anxiety and depression.

Antidepressant-like actions of pregnancy, and progesterone in Wistar rats forced to swim.

In rats, some behavioral changes occurring during pregnancy related to the presence of progesterone may be analyzed in the forced swimming task (FST), which is designed to test the antidepressant profile of drugs. The present study was aimed to analyze in pregnant rats, in rats after delivery, or in rats after receiving progesterone those behavioral changes displayed in the FST. We hypothesize that pregnancy and progesterone will produce antidepressant-like effects in rats forced to swim. Therefore, pregnant rats (14th, 17th, and 20th days), or rats after delivery (3rd, and 7th days) were tested in the FST. Ovariectomized rats receiving saline (0.9%; i.p.), clomipramine (1.25 mg/kg; i.p.), or desipramine (2.14 mg/kg; i.p.) for 28 days were also tested in the FST. In a second series of experiments, ovariectomized rats receiving vehicle or progesterone (0.5 mg/kg; or 2.0 mg/kg; sc.) were tested in the FST. Locomotion was evaluated in the open field test. Results showed that in the FST: 1) pregnancy (P < 0.05), or progesterone (P < 0.05), or desipramine (P < 0.05), reduced immobility by increasing climbing; 2) clomipramine (P < 0.05) reduced immobility by increasing swimming; 3) rats tested after delivery displayed similar behavior than control rats. A lower locomotion was observed only at the end of pregnancy. In conclusion, results suggest that during pregnancy, a reproductive process characterized by its high levels of progesterone, antidepressant-like effects can be found.

Prefrontocortical dopamine depletion induces antidepressant-like effects in rats and alters the profile of desipramine during Porsolt's test

The objective of this study was to investigate whether bilateral dopamine depletion within the medial prefrontal cortex affects depression state, as well as the antidepressant efficacy of desipramine, in the forced swimming test. The rat's behaviour was evaluated by quantifying duration of immobility, climbing, swimming and diving. Immobility latency was also quantified and proved to be a suitable novel parameter. Monoamine levels within the medial prefrontal cortex were measured by high-performance liquid chromatography during Porsolt's test, as well as one week after it. While Porsolt's test was followed by a typical depression-like profile in sham rats, depletion of prefrontocortical dopamine (86% vs sham controls) reduced immobility and enhanced swimming, which is consistent with a diminished depression tonus. The observed enhancement of swimming was correlated with a high prefrontocortical serotonergic neurotransmission. On the other hand, desipramine induced antidepression-like effects in sham rats by increasing prefrontocortical noradrenaline and serotonin neurotransmisson, but also by blocking the normal increase in dopamine activity during the swimming test. Interestingly, desipramine behaved in a quite different manner in lesioned rats. Thus, immobility duration was not further reduced and only climbing, but not swimming, was enhanced. These effects were correlated with a preferential enhancement of noradrenaline neurotransmission. In conclusion, the results indicate that: (i) dopamine neurotransmission within the medial prefrontal cortex is a factor involved in depression, since dopamine reduction led to a low depression tonus; (ii) desipramine induces antidepression not only by enhancing prefrontocortical noradrenaline and serotonin neurotransmission, but also by blocking the normal increase in dopamine neurotransmission during a depressant situation; (iii) a selective enhancement of prefrontocortical serotonin neurotransmission mediates swimming; and (iv) a selectively augmented prefrontocortical noradrenaline activity mediates climbing during Porsolt's test.

The novel buspirone analogue, 8-[4-[2-(1,2,3,4-tetrahydroisoquinolinyl) [butyl]-8 -azaspiro[4.5] decane-7,9 dione, with anxiolytic-like and antidepressant-like effects in rats

In the conflict drinking test, used as a model to examine anxiolytic-like activity, the novel buspirone analogue 8-[4-[2-(1,2,3,4-tetrahydroisoquinolinyl)]butyl)-8-azaspiro[ 4.5]decane-7,9-dione (MM199) (0.62-2.5 mg/kg) and buspirone (0.62-5 mg/kg), significantly increased the punished drinking in water-deprived rats, without affecting water consumption or perception of the stimulus. The anticonflict activity of MM199 (1.25 mg/kg) was blocked by (S)-WAY 100135 (20 mg/kg), a 5-hydroxytrypatmine1A (5-HT1A) receptor antagonist. In the forced swimming test, used as a model to examine the antidepressant-like activity, MM199 (5-20 mg/kg) reduced the immobility time, while buspirone (5-20 mg/kg) had no such effect. The reduced immobility induced by MM199 (20 mg/kg) was antagonized by (S)-WAY100135 (10 mg/kg). The above findings suggest that MM199 possesses potent anxiolytic- and antidepressant-like properties which are mediated by activation of 5-HT1A receptors.

Plasma and platelet excitatory amino acids in psychiatric disorders

Plasma and platelet levels of excitatory amino acids were measured in 38 psychiatric out-patients and in 19 comparison subjects; the patients had DSM-III-R diagnoses of organic mental disorders (N = 3), mood disorders (N = 15), schizophrenia (N = 13), and anxiety disorders (N = 7). The glutamate plasma levels were significantly higher in the patients with mood disorders than in the comparison group.

Clonidine causes antidepressant-like effects in rats by activating α 2-adrenoceptors outside the locus coeruleus

Clonidine,0.05, 0.1 and 0.5 mg/kg administered i.p. as a three-injection course but not as single doses, significantly reduced the immobility of rats in the forced swimming test. Doses of 0.1 and 0.5, administered the same way, significantly reduced activity in an open field. The effect of 0.05 and 0.5 mg/kg clonidine on immobility was prevented by 1 mg/kg idazoxan, an α 2-adrenoceptor antagonists, but not by 3 mg/kg prazosin, which blocks α 2-adrenoceptors. An infusion of 6 μg/μl 6-hydroxydopamine in the locus coeruleus, which markedly depleted noradrenaline in terminal regions, did not modify the effect of 0.05 and 0.5 mg/kg clonidine on immobility. Chronic treatment with 5 mg/kg i.p. desipramine or 0.1 mg/kg i.p. clonidine, twice daily for 15 days, did not modify the effect of a three-injection course with 0.1 mg/kg clonidine. It is suggested that clonidine exerts antidepressants-like effects on rats in the forced swimming test by acting on central α 2-adrenoceptors outside the locus coerlus and presumably postsynaptically to noradrenalin-containing neurons. No tolerance or sensitization of the clonidine effect was found after chronic treatment with desipramine or clonidine. These findings are of significance for these effects of clonidine in subgroups of depressed patients.

A single dose of 8-OH-DPAT reduces raphe binding of [ 3H]8-OH-DPAT and increases the effect of raphe stimulation on 5-HT metabolism

8-Hydroxy-(di-n-propylamino)tetralin (8-OH-DPAT) has antidepressant-like effects in rats and selectively reduces presynaptic 5-HT 1A function a day after administration. In the present study, the effect of 8-OH-DPAT (1 mg/kg s.c.) pretreatment on presynaptic (raphe nuclei) and postsynaptic (frontal cortex and hippocampus) [ 3H]8-OH-DPAT binding was studied. B max values were markedly reduced in the raphe, but not in the hippocampus and frontal cortex. K d values were unchanged. Electrical stimulation of the dorsal raphe (300 μA, 1 ms, 20 Hz, 30 min) significantly increased 5-hydroxyindoleacetic acid in the frontal cortex, but not in the amygdala or the nucleus accumbens and caused smaller increases in the rest of the brain. The increase in the frontal cortex was significantly potentiated one day after giving 8-OH-DPAT. These results confirm the ability of 8-OH-DPAT to desensitise presynaptic 5-HT 1A receptors and suggest that this may lead to a loss of feedback control so that, on neuronal stimulation, the increase of 5-HT function is enhanced. This effect may underlie the antidepressant-like action of 8-OH-DPAT pretreatment, i.e. its ability to oppose restraint-induced defects in locomotion on placement in an open field one day later. A requirement of presynaptic 5-HT for this behavioural effect is consistent with its prevention by the 5-HT synthesis inhibitor parachlorophenylalanine.