Helplessness Paradigm In Rats Research Articles

Mechanism of action of flibanserin in the learned helplessness paradigm in rats

The mechanism of action of flibanserin, a 5-HT 1A receptor agonist and a 5-HT 2A receptor antagonist, was investigated in learned helplessness in rats. The effect of flibanserin (32 mg/kg, i.p. 30 min before testing) on learned helplessness was not antagonized by the (a) 5-HT synthesis inhibitor parachlorophenylalanine (pCPA; 150 mg/kg p.o.×3 times), which reduced brain 5-HT by 89%; (b) 5-HT 1A receptor antagonists (±)- N- tert-butyl-3-4-(2-ethoxyphenyl)piperazin-1yl-2-phenyl propionamide [WAY100135; 10 mg/kg, i.p. 30 min before flibanserin, or 40 mg/kg, s.c. 15 min before flibanserin] and tertatolol (2.5 and 5 mg/kg, i.p. 30 min before flibanserin); and (c) 5-HT 2 receptor agonist (±)-2,5-dimethoxy-4-iodoamphetamine (DOI; 3 mg/kg, s.c. simultaneously with flibanserin). The effect of flibanserin on learned helplessness was antagonized by the dopamine D 1 receptor antagonist [ R]-3-methyl-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1 H-3-benzazepine (SCH 23390; 0.1 mg/kg, i.p. 30 min before flibanserin) and by the opioid receptor antagonist naloxone (3 mg/kg, s.c. 15 min before flibanserin). Flibanserin (32 and 64 mg/kg) did not induce conditioned place preference. In conclusion, flibanserin improved rats' performance in the learned helplessness paradigm, by stimulating dopamine D1 and opioid receptors, probably indirectly, since flibanserin has a low affinity for these receptors.

Reversal of Learned Helplessness by Morphine in Rats: Involvement of a Dopamine Mediation

The aim of this study was to examine the role of dopamine neurotransmission in the effects of morphine in the learned helplessness paradigm in rats, a generally recognized model of depression. In this model, rats first exposed to inescapable shocks (stressed rats) exhibited an escape deficit in a subsequent shuttle-box test performed 48 h later for 3 consecutive days. The numbers of escape failures and intertrial crossings (motor activity during each intertrial interval) were recorded. Morphine was injected twice daily for 5 days (6 mg/kg/day, SC), and haloperidol, a preferential D 2-dopamine receptor antagonist, was injected IP 15 min before each shuttle-box session. At the highest dose tested (150 μg/kg) haloperidol mimicked the behavioral deficit produced by inescapable shocks. A 37.5 μg/kg dose of haloperidol, which was ineffective by itself, reversed the morphine-induced improvement of escape behavior in previously stressed rats and the morphine-induced increase in intertrial activity in both stressed and nonstressed animals. These results support roles (a) for a dysregulation of dopaminergic neuronal activity in the expression of escape deficit subsequent to an inescapable aversive situation, and (b) for a dopaminergic mediation in the effects of morphine in the learned helplessness paradigm.

Antidepressantlike Effects of Chronic Nicotine on Learned Helplessness Paradigm in Rats

Background: The association between smoking and depression has been widely investigated. Smoking cessation is known to induce depression to a variable extent, and patients with a history of depression are more likely to experience depressive symptoms. To investigate the hypothesis that nicotine may have an antidepressantlike effect, we used learned helpless rats as an animal model of depression. Methods: Learned helplessness was produced according to our previous method. Learned helpless rats were implanted with nicotine and escape test was performed at 7 and 14 days after the implantation. Results: The number of escape failure in the rats receiving 1.5 mg/kg/day of nicotine was significantly reduced ( p < .05) compared to control at day 14. Furthermore, this effect was blocked when the nicotinic receptor antagonist mecamylamine was coadministered. Conclusions: These results suggest that chronic nicotine may act as an antidepressant, probably via nicotinic receptors.

Involvement of GABA B receptor systems in experimental depression: baclofen but not bicuculline exacerbates helplessness in rats

There are two γ-aminobutyric acid (GABA) hypotheses of the antidepressants action: an increase in GABA A neurotransmission or a decrease in GABA B neurotransmission may contribute to action of antidepressants. In this study, involvement of GABA A and GABA B, receptor systems was examined in the learned helplessness paradigm in rats. Rats were injected with bicuculline or baclofen for 14 days. On day 14, the rats were subjected to 15 inescapable shocks. On day 15, they underwent the 40-trial escape test. Baclofen exacerbated the escape failures in the rats subjected to the inescapable shocks, although baclofen had no effects in the animals without shock pre-treatment. Bicuculline failed to influence the escape failures in the rats with the 15-shock pre-treatment. These results suggest that the long-term increase in GABA B, neurotransmission but not the long-term attenuation of GABA A neurotransmission may be related to helplessness in rats.

Involvement of GABA B receptor systems in action of antidepressants. II: Baclofen attenuates the effect of desipramine whereas muscimol has no effect in learned helplessness paradigm in rats

Involvement of GABAergic systems in action of antidepressants was examined in the learned helplessness paradigm in rats. Rats were treated with desipramine, Baclofen or muscimol for 14 days. On day 14, the rats were subjected to 90 inescapable shocks. On day 15, the rats received the 40-trial escape test. The inescapable shocks induced the subsequent increase in escape failures in the escape test. Desipramine dose-dependently improved the increased escape failures induced by the inescapable shocks. Baclofen attenuated the escape failures-improving effect of desipramine, although Baclofen had no effects on the increased escape failures when it was injected alone. Muscimol at any dose failed to influence the increased escape failures. Therefore, it is suggested that the long-term decrease in GABA B neurotransmission may be involved in the action of antidepressants. Our present results do not support the hypothesis that activation of GABA A receptors may contribute to the action of antidepressants.

Involvement of GABAB receptor systems in action of antidepressants. II: Baclofen attenuates the effect of desipramine whereas muscimol has no effect in learned helplessness paradigm in rats

Involvement of GABAergic systems in action of antidepressants was examined in the learned helplessness paradigm in rats. Rats were treated with desipramine, Baclofen or muscimol for 14 days. On day 14, the rats were subjected to 90 inescapable shocks. On day 15, the rats received the 40-trial escape test. The inescapable shocks induced the subsequent increase in escape failures in the escape test. Desipramine dose-dependently improved the increased escape failures induced by the inescapable shocks. Baclofen attenuated the escape failures-improving effect of desipramine, although Baclofen had no effects on the increased escape failures when it was injected alone. Muscimol at any dose failed to influence the increased escape failures. Therefore, it is suggested that the long-term decrease in GABAB neurotransmission may be involved in the action of antidepressants. Our present results do not support the hypothesis that activation of GABAA receptors may contribute to the action of antidepressants.

Antagonism by benzodiazepines of the effects of serotonin-, but not norepinephrine-, uptake blockers in the learned helplessness paradigm in rats

Benzodiazepines are routinely administered in combination with antidepressant drugs. Such combination can induce pharmacodynamic or pharmacokinetic interactions resulting in either a potentiation or a reduction of the effects of one of the drugs. The present study was undertaken to determine the effects of benzodiazepines alone and in combination with two classes of antidepressant drugs: "specific" norepinephrine uptake blockers (desipramine, maprotiline) and specific serotonin uptake blockers (indalpine, fluvoxamine) in the learned helplessness paradigm in rats. The present results show that daily injection of diazepam (0.2-2 mg/kg) and lorazepam (0.06-0.25 mg/kg) did not reverse the helpless behavior. The reversal of helpless behavior induced by indalpine (1 mg/kg/day) or fluvoxamine (4 mg/kg/day) was antagonized dose-dependently by daily coadministration of benzodiazepines. In contrast, the effects of desipramine (24 mg/kg/day) or maprotiline (48 mg/kg/day) were not modified.

Antidepressant action of lithium gluconate alone and in co-administration with tricyclics in the learned helplessness paradigm in rats

Antidepressant action of lithium gluconate alone and in co-administration with tricyclics in the learned helplessness paradigm in rats

Antidepressant action of lithium gluconate alone and in co-administration with tricyclics in the learned helplessness paradigm in rats

Antidepressant action of lithium gluconate alone and in co-administration with tricyclics in the learned helplessness paradigm in rats

1-(2-Pyrimidinyl)-piperazine may alter the effects of the 5-HT1A agonists in the learned helplessness paradigm in rats

The 5-HT1A agonists buspirone, gepirone and ipsapirone have been shown to possess antidepressive-like properties in several animal models of depression as well as in clinical studies. These compounds are metabolized to 1-(2-pyrimidinyl)-piperazine (1-PP) in rats and humans. In the learned helplessness paradigm, buspirone exhibits a biphasic action: at low or moderate doses it shows an antidepressant-like effect but this action progressively disappears as the doses are increased. In order to establish whether 1-PP affects the reversal of helpless behaviour induced by the 5-HT1A agonists at high doses in rats, we have investigated its role in the learned helplessness. Thus, 1-PP has been evaluated alone (0.06-4 mg/kg/day) or in combination with a selective 5-HT1A agonist 8-OH-DPAT (0.25 mg/kg/day) which is not metabolized to 1-PP and buspirone (0.5 mg/kg/day). In addition, buspirone at a higher dose (2 mg/kg/day) has also been examined in the presence of proadifen which inhibits oxidative metabolism. Our results show that i) daily injections of 1-PP did not reverse helpless behaviour, ii) the reversal of helpless behaviour by 8-OH-DPAT or active dose of buspirone was antagonized by daily coadministration of 1-PP, iii) in rats pretreated with proadifen, the highest "inactive" dose of buspirone induces a reversal of helpless behaviour. These results strongly suggest that up to a certain concentration 1-PP can impair the effects of the parent drug in the learned helplessness.

Is there a relationship between 5-HT 1B receptors and the mechanisms of action of antidepressant drugs in the learned helplessness paradigm in rats?

The present study was undertaken to investigate, in the learned helplessness paradigm, (1) the effects of CGS 12066B, a selective 5-HT 1B receptor agonist administered alone, and (2) the effects of CGS612066B co-asministered with tricyclics (clomipramine, imipramine) or 5-HT re-uptake blockers (citalopram, fluvoxamine). The results showed that (1) the selective 5-HT 1B agonist failed to reverse the escape deficit, and (2) in the drug interaction studies, CGS 12066B did not modify the ability of tricyclics to reverse the escape deficit. The 5-HT 1B agonist, however, did significantly reduce the ability of 5-HT re-uptake blockers to reverse the escape deficit. The e result suggest that modulation of 5-HT 1B sites might modify the enhancement of 5-HT neurotransmission by antidepressants, particularly 5-HT re-uptake blockers.

Captopril as an antidepressant? Effects on the learned helplessness paradigm in rats

Several clinical investigations have suggested that captopril, an angiotensin-converting enzyme inhibitor (ACEI), currently used as an antihypertensive agent, exhibited antidepressant properties in humans. The present experiment was evaluated for potential antidepressive activity of captopril on the learned helplessness paradigm in rats. Captopril (8, 16, 32 mg/kg/day, IP) induced a reversal of escape deficits but did not affect significantly the motor activity, suggesting that this effect was not due to motor stimulation. This antidepressant-like activity was comparable to that of imipramine (16, 32 mg/kg/day, IP). Naloxone (0.5; 1 mg/kg, IP) blocked the effect of captopril (16 mg/kg, IP) in this test. These results suggest that an opioid mediation could be responsible at least in part for its behavioral effect.

Proceedings: Pathogenetic implications of the lesion complex of hyaline membrane disease.

Reflecting its potent inhibition of serotonin (5-HT) reuptake (accompanying paper), S33005 blocked spontaneous tail-flicks induced by parachloroamphetamine in rats. This action was mimicked by the 5-HT reuptake inhibitor, citalopram, and the 5-HT/norepinephrine (NE) reuptake inhibitor, venlafaxine, whereas the preferential NE reuptake inhibitor, reboxetine, was inactive. Consistent with its less potent interaction with NE transporters, higher doses of S33005 attenuated induction of hypothermia by reserpine, an action mimicked by reboxetine and venlafaxine, whereas citalopram was ineffective. In mice, S33005 reduced immobility in forced-swim and tail-suspension procedures. It also inhibited marble-burying behavior and suppressed aggressive behavior between resident and intruder animals. In rats, S33005 generalized to a discriminative stimulus elicited by citalopram and attenuated hypnotic-sedative actions of the α₂-adrenoceptor agonist, S18616. For these parameters, S33005 was a more potent agent (median, 1.2 mg/kg, s.c.) than venlafaxine, citalopram, reboxetine, or the tricyclic agent, clomipramine. Even at markedly higher doses (40.0–80.0 mg/kg, s.c.), S33005 little affected motor behavior. S33005 (10.0 mg/kg, s.c.) also increased responses in a learned helplessness paradigm in rats, whereas venlafaxine was ineffective. Finally, in a rat chronic mild-stress model, S33005 dose- (2.5–40.0 mg/kg) and time- (2–5 weeks) dependently enhanced sucrose consumption. Venlafaxine was likewise active in this procedure. In conclusion, in line with its inhibition of 5-HT and (less potently) NE reuptake, S33005 is active in a broad range of models suggestive of antidepressant activity. It exerts its actions more potently than venlafaxine and clomipramine, and its overall profile is distinct from those of citalopram and reboxetine.