Evidence for the locus coeruleus involvement in desipramine action in animal models of depression

Desipramine (DMI) effectively antagonized hypothermia induced by reserpine and clonidine in rats. DMI effects were attenuated or even abolished after electrolytic or 6-hydroxydopamine-induced lesion of the locus coeruleus (LC) as well as by administration of DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine), a selective noradrenergic neurotoxin. Contrary to the LC lesions, electrolytic destruction of the ventral noradrenergic bundle did not change DMI action but antagonized reserpine-induced hypothermia by itself. Our results underline a possible involvement of the LC system in mechanism of antidepressive action, which was suggested previously in this laboratory.     

Possible relationship of the locus coeruleus--hippocampal noradrenergic neurons to depression and mode of action of antidepressant drugs

Recent studies performed in our laboratory suggest involvement of locus coeruleus (LC) and hippocampal noradrenergic (NE) neurons in the mechanism of depression and mode of action of antidepressants. Both electrolytic and 6-OHDA lesions to the LC abolished desipramine action in forced swim test in rats. The action of desipramine was also reduced in rats pretreated with alpha 1 adrenolytic drugs -- phenoxybenzamine and prazosin. Electrical stimulation of the LC produced, like desipramine, activating effect in forced swim test, the phenomenon never observed in phenoxybenzamine-pretreated animals. Chronic (but not acute) administration of desipramine potentiated activatory effects of intrahippocampal injections of NE and phenylephrine but not isoprenaline in both open field and forced swim test. Depressant effect of intrahippocampal clonidine was reversed by chronic desipramine (in the open field test). The effect of desipramine was partially shared by citalopram.     

Studies on the locus coeruleus system in an animal model for antidepressive activity

The present study was performed in order to evaluate the role of brain noradrenergic system of the locus coeruleus (LC) in mediating the effect of desipramine (DMI) in the behavioral despair (immobility) induced by forced swim in rats. Both single and repetitive doses of DMI significantly reduced the immobility. The effect of single dose of drug was reduced in LC lesioned rats. On the other hand, lesions failed to influence the action of repetitive doses of DMI. A lesion of the LC alone failed to influence animals' behavior in the immobility test. Electrical stimulation of the LC (either unilateral or bilateral) significantly reduced the immobility i.e. produced an effect similar to that produced by DMI. The possible involvement of the LC in action of DMI and mechanisms of depression is discussed.     

Effect of cyclophosphamide on gene expression of cytochromes p450 and beta-actin in the HL-60 cell line

The novel antidepressant reboxetine is a selective norepinephrine reuptake inhibitor. In this study, the antidepressant-like effects of reboxetine were characterized in a modified rat forced swim test. Further, in order to investigate the role of the locus coeruleus and lateral tegmental noradrenergic systems in the mediation of reboxetine's effects, the impact of different chemical lesions of these two pathways was examined on the behavioral responses induced by reboxetine in the forced swim test. Reboxetine (5-20 mg/kg, s.c.) dose-dependently decreased immobility and swimming behavior in the forced swim test while it simultaneously increased climbing behavior. These effects were similar to those previously demonstrated with tricyclic antidepressants and are indicative of reboxetine's effects on the noradrenergic system. Discrete local injections of the neurotoxin 6-hydroxydopamine were employed to lesion the ventral noradrenergic bundle arising from cells located in the lateral tegmentum. This resulting lesion completely prevented reboxetine (10 mg/kg, s.c.)-induced decreases in immobility and increases in climbing behavior, demonstrating that an intact ventral noradrenergic bundle is required for the manifestation of reboxetine-induced antidepressant-like behavior in the test. In contrast, lesions of the dorsal noradrenergic bundle which consists of neurons arising from the nucleus locus coereleus, were achieved by systemic pretreatment with the selective noradrenergic neurotoxin N-(2-chloroethyl)-N-2-bromobenzylamine (DSP-4; 50 mg/kg, i.p.). The ability of reboxetine (10 mg/kg, s.c.) to increase climbing and decrease immobility was augmented by DSP-4 pretreatment. Furthermore, neither lesions of the dorsal noradrenergic bundle nor the ventral noradrenergic bundle altered baseline immobility scores in the forced swim test. Taken together, these data suggest that forebrain regions innervated by these two distinct noradrenergic pathways exert opposing influences on the behavioral response to reboxetine in the rat forced swim test.     

Are ascending noradrenergic and serotonergic pathways necessary for effects of electroconvulsive treatment? Clonidine hypothermia and forced swim study

Are ascending noradrenergic and serotonergic pathways necessary for effects of electroconvulsive treatment? Clonidine hypothermia and forced swim study. W. DANYSZ , W. KOSTOWSKI, M. HAUPTMANN, A. BIDZINSKI. Pol. J. Pharmacol. Pharm., 1989, 41, 15-22. Influence of chemical lesions to the noradrenergic locus coeruleus (intracerebral 6-OHDA injection, systemic administration of DSP-4) and serotonergic raphe system (intracerebral 5,7-DHT) on some effects produced by electroconvulsive shock (ECS) was studied. Administration of ECS slightly but significantly attenuated clonidine (CLO)-induced hypothermia and reduced rats immobility in forced swim test. DSP-4 reduced ECS action on CLO hypothermia remaining without effect upon ECS action in the second test. Other lesions were ineffective in both tests. This finding is in contrast to results obtained previously in animals receiving desipramine. The possible difference between ECS and antidepressant drugs action is discussed.     

Effects of desipramine and alprazolam in the forced swim test in rats after long-lasting termination of chronic exposure to picrotoxin and pentylenetetrazol

Rats were treated for 5 weeks with three subconvulsant doses of picrotoxin (PTX) and pentylenetetrazol (PTZ) per week to induce a persistent reduction of the GABA_A receptor function which results in chemical kindling. Fifteen days after termination of this treatment schedule, the effect of desipramine (DMI) and alpraxolam (ALP) on immobility time in the forced swim test (FST) was evaluated. Chronic PTX and PTZ did not alter the immobility time. Acute PTX and PTZ reduced the immobility of rats chronically treated with vehicle but not of those exposed chronically to PTX and PTZ. Chronic PTX did not influence the anti-immobility effect of DMI, but blocked that of ALP. Chronic PTZ markedly potentiated the anti-immobility effect of DMI but blocked that of ALP. Concomitant administration of chlordiazepoxide prevented the effects of chronic PTX and PTZ. These findings suggest that a long-lasting reduction in GABA_A receptor function, unlike acute reduction, does not play an important role in the mobility of rats in the FST and in the anti-immobility effect of DMI while it blocks that of ALP.     

Comparative studies on antidepressant action of alprazolam in different animal models

Alprazolam, a new benzodiazepine from triazolobenzodiazepine group, produced anxiolytic action in the conflict test with potency similar to that of diazepam. The myorelaxant activity of the drug was relatively weak. Unlike desipramine, alprazolam failed to reduce the immobility of rats in the forced swim test and was unable to prevent clonidine-induced hypothermia. Alprazolam, unlike desipramine, failed also to potentiate behavioral effect of noradrenaline injected into the hippocampus. Alprazolam after acute but not chronic administration antagonized the synchronizing effect of clonidine on EEG pattern. On the other hand, alprazolam similarly to tricyclic antidepressants, prevented the suppression of dominance behavior by clonidine in rats competing for food. The results indicate that alprazolam acts only weakly upon noradrenergic mechanisms related to depression and to antidepressant action of drugs.     

Antidepressant and anxiolytic effects of alprazolam versus the conventional antidepressant desipramine and the anxiolytic diazepam in the forced swim test in rats.

The antidepressant and anxiolytic effects of alprazolam were compared to those of desipramine, diazepam and buspirone in the forced swim test. Subchronic alprazolam induced a reduction in immobility similar to that of desipramine in 'non-pretested' and 'pretested' rats. In 'non-pretested' rats, the anti-immobility effect of desipramine was potentiated by diazepam and alprazolam, given before subchronic desipramine, while the anti-immobility effect of subchronic alprazolam was counteracted by diazepam. Diazepam, administered before the pretest session, counteracted, 24 h later, the anti-immobility effect of subchronic desipramine and alprazolam; alprazolam counteracted the anti-immobility effect of alprazolam but not of desipramine, buspirone at the highest doses tested potentiated the anti-immobility effect of subchronic desipramine but not of alprazolam. These data provide further support for the hypothesis that the GABA/benzodiazepine/Cl complex is directly implicated in the action of antidepressants and that systems other than the GABA system are involved in the antidepressant and anxiolytic effects of alprazolam.     

Influence of adrenocorticotrophic hormone on the behaviour in the swim test of rats treated chronically with desipramine

Chronic desipramine (DMI) administration induced a dose-dependent reduction in the immobility time of the swim test in rats. A combined treatment of ACTH (50 iu kg-1 s.c.) and DMI (5 or 10 mg kg-1 i.p.) for 7 days potentiated the anti-immobility effect of DMI. ACTH 4-10, a fragment peptide with little corticotrophic activity, mimicked ACTH-induced potentiation. No stimulating effect on locomotor activity was observed following seven daily co-administrations of ACTH or ACTH 4-10 and DMI (10 mg kg-1). This behavioural evidence indicates that ACTH potentiation involves a central mechanism and demonstrates a functional interaction between ACTH and DMI at the behavioural level.     

Effects of partial locus coeruleus denervation and chronic mild stress on behaviour and monoamine neurochemistry in the rat.

It has been proposed that lesions of the ascending noradrenergic projections render animals more vulnerable to stress. In this study, the effects of partial denervation of the locus coeruleus (LC) by DSP-4 (10 mg/kg) treatment, chronic mild stress (CMS) and their combination were examined. DSP-4 was administered to rats 1 week before the onset of CMS, which was applied for 5 weeks. In the forced swimming test, the immobility time was decreased by both DSP-4 and CMS. In the open field test, the number of defecations was increased after DSP-4 treatment plus CMS. Partial LC denervation decreased the levels of noradrenaline (NA) by 34%, increased NA turnover, and decreased the density of beta-adrenoceptors in the cerebral cortex. CMS decreased the binding affinity of beta-adrenoceptors, an effect not observed in the DSP-4 treated animals. In conclusion, 6 weeks after partial LC denervation NA turnover is increased in the cortex, and the effect of CMS on emotionality is enhanced.     

1-(3-Trifluoromethylphenyl) piperazine (TFMPP) in the ventral tegmental area reduces the effect of desipramine in the forced swimming test in rats: possible role of serotonin receptors

1-(3-Trifluoromethylphenyl)piperazine (TFMPP), a serotonin1 (5-HT1) receptor agonist, injected i.p. in doses of 0.1 and 0.6 mg/kg, did not modify the immobility time of rats in the forced swimming test but significantly antagonized the effect of a 7 days treatment with 10 mg/kg per day desipramine (DMI). A similar effect was found on infusing 1 and 5 micrograms/microliters TFMPP bilaterally into the ventral tegmental area (VTA). Infusion of 5 micrograms/microliters TFMPP into the nucleus accumbens or into the globus pallidus did not modify the effect of DMI. The effect of 5 micrograms TFMPP infused into the VTA was prevented by the i.p. administration of 5 mg/kg metergoline, a non-selective serotonin receptor antagonist. Infusion of 5 micrograms/microliters 8-hydroxy-2-(di-n-propylamino)tetralin, a specific 5-HT1A receptor agonist, into the VTA did not modify the effect of DMI. Besides acting as a 5-HT1B receptor agonist, TFMPP may also act on other 5-HT receptor types, but available evidence suggests that its former action is more important. It thus appears that 5-HT1 receptors in the VTA, presumably of the 5-HT1B type, act by preventing the anti-immobility effect of DMI. The role of VTA dopamine and non-dopamine cells in the effect of TFMPP is discussed.     

5-HT1A receptor antagonists neither potentiate nor inhibit the effects of fluoxetine and befloxatone in the forced swim test in rats.

Recent clinical data suggest that coadministration of pindolol with an antidepressant, particularly the 5-hydroxytryptamine (5-HT) reuptake inhibitor fluoxetine, can shorten the time to onset of clinical activity and increase the proportion of responders. We have examined the interaction of antidepressants with 5-HT1A receptors using the forced swim test in rats using both (+/-)-pindolol and the selective 5-HT1A receptor antagonist WAY 100,635 (N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(pyridinyl) cyclohexanecarboxamide trihydrochloride) in combination with either fluoxetine or the selective monoamine oxidase-A inhibitor befloxatone. 8-Hydroxy-dipropylaminotetralin (8-OH-DPAT; 0.125-1 mg/kg s.c.), used as a reference for 5-HT1A agonist activity, reduced immobility in the forced swim test and this effect was significantly antagonised by WAY 100,635. WAY 100,635 alone (0.01-0.1 mg/kg s.c.) was without effect, although a higher dose, 0.3 mg/kg s.c., had a nonsignificant tendency to increase immobility. In contrast, (+/-)-pindolol (1-16 mg/kg s.c.) significantly reduced immobility, but to a lesser extent than 8-OH-DPAT. As expected, the antidepressants fluoxetine (10-80 mg/kg p.o.) and befloxatone (0.03-1 mg/kg p.o.) dose-dependently reduced immobility time. When the antidepressants were combined with WAY 100,635 (0.1 mg/kg), WAY 100,635 either had no effect or, at relatively high doses, significantly reduced their activity in this test. Combination of the antidepressants with (+/-)-pindolol (2 or 4 mg/kg s.c.) failed to reveal a significant interaction. These results demonstrate that the anti-immobility effects of fluoxetine and befloxatone are neither facilitated nor antagonised by doses of WAY 100,635 that completely reverse the effects of 8-OH-DPAT. Furthermore, there was no evidence that coadministration of the antidepressants with (+/-)-pindolol was able to facilitate their antidepressant-like effects. Thus, whereas direct agonist activity at 5-HT1A receptors can modulate immobility in the forced swim test, this receptor subtype does not appear to play a major role in the antidepressant-like effects of fluoxetine or befloxatone under the conditions used in this study.     

Involvement of amygdaloid catecholaminergic mechanism in suppressive effects of desipramine and imipramine on duration of immobility in rats forced to swim

The suppressive effect of systemic injection of desipramine and imipramine on the duration of immobility in rats forced to swim was inhibited by 6-hydroxydopamine given into the medial amygdaloid nucleus as a pretreatment. Pretreatment with 5,7-dihydroxytryptamine given into the medial amygdaloid nucleus had no effect on the immobility-reducing effect of tricyclic antidepressants. The concentrations of catecholamines and serotonin in 6-hydroxydopamine- and 5,7-dihydroxytryptamine-pretreated rats, respectively, were significantly lower than those in the saline-injected rats. These results suggest that the suppressive effect of systemic injection of desipramine and imipramine on the duration of the immobility of rats forced to swim was mediated by the catecholaminergic but not the serotonergic mechanisms in the medial amygdaloid nucleus.     

The selective 5-HT(6) receptor antagonist SB-399885 enhances anti-immobility action of antidepressants in rats

The aim of the present study was to investigate the effect of antidepressant drugs (characterized by a different mechanism of action), administered jointly with the selective 5-HT(6) receptor antagonist N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide (SB-399885), in the forced swim test in rats. All the compounds under study were given intraperitoneally in doses which did not shorten the immobility time of rats. Co-administration of SB-399885 (3 mg/kg) and imipramine (20 mg/kg), desipramine (20 mg/kg), bupropion (5 mg/kg) or moclobemide (20 mg/kg), produced significant anti-immobility action, whereas SB-399885 (3 mg/kg) given jointly with citalopram (20 mg/kg) did not affect immobility time. None of the compounds studied, given alone or jointly, increased the general activity of rats measured in the open field test. The obtained results indicate that the blockade of 5-HT(6) receptors may facilitate the anti-immobility effect of imipramine, desipramine, bupropion or moclobemide in the forced swim test.     

The effect of 5,7-DHT-induced lesions of the median raphe nucleus and chronic desipramine administration upon motor behaviour of rats given intrahippocampal clonidine injection

The role of serotonergic (5-HT) innervation of rat hippocampus in clonidine- induced behavioural effects was studied in naive and desipramine-pretreated animals. 5,7- DHT-lesions of the median raphe nucleus (MR) produced about 50 per cent decrease of serotonin and 5-hydroxyindoloacetic acid (5-HIAA) content in the rat cortex and hippocampus. Lesions of the MR also accelerated the attenuating effect of desipramine upon locomotor inhibition produced by intrahippocampal clonidine injections. In the forced swim test (FST) the MR lesion revealed the stimulatory potency of clonidine upon rat active behaviour, which was statistically significant. However, no further potentiation by MR lesions of DMI effects upon behavioural action of clonidine could be observed in this test. It is concluded that hippocampal serotonergic innervation plays a minor role in the antidepressant-induced changes in behavioural effects of clonidine, which probably occur via modulation of local alpha-adrenoceptors. It is also conceivable that the stimulatory effect of intrahippocampal clonidine injections in the forced swim test in MR-lesioned rats, may be due to the increase in the alpha-(1)-adrenoceptor function in this brain area.     

Influence of sildenafil on the antidepressant activity of bupropion and venlafaxine in the forced swim test in mice

Recent studies highlight the involvement of the nitrergic system in the mechanism of action of antidepressant drugs. Sildenafil, a selective PDE5 inhibitor, was shown to abolish the anti-immobility effects of bupropion, venlafaxine and s-citalopram in mice. In this study we assessed the effects of sildenafil on the activity of bupropion and venlafaxine in the forced swim test in mice. Swim trials were conducted by placing mice in glass cylinders filled with water for 6 min and the duration of the behavioral immobility during the last 4 min of the test was evaluated. Locomotor activity was evaluated with photoresistor actimeters. Brain and serum concentrations of the studied antidepressants were determined by HPLC method. Sildenafil at a dose of 20 mg/kg, but not 5 and 10 mg/kg, significantly increased the anti-immobility action of bupropion (20 mg/kg). The antidepressant activity of venlafaxine (2 mg/kg) was potentiated by joint administration with sildenafil at doses of 10 and 20 mg/kg. Since the combined treatments did not increase the locomotor activity, the antidepressant-like effects were not related to non-specific behavioral activation. Data from pharmacokinetic studies revealed that sildenafil increased bupropion and venlafaxine levels in serum without affecting their concentrations in the brain. The present study demonstrates the enhancement of anti-immobility action of bupropion and venlafaxine by sildenafil co-administration. The observed changes might have been partly due to pharmacokinetic interactions. However, mechanisms underlying the effects of sildenafil on the antidepressant activity of bupropion and venlafaxine should be carefully evaluated in further studies.     

A possible common mechanism of action of antidepressant treatments

Summary The response of the norepinephrine (NE) sensitive cyclic AMP generating system in slices of the rat limbic forebrain after both the acute and chronic administration of the tricyclic antidepressants desipramine (DMI) and iprindole as well as electroconvulsive treatment (ECT) was investigated. Neither the basal level of cyclic AMP nor the hormonal response to NE were altered after the administration of a single dose or short term treatment with DMI and iprindole. However, the administration of the antidepressants on a clinically more relevant time basis markedly reduced the sensitivity of the cyclic AMP generating system to NE. This change in sensitivity was not related to the levels of the drugs in brain. The response of cyclic AMP to NE was also reduced by ECT, but the onset of this action was shorter than that observed with the antidepressants. ECT also antagonized the enhanced response of cyclic AMP to NE following destruction of central adrenergic nerve terminals with 6-hydroxydopamine. It thus appears that the therapeutic action of tricyclic antidepressants could be related to postsynaptic adaptive changes in the sensitivity of the noradrenergic adenylate cyclase receptor system rather than to acute presynaptic events.     

Further evidence that noradrenaline is not involved in the anti-immobility activity of chronic desipramine in the rat

The effect of 10 mg/kg per day desipramine for 7 days on performance in the forced swimming test was studied in rats given various treatments aimed at reducing central noradrenergic transmission. 6-Hydroxydopamine-induced destruction of noradrenaline-containing neurons originating in the locus coeruleus or ascending in the ventral bundle had no effect on the anti-immobility activity of desipramine. Likewise, no changes in the effect of desipramine were seen with an intraperitoneal injection of DSP-4 (50 mg/kg) which destroyed brain noradrenergic neurons, particularly those of the dorsal bundle ascending to the forebrain. The results argue against a role of noradrenaline in the mechanism by which repeated treatment with desipramine reduces the immobility of rats in the forced swimming test.     

Antidepressant-like actions of an AMPA receptor potentiator (LY392098)

LY392098 is a member of a novel class of biarylpropylsulfonamides that potentiates AMPA receptor-mediated responses both in vitro and in vivo. In this study, the effects of LY392098 were evaluated in two “behavioral despair” models (the forced swim and tail suspension tests) commonly used to identify clinically useful antidepressants. LY392098 reduced immobility in the forced swim test in both rats and mice, with a minimum effective dose of 0.5 mg/kg (i.p.) in both species. LY392098 (0.1–10 mg/kg, i.p.) did not affect motor activity of rats, indicating that the ability of this compound to reduce immobility in the forced swim test is unrelated to a motor stimulant action. LY392098 also reduced immobility in the tail suspension test in a dose-dependent manner, with a minimum effective dose of 5 mg/kg (i.p). A non-competitive AMPA antagonist (LY300168) blocked the activity of LY392098 in the forced swim test, but did not affect imipramine-induced reductions in immobility. Thus, AMPA receptor activation appears to be required for the antidepressant-like effect of LY392098, but not imipramine. These findings indicate that biarylpropylsulfonamides, exemplified by LY392098, may represent a novel class of antidepressants.     

Sex differences in response to oral amitriptyline in three animal models of depression in C57BL/6J mice

Rationale Knockout and transgenic mice provide a tool for assessing the mechanisms of action of antidepressants. The effectiveness of oral administration of the tricyclic antidepressant amitriptyline (AMI) was assessed in C57BL/6J (B6) mice, a common genetic background on which knockout and transgenic mice are maintained.Objectives We determined whether oral AMI would have antidepressant-like effects in B6 mice and whether these effects varied according to sex, duration of treatment, and the depression model utilized.Methods Male and female B6 mice were administered AMI (200 g/ml) in the drinking water as the sole source of fluid, along with 2% saccharin to increase palatability. Control mice were administered 2% saccharin alone. Mice were assessed for responsiveness to AMI in the tail suspension test (TST), the forced swim test (FST), and the learned helplessness (LH) paradigm.Results In the TST, AMI decreased immobility time regardless of sex or duration of treatment. AMI also decreased immobility time in the FST, but chronic treatment was necessary for full efficacy in both sexes. In the LH paradigm, both subchronic and chronic AMI treatment decreased escape latencies in female mice, but AMI was effective only after chronic treatment in males. The antidepressant-like effects of AMI could not be explained by differences in locomotor activity because activity levels were not altered by antidepressant treatment.Conclusions Overall, oral AMI administration provides a valid model for behavioral assessment of antidepressant-like effects in knockout and transgenic mice maintained on a B6 background, but the effectiveness of oral AMI varies depending on sex, duration of treatment, and the depression model used.