5-HT(1A) receptor full agonist, 8-OH-DPAT, exerts antidepressant-like effects in the forced swim test in ACTH-treated rats

We examined the effect of adrenocorticotropic hormone (ACTH) on the immobilization of rats in the forced swim test after administration of the 5-HT(1A) receptor agonist, 8-hydroxy-2-di-n-propylamino tetralin (8-OH-DPAT). Imipramine (3-30 mg/kg, i.p.) or 8-OH-DPAT (0.1-1 mg/kg, s.c.) significantly decreased the duration of immobility in normal rats. The immobility-decreasing effect of imipramine was blocked when ACTH was administered for 14 days. On the other hand, the immobility-decreasing effect induced by 8-OH-DPAT was not blocked by chronic administration of ACTH for 14 days. These findings indicate that 8-OH-DPAT can be useful in an animal model of depressive conditions resistant to antidepressant treatment.     

Indorenate produces antidepressant-like actions in the rat forced swimming test via 5-HT1A receptors

Abstract Rationale. Indorenate has been proposed to possess antihypertensive, anorectic, stimulus control and anxiolytic-like actions. This compound has affinity mainly for the serotonergic_1A/1B receptors, hence it could possess antidepressant-like activity. Objectives. The general purpose of this study was to explore the possible antidepressant-like effects of the serotonergic compound indorenate in the forced swimming test (FST). Methods. In a first approach, a comparison of the actions of several doses of indorenate (2.5, 5.0, 10 mg/kg) with those of other 5-HT_1A agonists, buspirone (5.0, 10.0 mg/kg) and 8-OH-DPAT (0.25, 0.50, 1.0 mg/kg), was performed in the FST. Secondly, in order to determine the serotonergic receptors that are participating in indorenate's action, different doses of serotonergic antagonists were administered. The compounds used were the 5-HT_1A/1B and β-adrenergic antagonist pindolol (2.5, 5.0 mg/kg), the 5-HT_1B receptor antagonist GR 55562 (0.75, 1.5, 3.0 mg/kg), the 5-HT_1A antagonist WAY 100635 (0.25, 0.5, 1.0 mg/kg) and the 5-HT₂ antagonist ketanserin (1.0, 2.0, 4.0 mg/kg). Results. Indorenate (10 mg/kg), 8-OH-DPAT (1.0 mg/kg) and buspirone (5.0 and 10.0 mg/kg) reduced immobility behaviour in the FST, considered as an antidepressant-like effect. Both doses of pindolol (2.5 and 5.0 mg/kg) and WAY 100635 (0.5 and 1.0 mg/kg) antagonised the antidepressant-like effect of indorenate. Neither 5-HT_1B (GR55562) nor 5-HT₂ (ketanserin) antagonists produced changes in the effect of indorenate in the FST. Conclusions. Indorenate produces antidepressant-like actions in the FST that are mediated by the stimulation of 5-HT_1A receptors. Electronic Publication     

Blockade of the antidepressant-like effects of 8-OH-DPAT,buspirone and desipramine in the rat forced swim test by 5HT1A receptor antagonists

This study examined whether the antidepressant-like effect of serotonin (5-HT)_1A receptor agonists in the forced swim test (FST) is mediated by 5-HT_1A receptors. The 5-HT_1A receptor agonists 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT) and buspirone decreased immobility in the FST. The effect of 8-OH-DPAT was blocked by the 5-HT_1A receptor antagonists NAN 190, BMY 7378 and pindolol. The effect of buspirone was blocked by NAN 190 and pindolol. The antagonists produced no effects on their own. The norepinephrine (NE) uptake inhibitor desipramine (DMI) also reduced immobility, and this was also blocked by NAN 190, BMY 7378 and pindolol. The ₁, ₁ and ₂ adrenergic antagonists prazosin, betaxolol and ICI 118,551 did not block either 8-OH-DPAT or DMI, and produced no effects on their own. These results provide evidence that the antidepressant-like effects of 5-HT_1A receptor agonists in the FST are mediated through 5-HT_1A receptors, probably located postsynaptically. The finding that the 5-HT_1A receptor antagonists blocked the effect of DMI suggests that the NE and 5-HT systems interact in the FST.     

The 5-HT1A agonists 8-OH-DPAT, buspirone and ipsapirone attenuate stress-induced anorexia in rats

The effects of 5-HT agonists and antagonists, benzodiazepine anxiolytics and tricyclic antidepressants on restraint stress-induced anorexia in rats were examined. The selective 5-HT(1A) agonists 8-hydroxy-2-(di- n-propylamino)tetralin (8-OH-DPAT), buspirone and ipsapirone, when injected 2 h after the termination of stress, attenuated stress-induced anor exia and body weight loss. The effects of 8-OH-DPAT on stress-induced anorexia were blocked by the 5-HT(1A) antagonist spiperone but not by the 5-HT(2) antagonist ketanserin. The preferential 5-HT(1B) agonists RU-24969 and quipazine induced anorexia in unstressed rats and tended to supplement the anorectic effects of stress. The benzodiazepines chlordiazepoxide and diazepam and the 5-HT antagonist cyproheptadine had no effect on stress-induced anorexia, when given (like the 5-HT(1A) agonists) 2 h after the stress. Similarly, daily injection for 2 weeks of the tricyclic antidepressants desipramine and sertraline had no beneficial effect. The data suggest that 8-OH-DPAT, buspirone and ipsapirone attenuate stress-induced anorexia in rodents by a hyperphagic action on 5-HT(1A) receptors.     

Behavioral and biochemical effects of the 5-HT1A receptor agonists flesinoxan and 8-OH-DPAT in the rat.

The 5-HT_1A receptor agonists flesinoxan (0.2–3.2 mg kg⁻¹ s.c.) and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (0.025–0.4 mg kg⁻¹ s.c.) produced (1) a dose-dependent facilitation of male rat ejaculatory behavior and (2) characteristic, dose-dependent effects on spontaneous motor activity. Thus, total locomotor activity and rearing activity were decreased. However, forward locomotion and peripheral locomotion were increased relative to the total horizontal activity. Furthermore, (3) 5-HTP accumulation, after inhibition of cerebral decarboxylase, was dose dependency decreased by both compounds in the ventral striatum and in the prefrontal cortex. There was a statistically significant decrease in DOPA accumulation in the ventral striatum after administration of a high dose of flesinoxan (3.2 mg kg⁻¹), and a tendency for 8-OH-DPAT to produce the same effect. The efficacy of the compounds to affect male rat sexual behavior, spontaneous motor activity in the open-field and forebrain 5-HT synthesis was approximately the same, whereas flesinoxan was about an order of magnitude less potent than 8-OH-DPAT.     

Participation of the 5-HT1A receptor in the antidepressant-like effect of estrogens in the forced swimming test.

The aim of the present study was to explore the possible participation of the 5-HT(1A) receptor in the antidepressant-like action of two estrogenic compounds: 17beta-estradiol (E(2)) and ethynil-estradiol (EE(2)) in the FST. Ovariectomized female Wistar rats were used in all experiments. As a positive control, the effect of the 5-HT(1A) receptor agonist, 8-hydroxy-2-(di-n)-propil-aminotetraline (8-OH-DPAT; 0.0625, 0.125, 0.25 and 0.5 mg/kg) alone or in combination with WAY 100635 (0.5 and 1.0 mg/kg) was analyzed in the FST. In order to analyze the participation of the 5-HT(1A) receptor in the antidepressant-like actions of estrogens, the effect of the selective antagonist WAY 100635 (0.5 and 1.0 mg/kg) in combination with E(2) (10 microg/rat) and EE(2) (5 microg/rat) was studied in the FST. In this case, WAY 100635 was administered either simultaneously with the estrogens (48 h before the FST test) or 30 min before the FST. On the other hand, a suboptimal dose of 8-OH-DPAT (0.0625 mg/kg), combined with a noneffective dose of E(2) (2.5 microg/rat) or EE(2) (1.25 microg/rat), was tested in the FST. The results showed that 8-OH-DPAT (0.25 and 0.5 mg/kg), E(2) (10 microg/rat), and EE(2) (5 microg/rat), by themselves, exerted an antidepressant-like action. The antagonist to the 5-HT(1A) receptor WAY 100635, when applied together with 8-OH-DPAT or E(2), blocked their antidepressant-like actions, but not the one induced by EE(2). Interestingly, when the antagonist was applied 30 min before the FST, it was able to cancel the actions of EE(2) on immobility behavior, and had no effect on the actions of E(2.) Finally, when a subthreshold dose of 8-OH-DPAT was combined with a noneffective dose of either E(2) or EE(2), an antidepressant-like action was observed. The results support the notion that the 5-HT(1A) receptor is one of the mediators of the antidepressant-like action of E(2), and could indirectly contribute to the one induced by EE(2).     

Response of cerebellar Purkinje cells to serotonin and the 5-HT1A agonists 8-OH-DPAT and ipsapirone in vitro

These studies were undertaken in an attempt to classify the receptor subtypes mediating the inhibitory effects of serotonin (5-HT) on cerebellar Purkinje cells in the in vitro slice preparation. 5-HT and the 5-HT1A specific agonists 8-hydroxy-2(di-n-propyl-amino)tetralin (8-OH-DPAT) and ipsapirone were iontophoretically applied to Purkinje cells during control periods and periods of concurrent application of the 5-HT1A/5-HT2 antagonist spiperone. 5-HT was found to produce three distinct effects on Purkinje cell spontaneous discharge: inhibition, excitation and a biphasic effect. Iontophoretically applied 8-OH-DPAT and ipsapirone elicited only inhibition of Purkinje cell firing in all cells tested. Purkinje cell inhibitions elicited by 5-HT, 8-OH-DPAT and ipsapirone were all found to be significantly dose-dependent. However, while dose-response curves for 8-OH-DPAT and ipsapirone were found to be identical, they both differed significantly from the 5-HT curve. Spiperone was shown to significantly attenuate Purkinje cell inhibition induced by 5-HT, 8-OH-DPAT and ipsapirone. In several cells 5-HT-induced inhibition of spontaneous discharge was reversed to excitation in the presence of spiperone. This was never observed with either 8-OH-DPAT or ipsapirone. Thus, our results suggest that 5-HT-induced Purkinje cell inhibitions are at least partially mediated by the 5-HT1A receptor subtype, and there also may be additional 5-HT receptor subtypes present mediating other responses. Ultimate Purkinje cell responses to 5-HT may be due to summation of responses induced by activation of several 5-HT receptor subtypes.     

Differences in the effects of 5-HT1A receptor agonists on forced swimming behavior and brain 5-HT metabolism between low and high aggressive mice

Rationale Male wild house-mice genetically selected for long attack latency (LAL) and short attack latency (SAL) differ in structural and functional properties of postsynaptic serotonergic-1A (5-HT_1A) receptors. These mouse lines also show divergent behavioral responses in the forced swimming test (FST, i.e., higher immobility by LAL versus SAL mice).Objectives We investigated whether the line difference in 5-HT_1A receptors is associated with a difference in brain 5-HT metabolism, and whether acute administration of a 5-HT_1A receptor agonist could differentially affect the behavioral responses of LAL and SAL mice.Methods 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) levels were measured in homogenates of several brain regions using high-performance liquid chromatography. The behavioral effect of the full 5-HT_1A receptor agonist, 8-OH-DPAT, and of the somatodendritic 5-HT_1A autoreceptor agonist, S-15535, was examined in the FST. The effect of 8-OH-DPAT on forced swimming-induced 5-HT metabolism in brain homogenates was determined.Results In most brain regions, 5-HT and 5-HIAA levels and 5-HT turnover were not significantly different between LAL and SAL mice. 8-OH-DPAT abolished the behavioral line difference in the FST by reducing immobility in LAL mice and reducing climbing in SAL mice. S-15535 induced a similar behavioral effect to 8-OH-DPAT in SAL mice, but did not alter the behavior of LAL mice. Compared with LAL, forced swimming elicited in SAL mice a higher brain 5-HT turnover, which was potently attenuated by 8-OH-DPAT.Conclusions It is unlikely that the difference in 5-HT_1A properties between LAL and SAL mice is an adaptive compensatory reaction to changes in 5-HT metabolism. Although unspecific motor effects, at least in SAL mice, cannot be ruled out, it is suggested that the behavioral effects of 8-OH-DPAT and S-15535 may be mediated by predominant activation of postsynaptic 5-HT_1A receptors in LAL mice and by presynaptic 5-HT_1A receptors in SAL mice.     

Involvement of 5-HT1A receptors in the antidepressant-like activity of gepirone in the forced swimming test in rats.

The antidepressant-like activity of gepirone, a drug with a high and selective affinity for 5-hydroxytryptamine1A (5-HT1A) receptors, was studied in the forced swimming test in rats. The drug, administered intraperitoneally in single doses of 2.5-20 mg/kg, potently and dose-dependently shortened the immobility time. The anti-immobility effect of gepirone (10 mg/kg) was dose-dependently antagonized by the 5-HT1A receptor and alpha 1-adrenoceptor antagonist, NAN-190 (0.25 and 0.5 mg/kg), the beta-adrenoceptor blocker with the affinity for 5-HT1A and 5-HT1B receptors, pindolol (2 and 4 mg/kg), the 5-HT1A, 5-HT2 and dopamine receptor blocker spiperone (0.01 and 0.03 mg/kg) and by the dopamine receptor antagonist, haloperidol (0.125 and 0.25 mg/kg). On the other hand, the non-selective 5-HT receptor antagonist, metergoline (2 and 4 mg/kg), the selective 5-HT2 receptor antagonist, ketanserin (1 and 2 mg/kg), the selective alpha 1-adrenoceptor blocker, prazosin (0.25 and 0.5 mg/kg) and the beta-blockers with no affinity for 5-HT receptors, betaxolol (4 and 8 mg/kg) and ICI 118,551 (4 and 8 mg/kg), did not affect the anti-immobility effect of gepirone. The effect of gepirone was not modified, either, in animals with a lesion of the 5-HT system, produced by p-chloroamphetamine (PCA, 2 x 10 mg/kg) or p-chlorophenylalanine (PCPA, 3 x 300 mg/kg). The results obtained suggest that the anti-immobility effect of gepirone is mediated by activation of 5-HT1A receptors, most probably located postsynaptically and that dopamine may be involved in this action.     

Idazoxan and 8-OH-DPAT modify the behavioral effects induced by either NA, or 5-HT, or dual NA/5-HT reuptake inhibition in the rat forced swimming test.

The rat forced swimming test (FST) predicts the efficacy of antidepressants, which decrease immobility duration in the test, and can distinguish selective serotonin (5-HT) and noradrenaline (NA) reuptake inhibitors, which, respectively, increase swimming and climbing behaviors. However, dual 5-HT and NA reuptake-inhibition produces climbing behavior solely, thereby suggesting with other data that the NA-system mediates inhibiting interactions on 5-HT-induced swimming in the FST. Since alpha(2)-adrenoreceptors and 5-HT(1A)-receptors have important regulatory functions and are involved in 5-HT/NA interactions, we examined whether the alpha(2)-receptor-antagonist idazoxan and the 5-HT(1A)-receptor-agonist 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) would modify the behavioral pattern induced in the FST by either selective or non-selective antidepressant treatments. The rats were treated subacutely (3 injections IP over 48 h) with: (a) idazoxan (0.5-10 mg/kg) alone, and in combination with desipramine (10 mg/kg), or desipramine + fluoxetine (10/10 mg/kg), or the dual serotonin/noradrenaline reuptake-inhibitor milnacipran (20 mg/kg). (b) 8-OH-DPAT (0.25-1 mg/kg) alone, and in combination with either desipramine (10 mg/kg) or fluoxetine (10 mg/kg). The results indicated: (a) Idazoxan (0.5, 5, 10 mg/kg) produced no anti-immobility effects per se in the FST, antagonized the effects of the NA-reuptake-inhibitor desipramine, and allowed desipramine + fluoxetine, as well as milnacipran, to increase swimming behavior. (b) 8-OH-DPAT produced non-significant effects per se, potentiated desipramine-induced antidepressant-like effects on immobility and climbing, and both antagonized swimming and produced climbing behavior in combination with fluoxetine. Our data support clinical trials suggesting that alpha(2)-receptor-antagonists and 5-HT(1A)-receptor-agonists may be of interest in augmentation strategies for antidepressant treatments. The scoring of active behaviors in the FST appears to be an interesting tool for studying 5-HT/NA interactions induced by antidepressants, as well as for the testing of augmentation strategies.     

Antidepressant-like effect of combined treatment with selective sigma receptor agonists and a 5-HT1A receptor agonist in the forced swimming test in rats

The interaction between the selective sigma (sigma) receptor agonists and 8-OH-DPAT, a serotonin (5-HT)(1A) receptor agonist, was examined in the forced swimming test in rats. The results indicate that joint administration of DTG (5 mg/kg) or SA4503 (3 mg/kg), the selective sigma(1)/sigma(2)- or sigma(1)-receptor agonists, respectively, and 8-OH-DPAT (0.1 or 0.3 mg/kg) induces an antidepressant-like effect. The doses of sigma agonists and 8-OH-DPAT used in the study were inactive per se in this model. The effect of DTG and 8-OH-DPAT co-administration was partly counteracted by WAY 100635 (0.1 mg/kg) as well as by BD 1047 (3 mg/kg), a 5-HT(1A) and sigma(1) receptor antagonists, respectively, suggesting the involvement of both receptor types in the anti-immobility effect in rats.     

The antidepressant effects of curcumin in the forced swimming test involve 5-HT1 and 5-HT2 receptors

Curcuma longa is a main constituent of many traditional Chinese medicines, such as Xiaoyao-san, used to manage mental disorders effectively. Curcumin is a major active component of C. longa and its antidepressant-like effect has been previously demonstrated in the forced swimming test. The purpose of this study was to explore the possible contribution of serotonin (5-HT) receptors in the behavioral effects induced by curcumin in this animal model of depression. 5-HT was depleted by the tryptophan hydroxylase inhibitor p-chlorophenylalanine (PCPA, 100 mg/kg, i.p.) prior to the administration of curcumin, and the consequent results showed that PCPA blocked the anti-immobility effect of curcumin in forced swimming test, suggesting the involvement of the serotonergic system. Moreover, pre-treatment of pindolol (10 mg/kg, i.p., a beta-adrenoceptors blocker/5-HT(1A/1B) receptor antagonist), 4-(2'-methoxy-phenyl)-1-[2'-(n-2'-pyridinyl)-p-iodobenzamino-]ethyl-piperazine (p-MPPI, 1 mg/kg, s.c., a selective 5-HT(1A) receptor antagonist), or 1-(2-(1-pyrrolyl)-phenoxy)-3-isopropylamino-2-propanol (isamoltane, 2.5 mg/kg, i.p., a 5-HT(1B) receptor antagonist) was found to prevent the effect of curcumin (10 mg/kg) in forced swimming test. On the other hand, a sub-effective dose of curcumin (2.5 mg/kg, p.o.) produced a synergistic effect when given jointly with (+)-8-hydroxy-2-(di-n-propylamino)tetralin, (8-OH-DPAT, 1 mg/kg, i.p., a 5-HT(1A) receptor agonist), anpirtoline (0.25 mg/kg, i.p., a 5-HT(1B) receptor agonist) or ritanserin (4 mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist), but not with ketanserin (5 mg/kg, i.p., a 5-HT(2A/2C) receptor antagonist with higher affinity to 5-HT(2A) receptor) or R(-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI, 1 mg/kg, i.p., a 5-HT(2A) receptor agonist). Taken together, these results indicate that the antidepressant-like effect of curcumin in the forced swimming test is related to serotonergic system and may be mediated by, at least in part, an interaction with 5-HT(1A/1B) and 5-HT(2C) receptors.     

Evidence that the 5-HT1A receptor agonists buspirone and ipsapirone activate adrenaline release in the conscious rat

The aim of this study was to investigate the effects of the 5-HT1A receptor agonists buspirone and ipsapirone (1-10 mg/kg) on plasma adrenaline (A) levels and on glycemia in the conscious rat. The results indicate that buspirone was able, within 5 min, to increase plasma A and glucose levels in a dose-dependent manner. Ipsapirone administration triggered similar patterns, except that the highest dose used (10 mg/kg) promoted a time-dependent increase in plasma A and glucose levels that was maximal at the end of analysis.     

50-kHz calls in rats: effects of MDMA and the 5-HT(1A) receptor agonist 8-OH-DPAT

In recent years, 50-kHz ultrasonic vocalizations of laboratory rats have become increasingly important behavioral measures in research on emotion and motivation, since these calls may help to study appetitive subjective states, for example in relation to addiction. Among others, 50-kHz calls occur when rats experience or expect rewards, including drugs of abuse, and it is assumed that these calls depend on dopamine function, especially in the meso-limbic system. One established means to induce 50-kHz calls is to challenge rats with d-amphetamine, a psychomotor stimulant, which acts largely by boosting dopamine and noradrenaline function in the brain. In a 1st experiment, we studied whether another psycho-stimulatory amphetamine, namely the derivative 3,4-methylene-dioxymethamphetamine (MDMA, Ecstasy), could also enhance 50-kHz calls by using an activity box and testing conditions, which had previously been found to be appropriate in case of d-amphetamine. In support of previous work, we found that MDMA (2.5, 5, 10 mg/kg, ip) dose-dependently increased locomotion and center time, together with decreases in rearing activity, but the drug did not elicit 50-kHz calls. Assuming that this lack of effect is due to the drug's substantial pro-serotonergic effects in the brain, which may inhibit 50-kHz calls, we performed a 2nd experiment where we tested the serotonin 5-HT_1A receptor agonist 8-hydroxy-2-tetralin (8-OH-DPAT; 0.05, 0.5, 2.5 mg/kg, ip). This drug dose-dependently stimulates serotonin autoreceptors and heteroreceptors, can act in a psycho-stimulatory way and can enhance dopamine function. In the activity box, 8-OH-DPAT increased locomotor activity (0.5, 2.5 mg/kg) and decreased rearing (2.5 mg/kg); that is, the drug seemed to share some psycho-stimulatory effects with MDMA. Unlike MDMA, 8-OH-DPAT enhanced 50-kHz calls in a dose-dependent way, namely only with the 0.5 mg/kg dose. These results are discussed with respect to their possible neurochemical mechanisms, especially on 5-HT and dopamine in the brain.     

The behavioural responses to 8-OH-DPAT,ipsapirone and the novel 5-HT1A receptor agonist Bay Vq 7813 in the pig

Summary In pigs, behavioural responses were examined after administration of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a full agonist at 5-hydroxytryptamine (5-HT) receptors of the 5-HT_1A subtype, and the pyrimidinylpiperazine derivatives ipsapirone and Bay Vq 7813 (2-[4-(2-pyrimidinyl)-1-piperazinylpropyl]-1,2-benzisothiazol-3(2H)one-1,1-dioxide), which act as partial agonists at 5-HT_1A receptors. The most prominent behavioural response examined after 8-OH-DPAT, 0.5 mg/kg i. m., ipsapirone, 2–5 mg/kg i.m., and Bay Vq 7813, 0.5–2 mg/kg i.m. or i.v., were head shakes. The potency of the three drugs to induce this behaviour correlated with their activity at 5-HT_1A receptors as determined by inhibition of forskolin-stimulated adenylate cyclase, substantiating that the head shake response has potential as a quantitative probe of in vivo receptor function. The 5-HT₂/5-HT_1C receptor antagonist ritanserin did not counteract the head shakes induced by ipsapirone, suggesting that neither 5-HT₂ nor 5-HT_1C receptors are involved in mediation of this response to this 5-HT_1A receptor agonist in pigs. Once daily administration of Bay Vq 7813 or ipsapirone for 3–5 days led to a reduction in the head shake response. 1-Pyrimidinylpiperazine (1-PP), a pharmacologically active metabolite shared by ipsapirone, Bay Vq 7813, and related pyrimidinylpiperazine derivatives, did not induce behavioural alterations in pigs. The data provide further evidence that marked species differences exist in functional responses to 5-HT receptor ligands. Send offprint requests to W. Löscher at the above address     

Nociceptin receptor antagonists display antidepressant-like properties in the mouse forced swimming test

The present study investigated the effects of nociceptin, the peptide nociceptin receptor antagonist, [Nphe(1)]-nociceptin (1-13)-NH(2), and the non-peptide antagonist, J-113397, in the mouse forced swimming test, an animal model used for the screening of potential antidepressant drugs. Additional studies were performed with naloxone to exclude effects on traditional opioid receptors. Intracerebroventricular (ICV) administration of nociceptin (0.01-1 nmole) was devoid of any activity in the mouse forced swimming test, as was intraperitoneal (i.p.) administration of naloxone (1-10 mg/kg). ICV treatment with [Nphe(1)]-nociceptin (1-13)-NH(2) (25 nmole and 50 nmole) induced significant antidepressant-like activity ( P<0.01), as did administration of J-113397 (20 mg/kg, i.p; P<0.05). Open field analysis revealed that acute treatment with these molecules did not induce significant changes in locomotor activity at the doses tested. These results suggest that nociceptin, and its receptor, may play a role in depressive disorders and that the nociceptin system could represent a novel target for the development of new antidepressant drugs.     

Effect of combined administration of 5-HT1A or 5-HT1B/1D receptor antagonists and antidepressants in the forced swimming test

In the present study, we examined effects of the selective serotonin (5-hydroxytryptamine, 5-HT) reuptake inhibitor citalopram, the 5-HT/noradrenaline reuptake inhibitor imipramine, the selective noradrenaline reuptake inhibitor desipramine or the monoamine oxidase-A inhibitor moclobemide, administered in combination with the 5-HT(1A) receptor antagonist N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridynyl)cyclohexanecarboxamide (WAY 100635) or the 5-HT(1B/1D) receptor antagonist N-[4-methoxy-3-(4-methyl-1-piperazinyl)phenyl]-2'-methyl-4'-(5-methyl-[1,2,4]oxadiazol-3-yl)1,1'-biphenyl-4-carboxamide (GR 127935) and the 5-HT(1B) receptor antagonist N-[3-(2-dimethylamino) ethoxy-4-methoxyphenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl)-(1,1'-biphenyl)-4-carboxamide (SB 216641) in the forced swimming test in rats. When given alone, citalopram (20 and 30 mg/kg), imipramine (20 mg/kg), desipramine (20 mg/kg), moclobemide (20 mg/kg), WAY 100635 (0.1 and 1 mg/kg), GR 127935 (10 and 20 mg/kg) or SB 216641 (2 mg/kg) did not shorten the immobility time of rats. Co-administration of WAY 100635 (0.1 and 1 mg/kg) and citalopram (20 mg/kg), or imipramine (20 mg/kg), or moclobemide (20 mg/kg) did not affect the immobility time of rats, whereas WAY 100635 given jointly with desipramine (20 mg/kg) induced a weak anti-immobility effect. GR 127935 (10 and 20 mg/kg) or SB 216641 (2 mg/kg) co-administered with imipramine, desipramine or moclobemide, but not citalopram, produced a significant anti-immobility action in the forced swimming test in rats. These results indicate that the blockade of 5-HT(1B) rather than 5-HT(1A) receptors may facilitate the anti-immobility effect of imipramine, desipramine or moclobemide in the forced swimming test. No interaction was observed between 5-HT(1A) or 5-HT(1B/1D) receptor antagonists and citalopram.     

Mediation of the antidepressant-like effect of 8-OH-DPAT in mice by postsynaptic 5-HT1A receptors.

1. The 5-hydroxytryptamine (5-HT)1A agonist 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT) has been evaluated in a mouse model for detecting potential antidepressants (Porsolt test). The effects of various receptor antagonists, lesions of brain monoaminergic neurones and chronic drug treatments on this 8-OH-DPAT-induced response have also been determined. 2. 8-OH-DPAT (0.3-10.0 mg kg-1, s.c.) dose-dependently increased the mobility of mice in the Porsolt test. Other selective 5-HT1A receptor ligands (0.3-30 mg kg-1, s.c.) either mimicked the 8-OH-DPAT response (ipsapirone, at 10 and 30 mg kg-1, s.c.) or were inactive (buspirone and gepirone). However, each of these compounds (< or = 100 mg kg-1, p.o.) inhibited the response to 8-OH-DPAT (3 mg kg-1, s.c.) when given concurrently. 3. The putative 5-HT1A antagonists, spiroxatrine (1-30 mg kg-1, p.o.), (+/-)-pindolol (30 mg kg-1, p.o.) and methiothepin (3-10 mg kg-1, p.o.), each attenuated the 8-OH-DPAT (3 mg kg-1, s.c.)-induced increase in mobility. 4. The dopamine D1 receptor antagonist, SCH 23390 (3-10 mg kg-1, p.o.), weakly reversed the 8-OH-DPAT response.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of 5-HT(2) receptor antagonists on the anti-immobility effects of imipramine in the forced swimming test with mice

The effects of 5-HT(2) receptor antagonists on antidepressant effects of imipramine were investigated in the forced swimming test. Imipramine induced anti-immobility effects in mice dose dependently. Pretreatment with the 5-HT(2A/2B/2C) receptor antagonist, 4-isopropyl-7-methyl-9-(2-hydroxy-1-methyl-propoxycarbonyl)-4,6A,7,8,9,10,10A-octahydro-indolo[4,3-FG]quinolone maleate (LY 53857) significantly enhanced the anti-immobility effects of imipramine. The 5-HT(2C/2B) receptor antagonist, N-3-pyridinyl-3,5-dihydro-5-methyl-benzo[1,2-b:4,5-b']dipyrrole-1(2H)-carboxamide (SB 206553), also enhanced, while the 5-HT(2A) receptor antagonist, ketanserin, was without effect. These results suggest that blockade of the 5-HT(2C/2B) receptor leads to potentiation of the antidepressant effects of imipramine.