Study into a possible mechanism responsible for the antidepressant-like activity of the selective 5-HT6 receptor antagonist SB-399885 in rats

The mechanism of the antidepressant-like activity of the selective 5-hydroxytryptamine(6) (5-HT(6) receptor antagonist N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide (SB-399885) was studied in the forced swim test in rats. SB-399885 administered intraperitoneally at a single dose of 10 mg/kg potently shortened the immobility time in rats. That potential antidepressant-like effect of SB-399885 was not modified in animals with a lesion of the 5-HT system produced by p-chloroamphetamine (p-CA, 2 x 10 mg/kg). The anti-immobility effect of SB-399885 was blocked by the dopamine D(1)- and D(2)-like receptor antagonists SCH 23390 (0.063 mg/kg) and sulpiride (10 mg/kg), respectively, as well as by the alpha(2)-adrenoceptor antagonist idazoxan (4 mg/kg), but it was not changed by the alpha(1)-adrenoceptor antagonist prazosin (1 mg/kg). Neither sulpiride (10 mg/kg) or idazoxan (4 mg/kg) nor SCH-23390 (0.063 mg/kg) administered jointly with SB-399885 (10 mg/kg) noticeably changed the exploratory locomotor activity of rats evaluated by the open field test. The results described in the present paper indicate that the anti-immobility activity of SB-399885 is not connected with 5-HT innervation, and that D(1)- and D(2)-like receptors and alpha(2)-adrenoceptors are involved in this action.     

Is dopamine implicated in the antidepressant-like effects of selective serotonin reuptake inhibitors in the mouse forced swimming test?

RATIONALE: Microdialysis, binding and behavioural studies have shown that the dopaminergic system plays a role in antidepressant treatment. OBJECTIVES: The present study determined whether the antidepressant-like effects of selective serotonin reuptake inhibitors measured in the mouse forced swimming test are mediated via dopamine receptors. METHODS: Male Swiss mice were randomly assigned to groups of 24 animals and injected IP with citalopram, fluoxetine, fluvoxamine, sertraline, or paroxetine alone or in combination with the dopamine D(1)agonist SKF 38393, the D(1) antagonist SCH 23390, the D(2) agonist bromocriptine, the D(2) antagonist sulpiride, the D(3) agonist PD 128 907, or the D(3) antagonist nafadotride. RESULTS: The anti-immobility effects of paroxetine, fluvoxamine and citalopram were increased by co-administration of SKF 38393 (0.5 and 2 mg/kg), SCH 23390 (0.06 mg/kg), bromocriptine (0.5 and 2 mg/kg) or PD 128 907 (1 and 2 mg/kg), and were attenuated by SCH 23390 (0.5 mg/kg). The anti-immobility effects of paroxetine and fluvoxamine were also increased with sulpiride (0.5 and 2 mg/kg). The anti-immobility effect of fluoxetine was increased by SKF 38393 (2 mg/kg) and PD 128 907(1 and 2 mg/kg) co-administration. The anti-immobility effect of sertraline (16 mg/kg) was increased by SKF 38393 (0.5 mg/kg), bromocriptine (2 mg/kg) and PD 128 907 (2 mg/kg) and the effect of sertraline (2 mg/kg) was increased by bromocriptine (2 mg/kg). The anti-immobility effect of paroxetine (4 mg/kg) was increased by nafadotride (2 mg/kg). CONCLUSIONS: These data indicate that the antidepressant activity of various SSRIs involves different dopamine receptor subtypes and that the serotoninergic and dopaminergic systems interact with each other.     

SCH 23390--a selective dopamine D-1 receptor antagonist with putative 5-HT1 receptor agonistic activity

The selective dopamine D-1 receptor antagonist SCH 23390 has been tested in vitro in the rat fundus model and in vivo in the electrically stimulated flexor reflex model. In the fundus model, SCH 23390 showed a potent agonistic activity compared to that of different 5-HT receptor agonists. Pindolol, 1-propranolol and pirenperone showed no or only weak inhibition of the SCH 23390-induced contractions in the fundus strip whereas methysergide was a potent inhibitor. The 5-HT3 receptor antagonist ICS 205-930 did not induce an inhibitory effect. In the electrically stimulated flexor reflex model in pithed rats, SCH 23390 induced a marked increase of the reflex. This increase was slightly inhibited by a mixed dopamine (DA) D-1/D-2 antagonist cis(Z)-flupentixol and by a specific DA D-2 antagonist YM 09151-2. Different reference antagonists: bicuculline (GABAergic), propranolol (beta-adrenergic), scopolamine (muscarinic), yohimbine (alpha 2-adrenergic), prazosin (alpha 1-adrenergic) were all without an antagonist effect on the SCH 23390-induced increase of the flexor reflex. Ketanserin, a selective 5-HT2 receptor antagonist, showed a weak and short-lasting inhibition of the SCH 23390 effect in high doses, whereas ritanserin showed only 35% inhibition of the SCH 23390-induced flexor reflex at a dose of 1.3 mumol/kg i.v. The mixed 5-HT1/5-HT2 antagonists methiothepin and metergoline showed a marked inhibitory effect at 2.6 mumol/kg i.v. and 3.1 mumol/kg i.v., respectively (1.3 mg/kg i.v.). These findings suggest that SCH 23390 might possess 5-HT1 receptor agonist activity.     

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.     

Mechanism of synergistic action following co-treatment with pramipexole and fluoxetine or sertraline in the forced swimming test in rats

The aim of the present study was to examine the effect of combined treatment of male Wistar rats with pramipexole and fluoxetine or sertraline in the forced swimming test. The obtained results showed that co-treatment with pramipexole (0.1 mg/kg) and fluoxetine (10 mg/kg) or sertraline (5 mg/kg) (in doses inactive per se) exhibited antidepressant-like activity in the forced swimming test. Sulpiride (a dopamine D(2/3) receptor antagonist) and WAY 100635 (a 5-HT(1A) receptor antagonist), either being ineffective in the forced swimming test, inhibited the antidepressant-like effect induced by co-administration of pramipexole and fluoxetine or sertraline. However, SCH 23390 (a dopamine D(1) receptor antagonist) only partly did not alter the effect of pramipexole given jointly with antidepressant drugs; on the other hand, S 33084 (a dopamine D(3) receptor antagonist) only partly decreased (in a statistically insignificant manner) that effect. Moreover, progesterone and BD 1047 (a sigma(1) receptor antagonist) counteracted the antidepressant-like effect induced by co-administration of pramipexole and sertraline (but not pramipexole and fluoxetine). In that test, active behavior did not reflect the increases in general activity, since combined administration of pramipexole and fluoxetine or sertraline failed to enhance the locomotor activity of rats. None of the tested drugs (SCH 23390, sulpiride, S 33084, WAY 100635, BD 1047 and progesterone) - alone or in combination with pramipexole and fluoxetine or sertraline - changed locomotor activity. The results described in the present paper indicate that co-administration of pramipexole and fluoxetine or sertraline may induce a more pronounced antidepressive activity than does treatment with pramipexole alone, and that in addition to other mechanisms, dopamine D(2/3) and 5-HT(1A) receptors may contribute to the antidepressant-like activity of pramipexole and fluoxetine or sertraline in the forced swimming test in rats. Moreover, sigma(1) receptors may constitute one of the possible mechanisms by which co-administration of pramipexole and sertraline induces antidepressant-like activity in that test.     

The antidepressant-like action of a simple selenium-containing molecule, methyl phenyl selenide, in mice

Selenium-containing molecules show promising pharmacological properties. The antidepressant-like action of CH(3)SePh in the mouse forced swimming test (FST) and the tail suspension test (TST), models predictive of depressant activity, were investigated in this study. Moreover, the involvement of dopaminergic system in the antidepressant-like action of CH(3)SePh was studied. The behavioral results showed that CH(3)SePh significantly reduced the immobility time in the FST (25 and 50 mg/kg, intragastrically; i.g.) and the TST (50 mg/kg, i.g.), without accompanying changes in ambulation when assessed in the open-field test (OFT). The anti-immobility effect of CH(3)SePh (50 mg/kg, intragastrically; i.g.) in the FST was prevented by pretreatment of mice with haloperidol (0.2 mg/kg, i.p., a dopamine D(2) receptor antagonist), SCH 23390 (R-(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-ol) (0.05 mg/kg, s.c., a dopamine D(1) receptor antagonist) and sulpiride (50 mg/kg, i.p., a dopamine D(2) and D(3) antagonist). These results suggest that CH(3)SePh produced an antidepressant-like action in the mouse FST and TST. The antidepressant-like action of CH(3)SePh, a simple selenium-containing molecule, seems most likely to be mediated through an interaction with the dopaminergic system.     

Antidepressant-like effects of Albizzia julibrissin in mice: involvement of the 5-HT1A receptor system

The present study was undertaken to investigate the antidepressant-like effects of the methylene chloride fraction of Albizzia julibrissin (MCAJ) using a tail suspension test in mice. MCAJ was orally administered at 50, 100, or 200 mg/kg to mice, 1 h before the tail suspension test. Acute treatment with MCAJ at 200 mg/kg significantly reduced the immobility time compared with the control group, and thus showed an antidepressant-like effect. This effect was comparable to that of imipramine at 10 mg/kg. This antidepressant-like effect was reversed by treatment with WAY-100635 (a 5-HT1A receptor antagonist) or pindolol (a 5-HT1A/1B receptor antagonist). However, the antidepressant effect of MCAJ was not effected by treatment with GR55562 (a 5-HT1B receptor antagonist) or ketanserin (a 5-HT2A receptor antagonist). Therefore, our findings suggest that MCAJ exerts its antidepressant-like effect via the 5-HT1A receptor system.     

SCH 23390: the first selective dopamine D1-like receptor antagonist

SCH 23390, the halobenzazepine (R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5- tetrahydro-1H-3-benzazepine, is a highly potent and selective dopamine D1-like receptor antagonist with a K(i) of 0.2 and 0.3 nM for the D1 and D5 dopamine receptor subtypes, respectively. In vitro, it also binds with high affinity to the 5-HT2 and 5-HT1C serotonin receptor subtypes. However, the doses required to induce a similar response in vivo are greater than 10-fold higher than those required to induce a D1-mediated response. Previous in vivo pharmacological studies with SCH 23390 have shown it to abolish generalized seizures evoked by the chemoconvulsants: pilocarpine and soman. These studies provide evidence of the potential importance of D1-like dopaminergic receptor mechanisms in facilitating the initiation and spread of seizures. The inference from a majority of studies is that the activation of dopamine D1 receptors facilitates seizure activity, whereas activation of D2 receptors may inhibit the development of seizures. SCH 23390 has also been used in studies of other neurological disorders in which the dopamine system has been implicated, such as psychosis and Parkinson's disease. Apart from the study of neurological disorders, SCH 23390 has been extensively used as a tool in the topographical determination of brain D1 receptors in rodents, nonhuman primates, and humans. In summary, SCH 23390 has been a major tool in gaining a better understanding of the role of the dopamine system, more specifically the D1 receptor, in neurological function and dysfunction.     

Administration of SCH 23390 into the medial prefrontal cortex blocks the expression of MDMA-induced behavioral sensitization in rats: an effect mediated by 5-HT2C receptor stimulation and not by D1 receptor blockade.

Akin to what has been reported for cocaine, systemic administration of the dopamine D1 receptor antagonist, SCH 23390 ((R)-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride), blocks the expression but not the induction of 3,4-methylenedioxymethamphetamine (MDMA)-induced behavioral sensitization. Since the medial prefrontal cortex (mPFC) appears to regulate the expression of sensitization to cocaine, this study examined whether microinjection of SCH 23390 into the mPFC would alter the expression of MDMA sensitization. Saline or MDMA was administered for 5 consecutive days. After 12 days of withdrawal, rats received a bilateral intra-mPFC microinjection of SCH 23390 or saline followed by an intraperitoneal (i.p.) challenge dose of MDMA. While SCH 23390 enhanced locomotion in MDMA-na?ve rats, it completely suppressed the expression of sensitization in MDMA-pretreated animals. Since, SCH 23390 has a fairly good affinity for 5-HT(2C) receptors, we went further to study the role of mPFC D1 and 5-HT(2C) receptors in this, apparently, paradoxical effect shown by SCH 23390. Thus, the microinjection of both SKF 81297 (R-(+)-6-chloro-7,8-dihydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide) and MK 212 (6-chloro-2-(1-piperazinyl)pyrazine hydrochloride), a D1 and 5-HT(2C) receptor agonist, respectively, blocked MDMA sensitization. By contrast, the 5-HT(2C) receptor antagonist, RS 102221 (8-[5-(2,4-dimethoxy-5-(4-trifluoromethylphenylsulfonamido)phenyl-5-oxopentyl]-1,3,8-triazaspiro[4,5]decane-2,4-dione hydrochloride), had no effect in MDMA-na?ve or MDMA-sensitized animals, but reversed the effects of SCH 23390 in MDMA-pretreated rats. These results demonstrate that suppression of MDMA-induced sensitization by SCH 23390 is mediated by 5-HT(2C) receptor stimulation in the mPFC and not by the blockade of mPFC D1 receptors. Furthermore, these data indicate that stimulation of 5-HT(2C) receptors by SCH 23390 is not a minor issue and should be considered when interpreting future data.     

Selective dopaminergic mechanism of dopamine and SKF38393 stimulation of inositol phosphate formation in rat brain.

We have previously reported that dopamine and the D1 receptor-selective agonist, SKF38393, stimulate the formation of inositol phosphates in rat brain slices (Undie and Friedman, 1990, J. Pharmacol. Exp. Ther. 253, 987). The present experiments were conducted to determine if actions at alpha-adrenoceptors or at serotonergic sites may contribute to, or interact with, the observed stimulation of phosphoinositide hydrolysis by dopamine receptor agonists. Rat striatal slices prelabeled with [3H]inositol were treated with up to 500 microM dopamine, norepinephrine, serotonin (5-HT), or the dopamine D1 receptor agonist, SKF38393, and accumulated inositol phosphates determined. The action of norepinephrine was dose-dependently blocked by the selective alpha 1-adrenoceptor antagonist, prazosin, but not by SCH23390. The actions of dopamine and SKF38393 were dose-dependently blocked by the dopamine D1 receptor antagonist, SCH23390, but not by prazosin. The effects of 5-HT were blocked by the nonselective 5-HT antagonist, methiotepin, the selective 5-HT2 antagonist, ketanserin, the mixed 5-HT2/5-HT1C antagonist, mianserin, and, with much less potency, by the selective 5-HT1C antagonist, mesulergine. On the contrary, the serotonin receptor antagonists did not block the response to SKF38393, and there was no dose-dependent blockade of the 5-HT response by SCH23390. These observations indicate that the actions of dopamine and SKF38393 in stimulating inositol phosphate formation are selectively mediated through a D1-like dopamine receptor.     

Stimulation of dopamine D-2 but not D-1 receptors reduces immobility time of rats in the forced swimming test: implication for antidepressant activity

The involvement of dopamine D-1 and D-2 receptor mechanisms was investigated in the forced swimming test with rats. d,1-Sulpiride, a D-2 receptor antagonist, reported to reduce desipramine-induced anti-immobility, did not alter the brain levels of desipramine. In addition, the anti-immobility effect of desipramine was not antagonized by SCH 23390, a D-1 receptor antagonist. Amineptine (20 mg/kg i.p., 60 min before testing), a dopamine uptake blocker, and LY171555 (0.2 mg/kg i.p., 60 min before testing), a dopaminergic D-2 stimulant reduced immobility time in the forced swimming test, but benserazide + 1-DOPA (200 mg/kg p.o., 45 min before testing), which increases dopamine release, or SKF 38393A (20 mg/kg s.c., 60 min before testing), a D-1 agent, did not. The anti-immobility effect but not the stereotypy was increased following chronic (21 days) LY171555 (0.1 and 0.2 mg/kg i.p.) treatment. The effect of acute or repeated (7 days) LY171555 (0.2 mg/kg i.p.) treatment was antagonized by 1-sulpiride (50 mg/kg i.p., 90 min before testing), a D-2 receptor antagonist. Neither SKF 38393A (20 mg/kg s.c., 60 min before testing) nor SCH 23390 (0.05 mg/kg s.c., 30 min before testing) modified the acute anti-immobility effect of LY171555 (0.2 mg/kg i.p.) SCH 23390 (0.025 and 0.05 mg/kg) increased the immobility time at doses which decreased motor activity. The increase in immobility time brought about by SCH 23390 was not antagonized by SKF 38393A (20 mg/kg). The findings indicate that activation of dopamine D-2 receptors could reduce immobility time.     

Inverse agonist properties of dopaminergic antagonists at the D(1A) dopamine receptor: uncoupling of the D(1A) dopamine receptor from G(s) protein.

The interaction of dopaminergic antagonists with the D(1A) dopamine receptor was assessed in PC2 cells that transiently express this receptor. The maximal binding and dissociation constants for the D(1A) dopamine receptor, using the ligand [(125)I]SCH23982 were 0.38 +/- 0.09 nM and 1 to 4 pmol/mg, respectively, when assessed 48 h after transfection with cDNA encoding the rat D(1A) receptor. Basal adenylyl cyclase activity increased 50 to 60% in membranes of transfected PC2 cells compared with control membranes. The dopaminergic antagonists clozapine, cis-flupenthixol, (+)-butaclamol, haloperidol, chlorpromazine, and fluphenazine inhibited constitutive adenylyl cyclase activity in membranes of cells expressing the D(1A) receptor. SCH23390, a selective D(1) dopamine receptor antagonist, and (-)-butaclamol did not alter basal cyclase activity, whereas dopamine increased enzyme activity in membranes expressing the D(1A) dopamine receptor. The coupling of D(1A) receptors with G(s) proteins was examined by immunoprecipitation of membrane G(salpha) followed by immunoblotting with a D(1A) dopamine receptor monoclonal antibody. Clozapine, cis-flupenthixol, (+)-butaclamol, haloperidol, and fluphenazine but not SCH23390 or (-)-butaclamol decreased D(1A) receptor-G(salpha) coupling by 70 to 80%, and SCH23390 was able to prevent the receptor-G(salpha) uncoupling induced by haloperidol or clozapine. These results indicate that some dopaminergic antagonists suppress basal signal transduction and behave as inverse agonists at the D(1A) dopamine receptor. This action of the dopamine receptor antagonists may contribute to their antidopaminergic properties that seem to underlie their clinical actions as antipsychotic drugs.     

Evidence of the involvement of D1 dopamine receptors in PCP-induced stereotypy and ataxia in rabbits

A behavioural study on the effects of D1 and D2 dopamine receptor antagonists (SCH 23390 and sulpiride respectively) and of an A1 adenosine receptor agonist (N6-L-phenylisopropyladenosine, L-PIA) against phencyclidine (PCP)-induced effects was assessed in adult male rabbits. SCH 23390 (0.003-0.01 mg/kg i.v.) and sulpiride (12.5 mg/kg i.v.) were able to significantly prevent PCP-induced stereotypy. Ataxia was reduced by SCH 23390 (0.003 mg/kg i.v.), while it was potentiated by sulpiride (12.5 mg/kg i.v.). Given alone at 12.5 mg/kg, sulpiride induced some EEG and behavioural effects in rabbits, while SCH 23390 (0.003 and 0.01 mg/kg) did not. L-PIA prevented both PCP-induced stereotypy and ataxia at the dose (0.1 mg/kg i.v.) devoid of behavioural or EEG effects by itself. Our results suggest that D1 dopamine receptors might play a more important role than D2 receptors in the expression of PCP-induced behaviour. They also propose that A1 adenosine receptors might be involved (e.g. via an influence on the dopamine release) in the behavioural effects of PCP.     

Preferential inhibition of ligand binding to calf striatal dopamine D1 receptors by SCH 23390

The phenylbenzazepine derivative, SCH 23390 was found to be a potent inhibitor of 3H-piflutixol binding to calf striatal dopamine D1 receptors. In contrast SCH 23390 was only a weak inhibitor of 3H-spiperone binding to dopamine D2 receptors. Although possessing some activity at serotonin S2 and alpha 2 adrenergic receptors, SCH 23390 appears to be a potent and selective D1 receptor antagonist.     

Sleep during acute dopamine D1 agonist SKF 38393 or D1 antagonist SCH 23390 administration in rats

The effect of the D1 dopamine (DA) receptor agonist SKF 38393 was compared with that produced by the D1-receptor antagonist, SCH 23390, in rats implanted with electrodes for chronic sleep recordings. SKF 38393 (0.1 to 4.0 mg/kg) significantly suppressed rapid-eye-movement sleep (REMS) after the highest dose. SCH 23390 (0.1 to 2.0 mg/kg) increased slow-wave sleep (SWS), whereas wakefulness (W) and REMS were decreased. Pretreatment with SKF 38393 (0.5 mg/kg) prevented the effects of SCH 23390 (0.25 mg/kg) on W and SWS. However, REM sleep showed a further depression. Pretreatment with SKF 38393 (2.0 mg/kg) or SCH 23390 (0.25 mg/kg) failed to modify the increase of SWS and decrease of W induced by D2 receptor agonist bromocriptine (0.5 mg/kg) in a dose that selectively stimulates DA autoreceptors. On the other hand, SCH 23390 (0.25 mg/kg) failed to prevent REMS depression induced by bromocriptine (6.0 mg/kg) in a dose that preferentially acts at postsynaptic sites. Pretreatment with SCH 23390 (0.25 mg/kg) prevented the increase of W and decrease of SWS induced by the 5-HT2 receptor agonist DOI (0.25 mg/kg). Given the "fragility" of REMS in the rat, nonspecific factors could be contributing to its depression after SKF 38389 or SCH 23390 administration. Inhibition of D1 receptors could be responsible for SCH 23390-induced increase of SWS and decrease of W. However, a blockade of 5-HT2 receptors could be partly involved in these effects. Neither SKF 38393 nor SCH 23390 exerted activity on the sleep-wake cycle, which could be considered to reflect effects at DA autoreceptors.     

The electrically-stimulated spinal reflex in pithed rats: a possible test model for evaluating blockade of central dopamine D1 and D2 receptors

Intravenous injection of the dopamine (DA) D1 receptor agonist SK&F 38393 (4.3 mumol/kg = 1.25 mg/kg), or the DA D2 receptor agonist pergolide (3.2 mumol/kg = 1.25 mg/kg) increased the electrically-stimulated spinal reflex in pithed rats by more than 600 per cent. The specific DA D1 receptor antagonist SCH 23390 potently inhibited the SK&F 38393-induced spinal reflex but not the pergolide-induced reflex. The DA D2 receptor antagonists clebopride and YM 09151-2 inhibited the pergolide-induced reflex only. Two mixed DA D1/D2 antagonists (cis(Z)-flupentixol and zuclopenthixol) inhibited the effects of both SK&F 38393 and pergolide on the spinal reflex, while the neuroleptically inactive isomer of clopenthixol (trans(E)-clopenthixol) was also inactive in this context. Various antagonists (prazosin (alpha 1), idazoxan (alpha 2), 1- propranolol (beta), bicuculline (GABA] were inactive in the test model. The 5-HT2 receptor antagonists altanserin and ketanserin also showed antagonistic effect. It is concluded that the electrically-stimulated spinal reflex in pithed rats can be used as a test model to estimate the blockade of central DA D1 and DA D2 receptors without influence from alpha 1-adrenergic, alpha 2-adrenergic, beta-adrenergic and GABA-ergic receptors. However, a serotonergic receptor antagonism does influence the specificity of the test model.     

Involvement of dopamine receptors in the anti-immobility effects of dopamine re-uptake inhibitors in the forced swimming test

The effects of dopamine re-uptake inhibitors, bupropion and nomifensine on immobility in the forced swimming test were studied in mice. Bupropion and nomifensine reduced immobility time dose-dependently. Both drugs significantly displayed anti-immobility effects at doses without altering locomotor activity. Anti-immobility effects of bupropion and nomifensine were inhibited by the dopamine D1 receptor antagonist R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine-HCl (SCH 23390) and the dopamine D2 receptor antagonist sulpiride. These findings suggest that dopamine may be related to depression and dopamine D1 and dopamine D2 receptors play a role in the effects of dopamine re-uptake inhibitors.     

Evaluation of the histamine H1-antagonist-induced place preference in rats

The place preferences by some histamine H1 antagonists, such as tripelennamine, optical isomers of chlorpheniramine (dl-, d- and l-forms) and pyrilamine, in rats were evaluated with the conditioned place preference paradigm. In the present study, tripelennamine and all of the optical isomers of chlorpheniramine, but not pyrilamine, produced a significant place preference. The degree of the place preference induced by optical isomers of chlorpheniramine (6.0 mg/kg) did not correlate with the H1-antagonistic potency of these drugs, suggesting that H1-antagonist-induced place preferences are not mediated by H1-receptor blockade. The tripelennamine (3.0 mg/kg)- and dl-chlorpheniramine (6.0 mg/kg)-induced place preferences were completely abolished by pretreatment with the dopamine D1-receptor antagonist SCH23390 (0.05 mg/kg). Furthermore, the doses of H1 antagonists that induced a place preference significantly reduced the levels of DOPAC, which may be mediated by inhibition of dopamine uptake, in the limbic forebrain (including the nucleus accumbens and olfactory tubercle). These results suggest that some H1 antagonists induce rewarding effects, which may be mediated by the activation of dopamine D1 receptors, followed by the inhibition of dopamine uptake.     

Role of dopamine D1 and D2 receptors in mediating the d-amphetamine discriminative cue.

The role of D1 and D2 dopamine (DA) receptors in mediating the discriminative cue produced by d-amphetamine (0.5 mg/kg) in rats has been assessed by using compounds which exert strong selectivity for each of these DA receptor subtypes. The D2 agonists quinpirole and RU 24213 substituted completely for d-amphetamine, while the D1 agonists SKF 38393 and SKF 81297 failed to exert such effects. On the other hand, the D2 antagonists raclopride and YM 09151-2, and D1 antagonists SCH 23390 and SKF 83566, all completely blocked d-amphetamine discrimination. The D2 antagonists produced more pronounced inhibitory effects on response rate than did D1 antagonists. Quinpirole substitution for d-amphetamine was blocked by YM 09151-2, but not by SCH 23390, while the locomotor stimulatory effect of quinpirole was inhibited by both drugs. The present findings confirm that D2 receptors play a primary role in the d-amphetamine discriminative cue, while the precise role of D1 receptors remains to be disclosed.     

Evidence that imipramine activates 5-HT1C receptor function.

The anti-immobility effect of imipramine (15 mg/kg) in the forced swimming test in mice was antagonized by the non-selective 5-hydroxytryptamine (5-HT) antagonist, metitepine (0.5 mg/kg), by the 5-HT1C/5-HT2 antagonist, mesulergine (15 mg/kg), and by the dopamine D2 antagonist, d,l-sulpiride (50 mg/kg). These three antagonists did not alter the behaviour of imipramine-treated mice in an open-field and did not reduce imipramine brain levels. The 5-HT2 antagonist, ritanserin (0.06 mg/kg), the 5-HT1A/5-HTB antagonist, l-propranolol (20 mg/kg), and the 5-HT3 antagonists, endo-2,3-dihydro-N-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)-2-oxo-1H- benzimidazole-1-carboxamide hydrochloride (DAU 6215; 0.1 mg/kg) and 1,2,3,9-tetrahydro-9-methyl-3[(2-methyl-1H-imidazol-1-yl)methyl]-4H- carbazol-4-one, HCl.2H2O) (GR 38032F; 0.1 mg/kg), failed to reduce imipramine-induced anti-immobility. Subthreshold doses of 8-hydroxy-2-(di-n-propylamino)tetralin hydrochloride (8-OH-DPAT; 0.5 mg/kg) and imipramine (7.5 mg/kg) did not synergize in reducing immobility. d,l-Sulpiride, but not mesulergine, antagonized the effect of desipramine (15 mg/kg) in the forced swimming test. All compounds were administered i.p. 6 min before imipramine or desipramine, given i.p. 30 min before the testing. Imipramine produced 50% inhibition of [3H]mesulergine binding to 5-HT1C receptors at 10 microM, a concentration below that obtained following i.p. imipramine administration. The results suggest a contribution of 5-HT1C receptors in the mechanism of the imipramine effect in the forced swimming test.