Effects of beclamide on isolation-induced aggression and locomotor activity in mice

The anti-aggressive effects of orally administered beclamide (N-Benzyl-beta-chloropropionamide) have been studied in male albino mice which were individually isolated for a 28-day period. Beclamide (50-250 mg kg-1 p.o.) caused an overall dose-dependent increase in the attack onset latency, a reduction in the percentage of animals attacking and the mean number of attacks/animal for this model of aggression. In addition, the highest dose of beclamide (250 mg kg-1 p.o.) did not significantly modify locomotor activity in mice. It was concluded that beclamide induced anti-aggressive effects at non-sedative doses. This anti-aggressive action was thought be at least partially mediated, through a beclamide-induced release of 5-HT from presynaptic sites.     

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)     

Modulation of sexual behaviour in the rat by a potent and selective alpha 2-adrenoceptor antagonist, delequamine (RS-15385-197).

1. The contributions of alpha 2-adrenoceptors and 5-HT1A receptors to sexual behaviour in the rat have been re-evaluated by use of a highly potent and selective alpha 2-adrenoceptor antagonist, delequamine (RS-15385-197), yohimbine, idazoxan and the partial agonist at 5-HT1A receptors, 8-hydroxy-2(di-n-propylamino)-tetralin (8-OH-DPAT). 2. In a model where naive male rats were introduced to oestrogen-progesterone primed, sexually receptive female rats, delequamine (0.4-6.4 mg kg-1, p.o.) dose-relatedly increased the sexual behaviour score over the entire dose-range whereas yohimbine was effective at only one dose, 2 mg kg-1, p.o.. Idazoxan was active only at 2.5 and 5 mg kg-1, p.o. Yohimbine, but neither delequamine nor idazoxan, decreased ejaculation latency. 8-OH-DPAT (0.1 and 0.25 mg kg-1, s.c.) reduced the time, and the number of intromissions to ejaculation without affecting other parameters. A combination of delequamine (0.4 mg kg-1, p.o.) and 8-OH-DPAT (0.1 mg kg-1 s.c.) increased the percentage of rats mounting, intromitting and ejaculating, and reduced ejaculation latency and the number of intromissions. 3. In orchidectomized, sexually experienced rats exposed to sexually receptive females, delequamine, idazoxan and yohimbine increased the number of rats mounting, and there was a tendency to increase the number of animals intromitting, but no effect on ejaculatory behaviour. 4. In ovariectomized female rats brought to low level receptivity by priming with low dose injections of oestradiol benzoate and progesterone, delequamine, at 1.6 and 6.4 mg kg-1 p.o., increased lordosis, while yohimbine, at 2, 4 and 8 mg kg-1 p.o., reduced lordotic responses to sexually experienced males in a dose-dependent manner. 8-OH-DPAT at 0.1, 0.25 mg kg-1, s.c. reduced lordosis in a dose-dependent manner. 5. These findings may be explained on the basis that yohimbine is an alpha 2-adrenoceptor antagonist with affinity for 5-HT1A receptors and that the effects of 5-HT1A receptors may modulate the sexual behaviour responses to alpha 2-receptor antagonism in some models. Thus, in contrast to yohimbine, the highly-selective alpha 2-adrenoceptor antagonist, delequamine, was very effective in increasing the behavioural score in male and female rats over a wide dose-range.     

COMPARATIVE BEHAVIOURAL EFFECTS OF BENZODIAZEPINE AND NON-BENZODIAZEPINE ANXIOLYTICS IN RHESUS MONKEYS

Quantitative behavioural assessment of benzodiazepines (chlordiazepoxide, diazepam and lorazepam) and non-benzodiazepines (buspirone) anxiolytics were investigated in unrestrained rhesus monkeys (Macaca mulatta) living in social colonies. The different behaviour, categorised as social, solitary and abnormal were video recorded and analysed. Chlordiazepoxide (2.5-5 mg kg-1, p.o.), diazepam (2.5-5 mg kg-1, p.o.) and lorazepam (0.5-1 mg kg-1, p.o.) induced dose-dependent significant changes in certain social and solitary behavioural responses. Thus increases in social grooming, approach, contact, self grooming, feeding and resting with eyes open and decreased aggressiveness and vigilance. On the other hand buspirone (5-10 mg kg-1, p.o.) produced no significant alteration in social and solitary behavioural patterns. On the basis of the above findings the social and solitary behaviour protocol in non-human primates can be a useful tool for studying the effect of a new anxiolytic compound before clinical trial.     

Enhancement of immobility in a forced swimming test by subacute or repeated treatment with phencyclidine: a new model of schizophrenia.

1. Immobility induced by forced swimming is well known as an animal model of depression. To develop an animal model for the negative symptoms of schizophrenia, in particular the depressive symptoms, the effect of phencyclidine (PCP) on immobility in the forced swimming test was investigated in mice, since PCP produces such negative symptoms in humans. 2. Repeated treatment with PCP (10 mg kg-1 day-1, s.c., once a day for 14 days) prolonged the immobility time in the forced swimming test 24 h after the final injection compared with saline treatment; the effect was not obtained by single or 5 treatments with PCP (10 mg kg-1, s.c.), or by repeated treatment with methamphetamine (0.5 and 1 mg kg-1 day-1, s.c., once a day for 14 days). 3. The enhancing effect of PCP (10 mg kg-1 day-1, s.c.) on the immobility persisted for at least 21 days after the withdrawal of the drug. 4. Haloperidol (0.3 and 1 mg kg-1, p.o.), ritanserin (3 and 10 mg kg-1, p.o.), risperidone (0.1-1 mg kg-1, p.o.), and clozapine (3 and 10 mg kg-1, p.o.) failed to attenuate the immobility induced by the forced swimming in mice repeatedly treated with saline when the drugs were administered 1 h before the forced swimming test. However, ritanserin (30 mg kg-1) and clozapine (30 mg kg-1) did attenuate this immobility. 5. The enhancing effect of PCP on the immobility was attenuated by ritanserin (3 and 10 mg kg-1, p.o.), risperidone (0.3 mg kg-1, p.o.), and clozapine (3 and 10 mg kg-1, p.o.), whereas haloperidol (0.3 and 1 mg kg-1, p.o.) had no effect. 6. These results suggest that the enhancement of immobility in the forced swimming test brought about by repeated PCP treatment could be used as a model of the negative symptoms, particularly the depression, of schizophrenia. This effect of PCP appeared to be mediated, at least in part, via 5-HT2A receptors.     

Role of oxygen radicals and arachidonic acid metabolites in the reverse passive Arthus reaction and carrageenin paw oedema in the rat.

1. The role of arachidonic acid metabolites and oxygen radicals in carrageenin-induced rat paw oedema and dermal reverse passive Arthus reaction (RPA) have been investigated. 2. Indomethacin (10 mg kg-1, p.o.) inhibited carrageenin paw oedema when administered 30 min before, but not 2 h after carrageenin. BWB70C (10 mg kg-1, p.o.), a selective inhibitor of 5-lipoxygenase, had no effect whether administered before or after carrageenin. Administration of both indomethacin and BWB70C had no greater anti-inflammatory effect than indomethacin alone. 3. BW755C (20 mg kg-1, p.o.), which inhibits the cyclo-oxygenase and lipoxygenase pathways of arachidonic acid metabolism, or superoxide dismutase-polyethylene glycol conjugate (SOD-PEG, 3000 u, i.v.) inhibited carrageenin paw oedema whether administered either 30 min before, or 2 h after carrageenin. 4. Pretreatment with dexamethasone (0.1 mg kg-1) or colchicine (2 mg kg-1), likewise suppressed carrageenin paw oedema. 5. BW755C (25-100 mg kg-1, p.o.) dose-dependently reduced plasma leakage in the RPA, whereas indomethacin (5 mg kg-1, p.o.) or BWB70C either alone or in combination, did not. 6. SOD-PEG (300-3000 u, i.v.) dose-dependently inhibited plasma leakage in the RPA. In addition, the iron chelator and peroxyl radical scavenger, desferrioxamine (200 mg kg-1, s.c.) also inhibited plasma leakage. 7. Pretreatment with dexamethasone (0.1 mg kg-1) or colchicine (1 mg kg-1) reduced the plasma leakage in RPA, whereas MK-886 (10 mg kg-1) had no effect.(ABSTRACT TRUNCATED AT 250 WORDS)     

A comparison of the effects of different serotonin reuptake blockers on sexual behaviour of the male rat.

In human males, SSRIs differentially affect (premature) ejaculation; paroxetine and fluoxetine markedly and sertraline, moderately inhibited ejaculation latency, whereas fluvoxamine did not inhibit this parameter (Waldinger, M.D., Hengeveld, M.W., Zwinderman, A.H., Olivier, B., The effect of SSRI antidepressants on ejaculation: a double-blind, randomised, placebo-controlled study with fluoxetine, fluvoxamine, paroxetine and sertraline. J. Clin. Psychopharmacol. (in press)). The present studies tried to investigate, using sexual behaviour in male rats, whether such differences could also be found in animal paradigms of sexual behaviour. In a series of three experiments we compared various specific serotonin reuptake inhibitors (SSRIs) for their ability to suppress sexual behaviour in male rats. In the first experiment sexually experienced rats were tested 60 min after oral administration of clomipramine, fluvoxamine, fluoxetine (all in a range of 0, 3, 10 and 30 mg/kg p.o.), sertraline or paroxetine (both in a range of 0, 1, 3 and 10 mg/kg p.o.). Clomipramine, paroxetine and fluvoxamine did not significantly inhibit male sexual behaviour, although some trends were observed. Sertraline inhibited sexual behaviour at 3 and 10 mg/kg p.o., the effects being stronger at 3 mg/kg p.o. Fluoxetine (3 mg/kg p.o.) facilitated sexual behaviour, while at 30 mg/kg p.o. a modest increase in the postejaculatory interval was noted. In the second experiment, sexual behaviour of sexually naive male rats was slightly inhibited by paroxetine 10 mg/kg p.o., but sertraline (range 1-10 mg/kg p.o.), fluvoxamine and fluoxetine (both in a range of 3-30 mg/kg p.o.) were ineffective. In the last experiment the effects of paroxetine (0-10 mg/kg p.o.), fluvoxamine and fluoxetine (both 0-30 mg/kg p.o.) were studied during an exhaustion design in sexually experienced male rats. As rats get more 'sluggish' when they have had multiple ejaculations, we hoped to see stronger inhibitory effects in the last cycle prior to exhaustion. None of the drugs dose-dependently inhibited the pattern of sexual behaviour during the first sexual cycle. In the last cycle the patterning of sexual behaviour differed, but only paroxetine (10 mg/kg p.o.) inhibited sexual behaviour significantly. The total number' of ejaculations during the test was not reduced by any of the SSRIs tested. Contrary to human findings, we did not find major inhibitory effects of SSRIs on male rat sexual behaviour at non-sedative doses. The only differentiation that could be made is that paroxetine and sertraline had slightly stronger effects than the other 5-HT reuptake inhibitors. Masculine sexual behaviour in rats does not constitute a suitable model to investigate the differential mechanism of sexual inhibition of SSRIs that have been described in human males.     

L-NG-nitro arginine methyl ester exhibits antinociceptive activity in the mouse.

1. L-NG-nitro arginine methyl ester (L-NAME, 1-75 mg kg-1) administered intraperitoneally (i.p.) elicits dose-related antinociception in the mouse assessed by the formalin-induced paw licking procedure. Antinociceptive activity is still present 24 h after injection. L-NAME (75 mg kg-1, i.p.) is also antinociceptive in the acetic acid-induced abdominal constriction and hot plate procedures. 2. L-NAME additionally produces a dose-related inhibition of formalin-induced paw licking following intracerebroventricular (i.c.v., 0.1-100 microgram per mouse) and oral (p.o., 75-150 mg kg-1) administration. 3. L-Arginine (600 mg kg-1, i.p.) but not D-arginine (600 mg kg-1) or naloxone (5 mg kg-1) reverses the antinociceptive effect of L-NAME in the formalin test. 4. High doses of L-NAME (37.5-600 mg kg-1) but not D-NAME (75 mg kg-1) administered i.p. produce dose-related increases in blood pressure of the urethane-anaesthetized mouse whilst i.c.v. injected L-NAME (0.1 and 100 microgram per mouse) in inactive. 5. L-NAME (75 mg kg-1, i.p.) did not inhibit oedema formation in the formalin-injected mouse hindpaw. 6. L-NAME (75 mg kg-1) did not produce any overt behavioural changes in treated mice and failed to influence locomotor activity or the incidence of dipping, crossing, rearing or circling behaviour assessed by a modified 'head-dipping' board procedure. A high dose of L-NAME (600 mg kg-1) reduced dipping behaviour and locomotor activity suggesting a possible sedative effect.(ABSTRACT TRUNCATED AT 250 WORDS)     

Modulation of morphine antinociception in the mouse by endogenous nitric oxide.

1. L-Arginine (100-1000 mg kg-1) administered orally (p.o.) or intraperitoneally (i.p.), but not intracerebroventricularly (i.c.v., 0.08 mg per mouse), reduced the antinociceptive effect of morphine (0.5-10 mg kg-1 s.c.) assessed in mice using three different tests: hot plate, tail-flick and acetic acid-induced writhing. D-Arginine (up to 1000 mg kg-1 p.o. or i.p.) was ineffective. 2. NG-Monomethyl-L-arginine (L-NMMA, 5-50 mg kg-1 i.p.) and NG-nitro-L-arginine methyl ester (L-NAME, 5- 30 mg kg-1 i.p.), but not NG-nitro-D-arginine methyl ester (D-NAME, 30 mg kg-1 i.p.), reversed in all assays the effect of L-arginine on morphine-induced antinociception. 3. Morphine (10 mg kg-1 s.c.), L-arginine (1000 mg kg-1 p.o.) or L-NAME (30 mg kg-1 i.p.), either alone or in combination, did not produce changes in locomotor activity or sensorimotor performance of animals. 4. These results suggest that the L-arginine-nitric oxide pathway plays a modulating role in the morphine-sensitive nociceptive processes.     

Triazolodiazepines: dissociation of their Paf (platelet activating factor) antagonistic and CNS activity.

The relationship between the activity of thieno- or benzo-triazolodiazepines on platelet-activating factor (Paf)-induced effects and on the CNS (central nervous system) was studied in vitro and in vivo. Brotizolam and triazolam inhibited Paf-induced human platelet aggregation. The IC50 -values were 0.54 and 7.6 microM, respectively. This inhibitory effect was not blocked by the specific central-type benzodiazepine (BDZ) antagonist, Ro 15-1788, or the specific peripheral-type BDZ ligand, Ro 5-4846. These BDZ ligands also showed an inhibitory effect on Paf-induced platelet aggregation (IC50 = 200 and 560 microM, respectively). Ro 15-1788 or Ro 5-4846 in combination with brotizolam or triazolam enhanced the Paf inhibitory effect of these triazolodiazepines. In guinea-pigs, Ro 15-1788, 100 mg kg-1 p.o. and 10 mg kg-1 i.v. completely inhibited the hypnogenic effect of 10 mg kg-1 p.o. and 1 mg kg-1 i.v. of brotizolam, respectively. Similar results were obtained with triazolam but at higher doses. In anaesthetized guinea-pigs, a dose of 100 mg kg-1 p.o. of Ro 15-1788 did not inhibit bronchoconstriction and hypotension caused by Paf (30 ng kg-1 min-1 i.v.). The combination of brotizolam (10 mg kg-1 p.o.) or triazolam (200 mg kg-1 p.o.) with this BDZ antagonist (100 and 400 mg kg-1 p.o., respectively) did not affect the Paf inhibitory activity of these triazolodiazepines. These results show that the Paf antagonistic properties of the triazolodiazepine can be dissociated from their CNS activity. It is conceivable that compounds of this structural type could be the forerunners of a novel series of potent Paf antagonists.     

Haemodynamic differences between cromakalim and pinacidil: comparison with nifedipine

The effects of cromakalim (0.015, 0.03 and 0.06 mg kg-1 p.o.), pinacidil (0.3, 0.6 and 1.2 mg kg-1 p.o.) and nifedipine (0.15, 0.3 and 0.6 mg kg-1 p.o.) were compared on mean arterial pressure (MAP), heart rate (HR), mean renal blood flow (MRBF) and plasma renin activity (PRA) in the conscious normotensive cat. All drugs elicited dose-related falls in MAP with cromakalim being about 10 times more potent than nifedipine or pinacidil, the latter two drugs being equipotent. For similar reductions in MAP, the increases in HR and PRA produced by cromakalim were significantly smaller than those produced by either nifedipine or pinacidil. Cromakalim (0.015-0.06 mg kg-1 p.o) elicited dose-related increases in MRBF with the peak effect occurring 2-2.5 h post-dose. Thereafter, MRBF recovered toward pretreatment levels despite MAP being almost maximally reduced. Neither nifedipine nor pinacidil affected MRBF though nifedipine (0.3 mg/kg-1 p.o.) caused a significant reduction in renal vascular resistance. This study has shown that important haemodynamic differences exist between cromakalim, nifedipine and pinacidil suggesting that increased MRBF is not a general property of K+ channel activation or of Ca2+ slow channel blockade.     

In-vivo pharmacological studies of 2-N-carboxamidinonormianserin, a histamine and 5-hydroxytryptamine antagonist lacking central effects.

The in-vivo pharmacological properties have been examined of FCC5 (2-N-carboxamidino-1,2,-3, 4, 10, 14b-hexahydrodibenzo (c.f.) pyrazino (1, 2-alpha)azepine hydrochloride), a guanidino analogue of mianserin. FCC5 (30-100 micrograms kg-1, i.v.) caused long-lasting (> 1 h) attenuation of histamine- and 5-hydroxytryptamine (5-HT)-induced bronchoconstriction in the anaesthetized guinea-pig. FCC5 (< or = 1 mg kg-1, i.v.) had no effect on submaximal bronchoconstrictor responses caused by i.v. acetylcholine or the thromboxane A2-mimetic U46619 ((15S)-hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5Z,13E-dienoic acid). The pressor effects of 5-HT in anaesthetized and pithed rats were inhibited by FCC5 (0.3-1.0 mg kg-1, i.v.). Higher doses of FCC5 (3 mg kg-1, i.v.) reduced bradycardia and depressor responses to 5-HT in anaesthetized rats. In anaesthetized cats and rats and also pithed rats, FCC5 (0.1-1.0 mg kg-1, i.v.) caused sympathomimetic effects as demonstrated by pressor responses and tachycardia. FCC5 (0.1-0.3 mg kg-1, i.v.) inhibited pressor responses to tyramine whereas those to noradrenaline and sympathetic nerve stimulation were potentiated. Oedema in the rat paw caused by intraplantar 5-HT was inhibited by FCC5 (ID50 0.76 mg kg-1, i.p.; and 2.7 mg kg-1, p.o.). In decerebrate rats which had been spinalized at T6-8, fenfluramine-induced facilitation of the flexor reflex of the anterior tibialis muscle was inhibited by mianserin (ID50 0.36 mg kg-1, i.p.) but not by FCC5 (< or = 3 mg kg-1, i.p.).(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of cetirizine on antigen-dependent leucopenia in the guinea-pig.

1. Intravenous administration of ovalbumin (1 mg kg-1) to guinea-pigs that had previously been injected with 3.5 x 10(9) platelets from actively sensitized animals induced an approximately 40% decrease in the number of circulating leucocytes 30-60 min later, whereas the number of platelets was not affected. 2. In contrast, there was no change in the leucocyte number following antigen challenge of guinea-pigs that had received platelets from non-immunised animals. 3. This platelet-dependent leucopenia was inhibited by prior treatment of the recipient animal with cetirizine (10-30 mg kg-1, i.v.). Terfenadine (50 mg kg-1, p.o.) and mepyramine (2 mg kg-1, i.v.) were completely inactive in this respect. All doses of anti-histamines were used at concentrations which completely inhibited the bronchoconstriction to an i.v. injection of 5 micrograms kg-1 of histamine. 4. The site of action of cetirizine is most likely to be the platelet as leucopenia induced by the neutrophil agonists leukotriene B4 (LTB4) (30 ng kg-1) and platelet activating factor (PAF) (30 ng kg-1) were not modified by cetirizine treatment. 5. In these experiments, we failed to support a role for lipoxygenase products as mediators of the platelet-dependent leucopenia, as the selective lipoxygenase inhibitor BWA4C (50 mg kg-1, p.o.) was ineffective. 6. Our present results confirm and extend previous data demonstrating that antigen stimulated platelets can induce leucopenia in non-immunised animals and this can be inhibited by the anti-allergic agent, cetirizine, by an action which is probably unrelated to its anti-histamine properties.(ABSTRACT TRUNCATED AT 250 WORDS)     

Preferential decrease in dopamine utilization in prefrontal cortex by zopiclone, diazepam and zolpidem in unstressed rats

This study has compared the effects of a cyclopyrrolone, zopiclone, a benzodiazepine, diazepam, and an imidazopyridine, zolpidem, on dopamine (DA) and DOPAC levels, and DA utilization (DOPAC/DA ratio) in rat striatum and prefrontal cortex. The endogenous levels of DA were significantly increased by both zopiclone (2.5, 10 and 40 mg kg-1 p.o.) and diazepam (10 and 40 mg kg-1 p.o.) in the prefrontal cortex, whereas striatal DA content was significantly increased only with the highest dose of diazepam (40 mg kg-1 p.o.). Diazepam (10 and 40 mg kg-1 p.o.) decreased cortical level of DOPAC more markedly than striatal levels, whereas zopiclone (40 mg kg-1 p.o.) only slightly decreased striatal DOPAC levels. Zopiclone and diazepam dose-dependently decreased DA utilization, an effect which was more marked in prefrontal cortex than in striatum. This result was confirmed with zolpidem, another benzodiazepine ligand. Zopiclone was most potent at decreasing DA utilization at the cortical level. The diazepam-induced decreases in DA metabolism and utilization were antagonized by Ro 15-1788, suggesting that the effects seen were mediated by specific benzodiazepine receptors. Thus, our results clearly show that ligands acting on the benzodiazepine receptor GABA receptor chloride ionophore complex can decrease the utilization of dopamine in unstressed rats. The preferential decrease in cortical DA utilization induced by benzodiazepine ligands may be compared to the well-known activation by stress of the mesocortical DAergic system.     

A behavioural and biochemical study in mice and rats of putative selective agonists and antagonists for 5-HT1 and 5-HT2 receptors.

Radioligand binding techniques have demonstrated the existence of 5-hydroxytryptamine (5-HT) binding subtypes: 5-HT2, 5-HT1A and 5-HT1B. These techniques have also indicated that certain drugs appear to show sub-type specificity: 8-hydroxy-2-(di-n-propylamino)tetralin(8-OH-DPAT), a 5-HT1A agonist; 5-methoxy-3(1,2,3,6-tetrahydropyridin-4-yl)1-H indole (RU 24969), a 5-HT1B agonist; and ritanserin, a 5-HT2 antagonist. (-)-Propranolol is a 5-HT1 antagonist of uncertain sub-type specificity. An examination has been made in mice and rats of the behavioural and biochemical effects of these drugs to determine whether the binding sites have physiological functions and further characterise the behavioural models. Administration of carbidopa (25 mg kg-1) plus 5-hydroxytryptophan (100 mg kg-1) produced head-twitch behaviour in mice which was antagonized by ritanserin (ED50 = 65 micrograms kg-1) but not (-)-propranolol (20 mg kg-1). 8-OH-DPAT (1-10 mg kg-1 s.c.) and RU 24949 (5 mg kg-1 i.p.) did not produce head-twitch behaviour. 8-OH-DPAT decreased 5-HTP- but not 5-methoxy-N-N-dimethyltryptamine (5 mg kg-1)-induced head-twitch by a (-)-propranolol-insensitive mechanism. Locomotor activity produced in mice by RU 24969 (3 mg kg-1) was antagonized by (-)-propranolol (20 mg kg-1) but not the (+)-isomer. (-)-Propranolol did not antagonize the behaviour induced in rats. In mice, both 8-OH-DPAT and RU 24969 markedly inhibited whole brain 5-HT synthesis and this effect was not antagonized by (-)-propranolol. In rats, 8-OH-DPAT (3 mg kg-1 s.c.) produced all the behavioural changes seen after quipazine (25 mg kg-1). (-)-Propranolol inhibited the behaviour changes produced by both agonists, while ritanserin antagonized the behaviour produced by quipazine but not 8-OH-DPAT. It is concluded, therefore, that the 5-HT1A receptor exists between the 5-HT2 receptor and the behavioural effectors. 8-OH-DPAT (at 20 degrees C ambient temperature) rapidly decreased rat body temperature, an effect antagonized by (-)-propranolol but not ritanserin. Quipazine (at 27 degrees C ambient temperature, but not 20 degrees C) increased body temperature but the effect was not blocked by either antagonist. Ritanserin does not antagonize apomorphine-induced locomotion in either species.(ABSTRACT TRUNCATED AT 400 WORDS)     

Increased total activity in the rat after L-tryptophan plus the monoamine oxidase-A inhibitor amiflamine but not after L-tryptophan plus clorgyline.

The effect of pretreatment with either saline or the monoamine oxidase-A inhibitors clorgyline and amiflamine upon the total activity, locomotion and rearing behaviour of the rat induced by various doses of the monoamine precursor L-tryptophan was studied by use of automated activity boxes. Amiflamine (2.5 and 5.0 mg kg-1, i.p.) increased in a dose-dependent manner total activity and to a lesser extent, locomotion when given 60 min before L-tryptophan (100 mg kg-1, i.p.). The increased activity was seen after amiflamine plus either 25 or 75 mg kg-1 L-tryptophan. Rearing behaviour was not affected. Analysis of 5-hydroxytryptamine (5-HT) and its deaminated metabolite 5-hydroxyindoleacetic acid (5-HIAA) by high performance liquid chromatography with electrochemical detection indicated that in both frontal cortex and hypothalamus, amiflamine (at both doses) increased 5-HT and reduced 5-HIAA concentrations. Combination of amiflamine with L-tryptophan (100 mg kg-1, i.p.) resulted in a higher 5-HT concentration being found than after amiflamine alone. L-Tryptophan treatment alone did not change 5-HT concentrations but increased 5-HIAA concentrations. Clorgyline, at a dose of either 1 or 5 mg kg-1 i.p. plus L-tryptophan (25 or 100 mg kg-1, i.p.) did not increase total activity, locomotion or behaviour. A number of possible explanations for the differences in the behavioural effects of clorgyline and amiflamine when given with L-tryptophan are discussed. It is concluded that in addition to monoamine oxidase-A inhibition, other pharmacological effects of the drugs, such as 5-HT release (amiflamine) and inhibition of tryptophan hydroxylation (clorgyline) may be of importance in determining the magnitude of the increase in activity when the compounds are given together with L-tryptophan.     

The effects of Ca2+ antagonists and hydralazine on central 5-hydroxytryptamine biochemistry and function in rats and mice.

1. The effects of calcium antagonists on behaviour mediated by 5-hydroxytryptamine (5-HT) have been studied in rats and mice together with an investigation of the effects of these drugs on 5-HT synthesis in rat brain and endogenous 5-HT release from brain slices. 2. Administration of felodipine (35 mg kg-1 i.p.) to rats pretreated with tranylcypromine (20 mg kg-1, i.p.) resulted in the animals displaying the complete 5-HT-mediated behavioural syndrome (including head weaving, reciprocal forepaw treading and hind limb abduction) 75 min later. No evidence was obtained for the rate of 5-HT synthesis in brain regions differing between control and felodipine-treated rats. 3. Pretreatment with felodipine (10 or 35 mg kg-1) enhanced the 5-HT-mediated behavioural syndrome induced by injection of tranylcypromine and L-tryptophan. The rate of 5-HT accumulation in the brain was similar in both groups. Administration of Bay K 8644 (1 mg kg-1, i.p.) did not prevent the enhanced behaviour induced by felodipine (10 mg kg-1). 4. The 5-HT behavioural syndrome induced by injection of the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was unaltered by either acute injection of felodipine (35 mg kg-1) or administration of felodipine twice daily for 3 days. 5. Felodipine (10 microM), verapamil (10 microM) and Bay K 8644 (10 microM) did not alter either basal release of endogenous 5-HT from slices prepared from frontal cortex or hind brain, or release following addition of K+ at a concentration of 20 mM, or 35 mM.(ABSTRACT TRUNCATED AT 250 WORDS)     

The antidyskinetic action of dihomo-gamma-linolenic acid in the rodent

The antidyskinetic action of dihomo-gamma-linolenic acid (DHLA) was assessed against dyskinesias induced in the guinea-pig by dopamine injected into the striatum (200 micrograms bilateral 2 h after nialamide, 75 mg kg-1, i.p.) and in the guinea-pig and rat by 2-di-n-propylamino-5, 6-dihydroxytetralin (tetralin), 0.025 mg kg-1, s.c. Dopamine and tetralin-induced dyskinesias in the guinea-pig were reduced or abolished by DHLA given i.p., 30-100 mg kg-1, given once daily for 5-10 days. Tetralin-induced dyskinesias were antagonized by DHLA given orally to the guinea-pig (50-200 mg kg-1, 5 days) or in the diet to the rat (approximately 200 mg kg-1 daily for 10-14 days). DHLA injected into the striatum (2.5-20 micrograms bilateral, 2-4 days) also antagonized tetralin-induced dyskinesias in the rat. The antidyskinetic action of DHLA given i.p. to the guinea-pig could be antagonized by aspirin or eicosa-5,8,11,14-tetraynoic acid (100 mg kg-1 i.p. daily, starting 2 days before a 5 day treatment with DHLA). Aspirin (25-100 mg kg-1, i.p.) dose-dependently antagonized the antidyskinetic activity of 5 and 20 micrograms DHLA given bilaterally into the striatum (2 days). DHLA (100 mg kg-1 i.p.) given daily for 10 days or approximately 200 mg kg-1 DHLA (daily for 10-14 days given in the diet) administration to the rat failed to modify the stereotyped behaviour induced by apomorphine, 0.5 or 2 mg kg-1 s.c., to induce catalepsy, or to modify the cataleptic effects of haloperidol 0.25 or 1 mg kg-1 i.p.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of CCK receptor antagonists on the antinociceptive, reinforcing and gut motility properties of morphine.

1. The ability of a selective CCKA receptor antagonist PD 140548 and a selective CCKB receptor antagonist CI-988 (formerly PD 134308) to modulate the various in vivo properties of morphine was investigated in the rat. 2. PD 140548 dose-dependently (0.001-1.0 mg kg-1, i.p.) antagonised the development of conditioned place preference to morphine (2.0 mg kg-1, s.c.). In contrast, CI-988 (0.01-1.0 mg kg-1, i.p.) did not affect this morphine-induced behaviour. Neither of the CCK receptor antagonists blocked or generalised to the morphine (3.0 mg kg-1, i.p.) discriminative stimulus. 3. CI-988 (0.001-10.0 mg kg-1, s.c.) at doses of 0.05 and 0.1 mg kg-1 (s.c.), potentiated the antinociceptive action of a threshold dose of morphine (5.0 mg kg-1, i.p.) in a radiant heat model of acute nociception, the rat tail flick test. Furthermore, at 0.01 mg kg-1 it potentiated the antinociceptive action of morphine (3.0 mg kg-1) during the acute phase of the rat paw formalin test. And at doses of 0.01 and 0.1 mg kg-1 it also potentiated the antinociceptive action of morphine (1.0 mg kg-1) during the tonic phase of the formalin test. However, in both models, higher doses of CI-988 were ineffective. In contrast, PD 140548 (0.001-10 mg kg-1, s.c.) was only active at a dose of 1.0 mg kg-1 (s.c.) and only in the tonic phase of the formalin test. Neither CI-988 nor PD 140548 possessed any intrinsic antinociceptive action in either of the tests. Chronic treatment with CI-988 (0.01 mg kg-1, s.c.) prevented the development of tolerance to morphine antinociception (4 mg kg-1, s.c.) following a 6 day period of twice daily injections of morphine escalating from 1 to 16 mg kg-1 (i.p.). 4. Morphine dose-dependently (1-10 mg kg-1, s.c.) reduced the distance travelled by a charcoal meal in the rat intestine. Neither PD 140548 (0.01-1.0 mg kg-1, i.p.) nor CI-988 (0.01-1.0 mg kg-1, i.p.) potentiated or suppressed this inhibitory action of morphine. 5. In conclusion, the results of the present study indicate that CCKA and CCKB receptors modulate different properties of morphine. Thus, whilst a selective CCKA receptor antagonist blocked the rewarding properties of morphine, a selective CCKB receptor antagonist potentiated the antinociceptive action. However, neither compound displayed a potential for modulating the influence of morphine on gastro-intestinal motility. It is suggested that these findings may have important implications for development of CCK receptor antagonists as analgesic adjuncts to the therapeutic use of morphine.     

Effect of urethane on hydralazine-induced tachycardia in rats.

1. In conscious normotensive rats, hydralazine (5-10 mg kg-1 p.o.) produced a dose-related fall in systolic blood pressure, accompanied by a pronounced increase in heart rate. 2. The tachycardia induced by hydralazine (10 mg kg-1 p.o.) in conscious normotensive rats was strongly inhibited after anaesthesia with urethane (1.26 g kg-1 i.p.). 3. In anaesthetized normotensive rats, hydralazine (1 mg kg-1 i.v.) caused a fall in mean blood pressure, accompanied by irregular effects on the heart rate that consisted in a combination of initial tachycardia followed by bradycardia. 4. In pithed rats, hydralazine (1 mg kg-1 i.v.) did not affect mean arterial blood pressure but produced a significant decrease in heart rate. 5. In rat isolated atria, hydralazine (2 mM) produced a positive inotropic/negative chronotropic effect. 6. These results suggest that urethane inhibits the cardiovascular reflex that causes the tachycardia induced by hydralazine in conscious normotensive rats. For this reason, in anaesthetized normotensive rats appear the direct effect of the drug on the heart.