An α-adrenoceptor-mediated mechanism of hypoactivity induced by β-amyrin palmitate

Abstract— Inhibitory effects of β-amyrin palmitate in locomotor activity of mice were studied by combining this compound with α-adrenergic agonists or antagonists and a dopaminergic agonist. β-Amyrin palmitate (2·5, 5·0 and 10·0 mg kg^?1, i.p.) decreased locomotor activity of mice in a dose-dependent manner. It enhanced hypoactivity of mice treated with clonidine (0·025 mg kg^?1, i.p.) and antagonized hyperactivity produced by phenylephrine (40 μg, i.c.v.). The inhibitory action of β-amyrin palmitate was not affected by yohimbine (1·5 mg kg^?1, i.p.), but was potentiated by prazosin (0·75 mg kg^?1, i.p.). When combined with a dopaminergic agonist, apomorphine (2·0 mg kg^?1, i.p.), β-amyrin palmitate (5·0 and 10·0 mg kg^?1, i.p.) did not affect locomotor stimulation produced by apomorphine. These results suggest that β-amyrin palmitate might inhibit α₁-adrenoceptors.     

Influence of α‐Adrenoceptor Agonists and Antagonists on Imipramine‐Induced Hypothermia in Mice

Abstract: Effects of adrenoceptor agonists and antagonists on imipramine‐induced hypothermia in mice were studied. Intraperitoneal injection of imipramine (10–40 mg kg^?1), α₂‐adrenoceptor agonist clonidine (0.05–0.1 mg kg^?1), α₁‐adrenoceptor agonist phenylephrine (6 mg kg^?1) and α₁‐adrenoceptor antagonist prazosin (1–4 mg kg^?1) but not α₂‐adrenoceptor antagonist yohimbine (1–4 mg kg^?1) induced significant hypothermia. The hypothermic response induced by imipramine (10–30 mg kg^?1) was not altered by clonidine (0.05–0.1 mg kg^?1) or phenylephrine (2–6 mg kg^?1). The response of imipramine (10–30 mg kg^?1) was reduced significantly by yohimbine (2 mg kg^?1) and was potentiated by prazosin (1 mg kg^?1). The hypothermic effect of clonidine (0.1 mg kg^?1) and imipramine (20 mg kg^?1) were also decreased significantly by different doses of yohimbine (1–4 mg kg^?1). The hypothermia induced by different doses of prazosin (1–4 mg kg^?1) was not altered by yohimbine (2 mg kg^?1) or by low dose of imipramine (10 mg kg^?1). It is concluded that α₂‐adrenoceptor mechanism may be involved in the hypothermic effect of imipramine.     

Dextromethorphan-monoamine oxidase inhibitor interaction in rabbits

Severe toxic reactions may occur clinically when imipramine, pethidine or dextromethorphan is administered to a patient being treated with a monoamine oxidase inhibitor (MAOI). Previous reports indicate that imipramine or pethidine produces symptoms characterized by motor restlessness, tremor, extreme hyperpyrexia and death when administered to phenelzine-pretreated rabbits. The present study shows that dextromethorphan (5 mg kg^?1) produces identical symptoms in rabbits pretreated with phenelzine sulphate (30 mg kg^?1) or nialamide HCl (50 mg kg^?1) 42 and 18 h before temperature recording. The dextromethorphan-MAOI interaction appears to be due to a 5-hydroxytryptamine potentiation. In the unanaesthetized cat nictitating membrane preparation, dextromethorphan (5 mg kg^?1) markedly enhanced the response of noradrenaline and 5-HT but antagonized the effects of tyramine. This suggests that dextromethorphan blocks the uptake of these amines in the adrenergic nerve endings.     

Behavioural Profile of Two Potential Antidepressant Pyridazine Derivatives Including Arylpiperazinyl Moieties in Their Structure,in Mice

The potential antidepressant effects of two pyridazine derivatives, 5-benzyl 6-methyl 2-[4-(3-trifluoro-methyl phenyl) piperazin-1-yl] methylpyridazin-3-one (PC4) and 5-benzyl 6-methyl 2-[4-(3-chlorophenyl) piperazin-1-yl] methylpyridazin-3-one (PCI3), were evaluated using classical psychopharmacological tests in mice. The intraperitoneal LD50 values of PC4 and PC13 were respectively 1125·8 and 429-6mg kg^?1. Only at intraperitoneal doses of 100mg kg^?1 did PC4 or PC13 significantly decrease locomotor activity. Both compounds (5–20 mg kg^?1, i.p.) reduced the duration of immobility of mice in the forced swimming test, antagonized reserpine (2–5 mg kg^?1, i.p.)-induced ptosis, and potentiated reserpine (2–5 mg kg^?1, i.p.)-induced hypothermia. PC4 and PCI3 (20mg kg^?1, i.p.) partly reversed hypothermia induced by low dose apomorphine (5 mg kg^?1, s.c.) but were less effective for higher doses of apomorphine (16 mg kg^?1, s.c). At 200 mg kg^?1, intraperitoneal PC13 enhanced the toxic effects of yohimbine (30 mg kg^?1, s.c), while PC4 was inactive. Head twitches produced either by L-5-hydroxytryptophan (4 mg kg^?1, i.p.) in mice pretreated with pargyline (100mg kg^?1, i.p.) or by 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (3 mg kg^?1, i.p.) were antagonized by both pyridazine derivatives (20 mg kg^?1, i.p.). PC4 and PC13 showed analgesic properties in the phenylbenzoquinone-induced abdominal constriction test (50 < ED50 < 5-5mg kg^?1, i.p.) and in the hot-plate test (10 to 37% of analgesia at 10 mg kg^?1, i.p.). These antinociceptive effects were not significantly diminished by naloxone (1 mg kg^?1, i.p.). Furthermore, acute intraperitoneal administration of both compounds (20 mg kg^?1 for PC4 and 5mg kg^?1 for PC13) potentiated morphine (7–5 mg kg^?1, s.c.) analgesia in the hot-plate test. Thus, these results suggest that PC4 and PC 13 possess potential antidepressant effects related to different aminergic mechanisms, especially at the 5-HT₂ receptor level.     

The Action of 1,2,3,5,6,11b-Hexahydro-[1]benzothieno [3,2-g]indolizine Hydrochloride (ADT 16) on Peripheral and Central Responses Mediated by 5-Hydroxytryptaminergic and Adrenergic Systems of the Rat

Abstract— Some acute pharmacological effects have been examined of racemic ADT 16 (1,2,3,5,6,11b-hexahydro[1]benzothieno[3,2-g]indolizine hydrochloride), on peripheral and central responses mediated by 5-HT and adrenergic systems in the rat. In-vitro, ADT 16(10–1000 Nm ), similarly to mianserin, antagonized the inhibitory responses to B-HT 920 of the electrically-stimulated rat isolated prostatic vas deferens. High concentrations of ADT 16 (10 μm ), also resembled those of mianserin by potentiating twitch responses to electrical stimulation of the tissue. Contractile responses to phenylephrine of rat isolated epididymal vas deferens were antagonized by ADT 16 (0·3–1 μm ). In the rat stomach fundus strip, ADT 16 (1–3 μm ) antagonized contractions due to 5-HT. ADT 16 (0·1–1 μm ) had no effect on responses to acetylcholine of the guinea-pig isolated ileum. In-vivo, in spinalized, decerebrated rats, fenfluramine- or clonidine-induced facilitation of flexor reflex activity of the anterior tibialis muscle was attenuated by ADT 16 (3 and 10 mg kg^?1, i.v., and 3 mg kg^?1, i.v. respectively). In the anaesthetized rat, l -3,4-dihydroxyphenylalanine (l -dopa)- or l -5-hydroxytryptophan (l -5-HTP)-induced increases in the frequency of spontaneous twitches of the anterior digastricus muscle were attenuated by ADT 16 (1 and 3 mg kg^?1, i.v.; n = 4). It is concluded that ADT 16, similarly to mianserin, is a novel peripherally and centrally active antagonist of 5-HT and adrenergic responses in the rat.     

Antagonism of Reserpine-Induced Suppression of Spontaneous Motor Activity by Stimulation of 5-HT1A Receptors in Rats

Abstract: The 5-HT_1A and the DA D₂ receptor agonists 8-OH-DPAT (0.05–3.2 mg kg^–1 subcutaneously, –20 min.) and quinpirole (0.08–1.25 mg kg^–1 subcutaneously, –20 min.), respectively, both partially antagonized reserpine-induced (5 mg kg^–1 subcutaneously, –16 hr) suppression of spontaneous motor activity in the rat. Four different aspects of the spontaneous motor activity were recorded in a photocell-equipped open-field (8x8 photocells, 90 mm apart, defining two horizontal planes): locomotor activity (all photocell counts at the lower level); rearing (all photocell counts at the upper level); forward locomotion (the proportion movements across the arena); peripheral activity (the proportion locomotor activity as picked up by the photocell beam closest to the wall, i.e. 25 mm). As denned by these variables, the pattern of activity produced by 8-OH-DPAT or quinpirole were indistinguishable, The effects produced by 8-OH-DPAT were fully antagonized by the 5-HT₁ antagonist (–) pindolol (4 mg kg^–1 subcutaneously, –30 min.), but not by the DA D₂ receptor antagonist raclopride (2 mg kg^–1 subcutaneously, –30 min.) nor by the 5-HT₂ receptor antagonist ritanserin (2 mg kg^–1 subcutaneously, –30 min.), whereas effects produced by quinpirole were fully antagonized by raclopride (2 mg kg^–1 subcutaneously, –30 min.). Effects produced by quinpirole, but not 8-OH-DPAT, were potentiated by administration of the DA D₁ agonist SKF-38,393 (3 mg kg^–1 subcutaneously, –20 min.). It is concluded that effects by 8-OH-DPAT on spontaneous motor activity in the reserpine treated rat primarily are due to stimulation of postsynaptic 5-HT_1A receptors.     

Effects of 5-HT1A Receptor Agonists on Patterns of Rat Motor Activity in Relation to Effects on Forebrain Monoamine Synthesis

Abstract: The effects of the 5-HT_1A receptor agonists 8-OH-DPAT (0.15–2.5 μmol kg^?1 subcutaneously), flesinoxan (0.6–10.0 μmol kg^?1 subcutaneously) and buspirone (1.9–30.0 μmol kg^?1 subcutaneously) on spontaneous motor activity in male Sprague-Dawley rats was examined in a photocell-equipped open-field arena. Following motor activity observations, the cerebral aromatic L-amino acid decarboxylase inhibitor NSD-1015 (100 mg kg^?1 intraperitoneally) was administered and 30 min. later the animals were decapitated for subsequent analysis of the accumulated forebrain DOPA and 5-HTP levels, as an estimate of the rate of monoamine synthesis. 8-OH-DPAT and flesinoxan produced a similar and characteristic pattern of changes of the spontaneous motor activity in normal animals i.e. a moderate decrease in locomotor activity, a marked suppression of rearing and an increase in the relative amount of forward locomotion and of activity in the periphery of the open-field arena. This behavioural profile was closely related to a decrease in forebrain 5-HTP accumulation, indicating 5-HT receptor stimulation. In agreement with these observations buspirone also produced an increase in peripheral activity and a suppression of rearing. In contrast to effects by 8-OH-DPAT and flesinoxan, however, buspirone produced a further reduction of locomotor activity and reduced the forward locomotion. This difference in behavioural profile between buspirone and the other two compounds is probably explained by its DA receptor blocking properties, as indicated by an increased DOPA accumulation in the neostriatum. At least partially, 8-OH-DPAT, flesinoxan and buspirone, all antagonized reserpine-induced (5 mg kg^?1 subcutaneously – 16 hr) suppression of locomotor activity. This stimulation of locomotor activity in reserpine-treated rats is in all probability related to 5-HT_1A receptor stimulation since concomitant DA D₂ receptor blockade, in the case of buspirone, did not markedly affect this behavioural response.     

Effects of β-Adrenoceptor Antagonists on Portal Vein Hypertension and Ethanol-induced Gastric Mucosal Damage in Rats

Abstract— The effects of various β-adrenoceptor antagonists, with different pharmacological properties, on systemic and portal vein blood pressure and on ethanol-induced gastric mucosal damage were examined in surgically-induced portal hypertensive rats. Propranolol (5, 10 or 20 mg kg^?1), nadolol (5 or 10 mg kg^?1), metoprolol (10 or 20 mg kg^?1), labetalol (20 or 40 mg kg^?1) and pindolol (3 or 6 mg kg^?1) reduced systemic blood pressure to a similar degree in both portal vein-ligated and sham-operated rats. All β-adrenoceptor antagonists, except for pindolol, significantly reduced portal venous pressure and ethanol-induced macroscopic gastric mucosal damage in portal hypertensive animals. Sham-operated rats had lower portal venous pressure and less gastric damage compared with portal hypertensive rats, but both were unaffected by β-adrenoceptor antagonist pretreatment. We conclude that: propranolol, nadolol, metoprolol and labetalol are effective in reducing the portal venous pressure and ethanol-induced gastric mucosal damage in portal hypertensive rats, but not in portal normotensive animals; there was no direct relationship between the reduction of portal vein and systemic blood pressure; and local anaesthetic action is probably important in reducing the portal vein pressure and ethanol-induced gastric mucosal lesions, while the intrinsic sympathomimetic effect can counteract the actions of the β-adrenoceptor antagonists on portal venous pressure and gastric mucosa.     

Some biochemical aspects of the potential benefit of associating MD780515 with tricyclic antidepressants

In the rat, suitable oral doses of tricyclic antidepressants (amitriptyline 20 mg kg^?1, imipramine, desipramine 2·5 mg kg^?1) are able to antagonize the increase of cardiac levels of intravenous tyramine after a pharmacologically active dose (3·5 mg kg^?1 orally) of a reversible and specific type A MAO inhibitor, MD780515 (3-[4-(3-cyanophenyl-methoxy)phenyl]-5-(methoxymethyl)-2-oxazolidinone). MD780515, in oral doses up to 35 mg kg^?1, does not alter the liver microsomal drug metabolizing enzymes in the rat. Therefore, when given with tricyclic antidepressants, it should not interfere with their metabolism.     

Mesulergine antagonism towards the fluoxetine anti-immobility effect in the forced swimming test in mice

Abstract— The anti-immobility effect of fluoxetine (40 mg kg^?1) in the forced swimming test in mice was antagonized by the 5-HT_1c/2 antagonist mesulergine (7·5 mg kg^?1) and the dopamine D₂ antagonist (±)-sulpiride (12.5 mg kg^?1) but not by the 5-HT_2/1C antagonist ritanserine (2 mg kg^?1), the 5-HT_1A/1B antagonist (–)-propranolol (20 mg kg^?1) or the 5-HT₃ antagonist DAU 6215 (0·1 mg kg^?1). All compounds were administered intraperitoneally (i.p.) 6 min before fluoxetine, given i.p. 30 min before testing. The anti-immobility effect of fluoxetine was also prevented by pretreat-ment with p-chlorophenylalanine (300 mg kg^?1 twice daily for 3 days) which produced an 80% reduction of 5-HT in brain. The results suggest that fluoxetine reduces immobility time in mice forced to swim, by acting indirectly through a mesulergine-sensitive site, probably the 5-HT_1C receptor.     

Effects of Long-term Oral Administration of NZ-105, a Novel Calcium Antagonist,With or Without Propranolol in Spontaneously Hypertensive Rats

Abstract— A new calcium antagonist, NZ-105 ((±)-2-[benzyl(phenyl)amino]ethyl 1,4-dihydro-2,6-dimethyl-5- (5,5-dimethyl-2-oxo-1,3,2-dioxaphosphorinan-2-yl)-4-(3-nitrophenyl)-3-pyridinecarboxylate hydrochloride ethanol) (10 mg kg^?1, p.o.), showed slow-onset hypotensive effect in spontaneously hypertensive rats (SHRs). The tachycardia evoked by NZ-105 was completely prevented when combined with a β-adrenoceptor blocker, propranolol (20 mg kg^?1), which did not affect the hypotensive response to NZ-105. In long-term administration experiments for 12 weeks with SHRs, the systolic blood pressure in the control group increased with age and the heart rate was stable throughout the period. NZ-105 (10 mg kg^?1 day^?1) alone and its combined treatment with propranolol (20 mg kg^?1 day^?1) maintained the systolic blood pressure and heart rate at a low level compared with the control group. The hypotensive action of NZ-105 was reproducible after repeated dosing for 12 weeks. Long-term administration of propranolol affected neither the elevation of the systolic blood pressure nor the heart rate substantially. The heart weight per body weight was significantly reduced after the chronic combination of both drugs, suggesting that the cardiac hypertrophy accompanying hypertension was prevented.     

Opiate-receptor mediated changes in monoamine synthesis in rat brain

The effects of morphine, β-endorphin, naloxone and naltrexone on the rate of tyrosine and tryptophan hydroxylation were investigated in vivo by measuring the accumulation of dopa and 5-hydroxytryptophan (5-HTP) in different brain regions of rats after inhibition of the aromatic L-amino acid decarboxylase. The cerebral concentrations of tyrosine and tryptophan were also measured. Morphine (3–30 mg kg^?1) increased the accumulation of dopa dose-dependently (25–50%) in the dopamine-rich areas (limbic forebrain and corpus striatum). In the noradrenaline-predominant parts of the brain (containing hemispheres, diencephalon and lower brain stem) only the highest dose of morphine (30 mg kg^?1) significantly increased dopa formation (47%). Similarly to morphine, intracerebroventricularly injected β-endorphin (5–10 βg per rat) increased the formation of dopa. This increase was doubled in limbic forebrain, corpus striatum and cerebral hemispheres. Doses of 10 to 20 μg of β-endorphin were needed to increase dopa accumulation in the diencephalon and the lower brain stem. Naloxone antagonized the β-endorphin-induced increases in dopa. But naloxone and naltrexone (10–100 mg kg^?1) decreased the dopa formation in the dopamine-rich areas (about 20–25 %) but not in the noradrenaline-predominant areas. Morphine (30 mg kg^?1) and β-endorphin (5 μg per rat) increased the accumulation of 5-HTP whereas naloxone and naltrexone (10 mg kg^?1) tended to decrease its formation. Morphine and β-endorphine increased the concentrations of tyrosine and tryptophan, and naloxone decreased the cerebral tryptophan concentration. These results show that the effects of a narcotic agonist (morphine) and of pure narcotic antagonists (naloxone and naltrexone) on the synthesis of dopamine and 5-HT are opposite to each other. Furthermore, the effects of β-endorphine on brain monoamine synthesis are remarkably similar to those of morphine. Thus, it is probable that opiate receptors and their endogenous ligands are involved in the regulation of dopamine and 5-HT synthesis.     

Effect of caffeine and nicotine on avoidance learning in mice: lack of interaction

Abstract— Tested alone, nicotine (0·25 or 0·5 mg kg^?1) improved shuttle-box avoidance learning in mice of the CD-1 strain. Caffeine had no effect at doses of 2·5 and 5 mg kg^?1 and impaired performance at a dose of 10 mg kg^?1. Combinations of the two drugs did not increase avoidance responses more than nicotine alone, nor was nicotine able to attenuate performance depression induced by the highest dose of caffeine. Lack of drug interaction in the avoidance test contrasts with the occurrence of interactive effects of the two drugs in a locomotor activity test. When given in combination, caffeine and nicotine increased locomotor activity at doses ineffective by themselves. The results seem to indicate no advantage in combining caffeine and nicotine to improve active avoidance learning.     

beta-Amyrin and alpha-amyrin acetate isolated from the stem bark of Alstonia boonei display profound anti-inflammatory activity

Context: Alstonia boonei De Wild (Apocyanaceae) is used in ethnomedicine for the management of malaria, ulcer, rhematic pain, toothache, and inflammatory disorders.

Objective: To investigate the anti-inflammatory potential of β-amyrin and α-amyrin acetate isolated from the stem bark of Alstonia boonei using animal models.

Materials and methods: Chromatographic purification of the crude methanol extract led to the isolation and structure elucidation of β-amyrin and α-amyrin acetate. Their anti-inflammatory activities were evaluated in rodents using egg albumen-induced paw edema and xylene-induced ear edema models. The gastric ulcerogenic, in vivo leucocyte migration, and RBC membrane stabilization tests were also investigated.

Results: α-Amyrin acetate at 100?mg/kg showed significant (p?p?>?0.01) irritation of the gastric mucosa while significant (p?p?p?Discussion and conclusion: This study generally provided evidence of profound anti-inflammatory activity of β-amyrin and α-amyrin acetate isolated from the Alstonia boonei stem bark.     

Stimulus properties of antidepressants in the rat

Various doses of bupropion HCl (Wellbatrin) (5, 10, and 20 mg/kg), a new phenylaminoketone antidepressant, were employed as cues in a two-lever operant discrimination from saline control injections in rats on an FR10 schedule of food reinforcement. Subjects reached and maintained a high level of discrimination in the 0 vs 20 mg/kg bupropion stimulus condition but not at the lower doses. In generalization testing, the following compounds produced dose-related responding on the bupropion lever: viloxazine, nomifensine, caffeine, d-amphetamine, cocaine, methylphenidate, and benzylpiperazine. Drugs that failed to show dose-related generalization included phenethylamine, thyrotropin-releasing hormone, imipramine, nortriptyline, amitriptyline, desipramine, mianserin, chlordiazepoxide, diazepam, scopolamine, phenobarbital, and morphine. With the important exception of viloxazine, the generalization profile of bupropion seems to reflect its previously reported locomotor stimulant effects in the rat rather than its antidepressant activity and suggests that species differences exist between man and rat with regard to the pharmacologic activity of this new antidepressant.     

Evidence for a difference in mechanism of action between fenfluramine- and amphetamine-induced anorexia

The influence of drugs, active on 5-hydroxytryptamine (5-HT) mechanisms, has been examined on the anorexigenic activity of fenfluramine and (+)-amphetamine in rats trained to consume their daily food ration during 6 h. Chlorimipramine, which inhibits the re-uptake mechanisms in central 5-HT neurons, and the 5-HT blocking drugs methergoline and methysergide were used. Fenfluramine, 7.5 mg kg^?1, and amphetamine, 2.5 mg kg^?1, given 1/2 h before feeding reduced the food intake during the following 2 h to approximately 40% compared with control days. Pretreatment with methergoline in the optimal dose (1 mg kg^?1) produced only a weak but significant antagonism to amphetamine anorexia, whereas the fenfluramine anorexia was strongly antagonized by methergoline in all doses tested (0.3, 1 and 3 mg kg^?1). Methysergide (0.1, 0.3, 1 and 3 mg kg^?1) showed no significant antagonism against amphetamine or fenfluramine anorexia. Chlorimipramine produced a strong antagonistic effect to the fenfluramine anorexia, but showed no antagonism against amphetamine. In contrast the highest dose of chlorimipramine (20 mg kg^?1) potentiated amphetamine anorexia. The present results together with other evidence discussed support the conclusion that 5-HT mechanisms are involved in fenfluramine anorexia, whereas amphetamine anorexia seems mainly correlated with catecholamine dependent mechanisms.     

Locomotor effects of nitrous oxide in mice: requirement of newly-synthesized and main intraneuronal storage pools of dopamine

Abstract— Nitrous oxide increases locomotor activity in mice. Other locomotor stimulants are thought to act via central dopaminergic mechanisms and can be divided into two groups as determined by their antagonism by tyrosine hydroxylase inhibitors or by reserpine pretreatment. The purpose of the present study was to determine if nitrous oxide fits one or the other of the groups. Mice were acclimatized for 1 h to exposure chambers (4 L filtration flasks), in air, delivered at 4 L min^?1 and then exposed to N₂O:O₂ (50:50), also delivered at 4 L min^?1. Locomotor activity was evaluated at 10 min intervals throughout the experiment. Racemic α-methyltyrosine methyl ester HCl (200 mg kg^?1), administered at the beginning of acclimatization, almost totally eliminated the nitrous oxide effect but not that of methylphenidate HCl (20 mg kg^?1). Reserpine pretreatment (5 mg kg^?1 18 h) totally eliminated the nitrous oxide effect but not that of amphetamine (5 mg kg^?1). The results suggest that nitrous oxide requires both the newly synthesized and the main storage pools of dopamine and do not allow assignment of the agent, specifically, to either of the groups.     

Effects of olfactory bulbectomy and peripherallyinduced anosmia on thermoregulation in the rat: susceptibility to antidepressant type drugs

Olfactory bulb ablation in the rat produces an acquisition deficit in a step-down passive avoidance test, hyper-reactivity to environmental stimuli, elevated plasma-11-hydroxycorticosterone, and a deficit in the thermoregulatory response to low ambient temperatures, which is not evident at normal ambient temperatures. Like the other features of the bulbectomy syndrome, this thermoregulatory deficit is not related to anosmia per se, since rats made peripherally anosmic with intranasal ZnSO₄ (5%) do not show a thermoregulatory deficit at low ambient temperatures. The abnormal response to cold could be prevented by chronic daily administration of amitriptyline (10mg kg^?1), mianserin (10mg kg^?1), and the 5-HT uptake inhibitor, Org 6582 (10 mg kg^?1) for 7 days. The possibility that the thermoregulatory deficit has the same biochemical basis as the behavioural changes is discussed and a 5-HT involvement in the syndrome is considered.     

Increased ex-vivo colonic generation of PAF induced by diphenylmethane stimulant laxatives in rats,mice, guinea-pigs and rabbits

Abstract— The effects of in-vivo treatment with bisacodyl, phenolphthalein, picosulphate, sulphosuccinate, mannitol and lactulose laxatives were examined on the ex-vivo formation of platelet-activating factor (PAF) by duodenum and colon of rat, mouse, guinea-pig and rabbit. Bisacodyl (10 mg kg^?1), phenolphthalein (20 mg kg^?1) and picosulphate (10 mg hg^?1), but not sulphosuccinate (40 mg kg^?1), mannitol (50 mg kg^?1) or lactulose (50 mg kg^?1), at doses that all caused laxation, markedly increased PAF in the colon (P < 0·01) but not in the duodenum. Intraluminal release of acid phosphatase was also significantly increased in the colon of rats treated with bisacodyl, phenolphthalein and picosulphate, but not in colons of animals treated with sulphosuccinate, mannitol or lactulose. The data show that enhanced generation of PAF is associated with the colonic damage induced by diphenylmethane laxatives, but do not show whether this is a cause or a consequence of the pathophysiological changes.     

Dopamine Antagonists Can Inhibit Methamphetamine Sensitization,But Not Cocaine Sensitization,When Assessed by Ambulatory Activity in Mice

Abstract— The repeated subcutaneous administration of methamphetamine (2 mg kg^?1) and cocaine (10 mg kg^?1) at 3–4 day intervals induced sensitization to their ambulation-increasing effects in mice. Subcutaneous administration of SCH 23390 (R-(+)-7-chloro-8-hydroxy-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; 0·003–0·03 mg kg^?1) and YM-09151–2 (cis-N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-methylaminobenzamide; 0·003–0·03 mg kg^?1), the selective dopamine D₁ and D₂ antagonists, respectively, reduced dose-dependently the acute ambulation-increasing effect of methamphetamine. The development of methamphetamine sensitization was inhibited when it was administered in combination with either SCH 23390 or YM-09151–2 in the repeated administration schedule. Although SCH 23390 (0·01–0·1 mg kg^?1) and YM-09151–2 (0·01–0·1 mg kg^?1) also reduced the ambulation-increasing effect of cocaine (10 mg kg^?1), neither drug inhibited the cocaine sensitization. Mice given cocaine with SCH 23390 (0·03 mg kg^?1) or YM-09151–2 (0·03 and 0·1 mg kg^?1) showed higher sensitivity than those given cocaine alone. The present results suggest that, although both the dopamine D₁ and D₂ antagonists reduce the acute stimulant effects of both methamphetamine and cocaine, they are only effective for inhibition of the methamphetamine sensitization. Mechanisms other than the dopaminergic system appear to be involved in the cocaine sensitization.