Effect of repeated treatment with desipramine in the behavioral "despair" test in rats: antagonism by "atypical" but not "classical" neuroleptics or antiadrenergic drugs

A 7-day treatment with 20 mg/kg/day desipramine reduced the immobility time in the behavioral "despair" test in rats. The effect of DMI was antagonized by sulpiride (100 mg/kg i.p.), metoclopramide (20 mg/kg i.p.) and clopazine (20 mg/kg i.p.) but not by haloperidol (0.5 mg/kg i.p.) or chlorpromazine (5 mg/kg i.p.). Alpha-adrenoreceptor blockers (prazosin 3 mg/kg s.c.; aceperone 10 mg/kg i.p.; azapetine 24 mg/kg s.c.; phentolamine 20 mg/kg i.p.), dl-propranolol (5 mg/kg i.p.) and clonidine (0.1 mg/kg i.p.) failed to modify the anti-immobility effect of DMI. The data suggest that a particular subtype of dopamine receptors is involved in the anti-immobility effect of a 7-day treatment with DMI in the behavioral "despair" test in rats.     

Phencyclidine-induced stereotyped behavior and serotonergic syndrome in rat

Phencyclidine (50 mg/kg, i.p.) induced in rats a biphasic response consisting of serotonergic syndrome followed by stereotyped behavior. The initial serotonergic syndrome was significantly reduced by cinanserin (20 mg/kg, i.p.) and cyproheptadine (2.0 mg/kg, i.p.) but not influenced by haloperidol (0.5 mg/kg, i.p.). The later stereotyped behavior was significantly reduced by haloperidol (0.5 mg/kg, i.p.) but not influenced by cinanserin (20 mg/kg, i.p.) or cyproheptadine (2.0 mg/kg, i.p.). A lower dose of phencyclidine (5.0 mg/kg, i.p.) elicited only haloperidol-sensitive stereotyped behavior. These results indicate that serotonergic and dopaminergic mechanisms may mediate the behavioral effects of phencyclidine in rats.     

Caffeine-induced locomotor activity: Possible involvement of GABAergic-dopaminergic-adenosinergic interaction

Caffeine (10–40 mg/kg, p.o.) enhanced locomotor activity (LA). Administration of GABA antagonist, bicuculline (0.5–1.0 mg/kg, i.p.), potentiated this caffeine-induced increase of LA, as well as LA of control rats. Treatment with the GABA agonist, muscimol (0.25–1 mg/kg, i.p.) or dopaminergic antagonist, haloperidol (0.25–1 mg/kg, i.p.) or muscarinic receptor blocker, atropine (3.75–5 mg/kg, i.p.), or inhibitor of acetylcholine esterase physostigmine (0.05–0.30 mg/kg, i.p.) or nicotine (0.5–1.5 mg/kg, i.p.) an nicotinic receptor agonist all decreased the LA of both caffeinetreated and control rats. Haloperidol-induced reduction in caffeine-induced increase in LA was found to be withdrawn with higher dose of caffeine. The dopamine agonist L-Dopa (75–150 mg/kg, p.o.) along with carbidopa (10 mg/kg, p.o.) increased the LA in control rats and potentiated the LA of caffeine treated rats. The haloperidol attenuated the bicuculline-induced increase in LA and atropine or physostigmine attenuated the bicuculline or L-Dopa+carbidopa-induced increase in LA in both caffeine treated and control rats when those drugs were administered concomitantly with bicuculline or L-Dopa+carbidopa. These results suggest that (a) the GABAergic system has direct role in the regulation of LA, and (b) caffeine potentiates LA by antagonism of the adenosine receptor and activation of the dopaminergic system which, in turn, reduces GABAergic activity through the reduction of cholinergic system.     

Endothelin-induced sudden death and the possible involvement of platelet activating factor (PAF)

Endothelin (5 nmol/kg, i.v.) caused a transient hypotension followed by a lasting hypertension in rats. However, an abrupt fall in the blood pressure was observed in most rats 6 to 30 min after the injection of endothelin and sudden death followed with lethality noted over 60 min. An abnormal electrocardiogram (ECG) (ventricular arrhythmias) was observed in rats injected with endothelin. Endothelin (i.v.) also caused sudden death in mice. Pretreatment (5 or 60 min) with specific PAF antagonists, CV-6209 (0.1-3 mg/kg, i.v.) and WEB 2086 (30 mg/kg, p.o.), and a calcium channel blocker, diltiazem (60 mg/kg, p.o.) prevented death and attenuated the ECG changes induced by endothelin, but CV-6209 did not prevent the blood pressure changes induced by endothelin. CV-6209 (0.5-3 mg/kg, i.v.), WEB 2086, diltiazem and dexamethasone (5 mg/kg, i.v.) protected mice against the death induced by endothelin. On the other hand, aspirin (cyclooxygenase inhibitor, 100 mg/kg, p.o.) did not protect mice from the death. Thus, endothelin is a highly toxic peptide with cardiotoxic effects, and PAF may be involved in the pathogenesis of the sudden death.     

Oleuropein reduces anxiety-like responses by activating of serotonergic and neuropeptide Y (NPY)-ergic systems in a rat model of post-traumatic stress disorder

Post-traumatic stress disorder (PTSD) is a stress-related mental disorder caused by traumatic experiences. This psychopathological response to traumatic stressors induces anxiety in rats. Oleuropein (OLE), a major compound in olive leaves, reportedly possesses several pharmacological properties, including anti-cancer, anti-diabetic, and anti-atherosclerotic and neuropsychiatric activities. However, the anxiolytic-like effects of OLE and its mechanism of action in PTSD are unclear. The present study used several behavioral tests to examine the effects of OLE on symptoms of anxiety in rats after a single prolonged stress (SPS) exposure by inhibiting the hypothalamic-pituitary-adrenal axis. Male Sprague Dawley rats received OLE (10, 50 and 70?mg/kg, i.p., once daily) for 14 days after SPS exposure. Daily OLE (70?mg/kg) administration significantly increased the number and duration of open arm visits in the elevated plus maze (EPM) test, reduced the anxiety index and grooming behavior in the EPM test, and increased the time spent and number of central zone crossings in the open field test. OLE also blocked the SPS-induced decrease in hippocampal serotonin and neuropeptide Y expression in hippocampus. These findings suggest that OLE has anxiolytic-like effects on behavioral and biochemical symptoms similar to those observed in patients with PTSD.     

Nutritional parameters modify muricidal behavior of male Wistar rats: preventive effects of amino acids and 4' Cl diazepam.

In male Wistar rats fed a diet enriched in polyunsaturated fatty acids and starch (PUFA+S), the percentage of muricidal (Mu) rats increased to 82% within 60 days. Mu rats had higher serum triglyceride levels and lower cholesterol levels than non-Mu rats. Water intake decreased in all rats on the PUFA+S diet concurrently with the increase in the proportion of Mu rats; protracted water restriction in rats fed standard diet also increased the percentage of Mu rats. In the offspring of two Wistar females fed the PUFA+S diet, the proportion of young Mu rats was 67%. When the PUFA+S diet was replaced with standard diet, the induced Mu behavior was not reversed. PK11195 (6 mg/kg i.p.), clonazepam (0.2 mg/kg i.p.), and flumazenil (15 mg/kg i.p.) were ineffective in reversing the induced Mu behavior, whereas 4'-chlorodiazepam (5 mg/kg i.p.) or muscimol (0.5 mg/kg i.p.) caused reversals of 63% or 50%, respectively. A 5-hydroxytryptophan overload (60 mg/kg i.p.) also reversed Mu behavior by 71%. All reversal effects were temporary. Pretreatment with yeast for 7 days before the PUFA+S diet was given prevented induction for more than 90 days on the PUFA+S diet, while similar pretreatment 4'Cl-diazepam resulted in 71% prevention of induction. The results are analyzed in terms of the involvement of endozepin, vasopressin, and serotonin receptors, and of possible genetic parameters.     

Antidepressant-like effect of 17beta-estradiol: involvement of dopaminergic, serotonergic, and (or) sigma-1 receptor systems

17beta-estradiol has been reported to possess antidepressant-like activity in animal models of depression, although the mechanism for its effect is not well understood. The present study is an effort in this direction to explore the mechanism of the antidepressant-like effect of 17beta-estradiol in a mouse model(s) of behavioral depression (despair behavior). Despair behavior, expressed as helplessness to escape from a situation (immobility period), as in a forced swim test in which the animals are forced to swim for a total of 6 min, was recorded. The antiimmobility effects (antidepressant-like) of 17beta-estradiol were compared with those of standard drugs like venlafaxine (16 mg/kg, i.p.). 17beta-estradiol produced a U-shaped effect in decreasing the immobility period. It had no effect on locomotor activity of the animal. The antidepressant-like effect was comparable to that of venlafaxine (16 mg/kg, i.p.). 17beta-estradiol also exhibited a similar profile of antidepressant action in the tail suspension test. When coadministered with other antidepressant drugs, 17beta-estradiol (5 microg/kg, i.p.) potentiated the antiimmobility effect of subeffective doses of fluoxetine (5 mg/kg, i.p.), venlafaxine (2 mg/kg, i.p.), or bupropion (10 mg/kg, i.p.), but not of desipramine (5 mg/kg, i.p.) or tranylcypromine (2 mg/kg, i.p.), in the forced swim test. The reduction in the immobility period elicited by 17beta-estradiol (20 microg/kg, i.p.) was reversed by haloperidol (0.5 mg/kg, i.p.; a D(2) dopamine receptor antagonist), SCH 23390 (0.5 mg/kg, i.p.; a D(1) dopamine receptor antagonist), and sulpiride (5 mg/kg, i.p.; a specific dopamine D(2) receptor antagonist). In mice pretreated with (+)-pentazocine (2.5 mg/kg, i.p.; a high-affinity sigma-1 receptor agonist), 17beta-estradiol (5 microg/kg, i.p.) produced a synergistic effect. In contrast, pretreatment with progesterone (10 mg/kg, s.c.; a sigma-1 receptor antagonist neurosteroid), rimcazole (5 mg/kg, i.p.; another sigma-1 receptor antagonist), or BD 1047 (1 mg/kg, i.p.; a novel sigma-1 receptor antagonist) reversed the antiimmobility effects of 17beta-estradiol (20 microg/kg, i.p.). Similarly, in mice pretreated with a subthreshold dose of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, a 5-HT1A serotonin receptor agonist), 17beta-estradiol (5 microg/kg, i.p.) produced an antidepressant-like effect. These findings demonstrate that 17beta-estradiol exerted an antidepressant-like effect preferentially through the modulation of dopaminergic and serotonergic receptors. This action may also involve the participation of sigma-1 receptors.     

Effect of anxiolytic drugs on air-puff-elicited ultrasonic vocalization in adult rats.

Ultrasonic vocalization (USV) responses elicited by air-puff stimuli were compared in regard to both quality and quantity with those elicited by electric foot-shock(s) in adult rats. Frequency pattern, duration, repetition rate and interpulse interval of air-puff-elicited USV were comparable to those observed on foot-shock-elicited USV. Diazepam (0.25-1.0 mg/kg, s.c.) and buspirone (0.1-1.0 mg/kg, s.c.) attenuated equally and dose-dependently the USV responses elicited by both aversive stimuli. Air-puff-elicited USV was specifically attenuated in a dose-dependent manner by the anxiolytic properties of several psychotropic agents: diazepam (1.0-10.0 mg/kg, p.o.), buspirone (10.0-100.0 mg/kg, p.o.), 8-OH-DPAT (0.01-0.5 mg/kg, s.c.). Haloperidol (0.2-1.0 mg/kg, s.c.) weakly attenuated the USV response. Imipramine (0.2-1.0 mg/kg, s.c.) which has no anxiolytic property had no effect. Consequently, air-puff-elicited USV as well as foot-shock-elicited USV may provide a reliable tool for the study of anxiety.     

Etazolate rescues behavioral deficits in chronic unpredictable mild stress model: Modulation of hypothalamic–pituitary–adrenal axis activity and brain-derived neurotrophic factor level

Preliminary study in our laboratory showed that etazolate produced antidepressant- and anxiolytic-like effects in rodent models, however, the ability of etazolate to produce antidepressant- and anxiolytic-like effects and underlying mechanism(s) in chronic unpredictable mild stress (CUMS) model have not been adequately addressed. This study was aimed to investigate the beneficial effects of etazolate on CUMS-induced behavioral deficits (depression- and anxiety-like behaviors). In addition, the possible underlying mechanism(s) of etazolate in CUMS model was also investigated by measuring serum corticosterone (CORT) and brain-derived neurotrophic factor (BDNF) levels. Mice were subjected to a battery of stressors for 28 days. Etazolate (0.5 and 1 mg/kg, p.o.) and fluoxetine (20 mg/kg, p.o.) were administered during the last 21 days (8–28th) of the CUMS paradigm. The results showed that 4-weeks CUMS produces significant depression-like behavior in tail suspension test (TST) and partial anxiety-like behavior in elevated plus maze (EPM) and open field test (OFT). Stressed mice have also shown a significant high serum CORT and low BDNF level. Chronic treatment with etazolate (0.5 and 1 mg/kg., p.o.) and fluoxetine (20 mg/kg., p.o.) produced significant antidepressant-like behavior in TST (decreased duration of immobility), whereas, partial anxiolytic-like behavior in EPM (increased percentage of open arm entries) and OFT (increased % central ambulation score, total ambulation score and time spent in center zone). In addition, etazolate and fluoxetine treatment significantly (p < 0.05) increased the BDNF level and inhibited the hypothalamic–pituitary–adrenocortical (HPA) axis hyperactivity, as evidenced by low serum CORT level in stressed mice. In addition, etazolate and fluoxetine also showed significant antidepressant- and anxiolytic-like effects in normal control mice. In this study no significant changes were observed in locomotor activity in actophotometer test. Moreover, we did not find any effect of etazolate and fluoxetine on CORT and BDNF levels in normal control mice. In conclusion, the results of the present study suggested compelling evidences that etazolate has more marked effect on depression-like behavior in mice, which is atleast in part may be related to their modulating effects on the HPA axis and BDNF level.     

Pro-convulsant effect of cefazolin sodium against pentylenetetrazol- or picrotoxin-induced convulsions in mice

Cefazolin injection (3000 mg/kg, i.v.) in mice showed several behavioral excitations such as wild running, jumping, rolling, and finally undergoing severe convulsions followed by death. It's lower doses (500-2000 mg/kg, i.v.) were unable to produce any convulsions or behavioral excitations in mice. However, cefazolin (500 or 1000 mg/kg, i.v.) when administered before different doses of pentylenetetrazol (PTZ; 40 or 60 mg/kg, i.p.) or picrotoxin (PTX; 4 or 8 mg/kg, i.p.), it produced severe tonic-clonic convulsions in mice. The convulsions or behavioral excitations produced by 3000 mg/kg, i.v. cefazolin was also reversed by different doses of diazepam (0.5-2 mg/kg, i.p.) further proving the GABAergic modulatory effect of cefazolin. The results conclude the pro-convulsant action of cefazolin on PTZ- or PTX-induced convulsions, and further confirm the clinical reports.     

Repeated treatment with imipramine, fluvoxamine and tranylcypromine decreases the number of escape failures by activating dopaminergic systems in a rat learned helplessness test.

Chronic administration of antidepressants has been shown to reduce the number of escape failures in the rat learned helplessness test (LH). In the present study we investigated the role of D1, D2 and D3 receptors in mediating this effect. In our first series of experiments, we demonstrated that SKF38393, D1 receptor agonist, in a dose of 2.5 mg/kg (i.p.) and quinpirole, D2 receptor agonist in a dose of 0.5 mg/kg (i.p.), significantly decreased the number of escape failures in LH, and these were reversed by SCH23390 (0.015 mg/kg), D1 receptor antagonist, and by sulpiride (25 mg/kg), D2 receptor antagonist, respectively. In contrast, 7-OH-DPAT, a D3 receptor agonist, in a dose of 10 mg/kg (i.p.) did not affect the number of escape failures in LH. In a second series of experiments, we showed that eight days of repeated treatment with imipramine (10 mg/kg, p.o.), fluvoxamine (1.25 mg/kg, p.o.) and tranylcypromine (1.25 mg/kg, p.o.) significantly decreased the number of escape failures in LH. The decrease in escape failures seen with use of imipramine and tranylcypromine was reversed by sulpiride in LH, but not by SCH23390. On the other hand, the effect of fluvoxamine was reversed by both SCH23390 and sulpiride. These findings indicate that stimulation of D1 and D2 receptors decreased the number of escape failures in LH, respectively. Thus, D2 and/or D1 receptors are probably involved in the decreased number of escape failures in case of repeated treatment with antidepressants in LH.     

Comparison of the discriminative stimulus effects of midazolam after intracranial and peripheral administration in the rat.

Rats were trained in a two-lever drug discrimination paradigm to discriminate midazolam (0.32 mg/kg, i.p. or 1.0 mg/kg, i.p.) from the no-drug condition. After completion of i.p. and s.c. midazolam generalization gradients (0.032-1.0 mg/kg), rats were surgically implanted with unilateral cannulae into the lateral ventricles. Intracerebroventricular (i.c.v.) doses of 1.1-44.2 micrograms midazolam were delivered to unrestrained rats. Midazolam produced dose-dependent increases in drug-appropriate responding by all three routes of administration, but was 2.4- to 4.3-fold more potent when given i.c.v. than when given s.c. or i.p. Midazolam, over the dose range tested, did not produce substantial decreases in response rate by any route of administration. The discriminative-stimulus effect of i.c.v. midazolam was blocked by peripherally administered flumazenil, and such antagonism was surmounted by a 2- to 5-fold increase in the i.c.v. midazolam dose. Taken together, these data suggest that the discriminative-stimulus effects of midazolam are mediated via central benzodiazepine (BZ) receptors.     

Role of prostaglandins and nitric oxide in the lipopolysaccharide-induced ACTH and corticosterone response.

This study was designed to determine the role of endogenous prostaglandins (PG) and nitric oxide (NO) in the lipopolysaccharide (LPS)-induced ACTH and corticosterone secretion in conscious rats. LPS (0.5 and 1 mg/kg) given i.p. stimulated the hypothalamic-pituitary-adrenocortical (HPA) activity measured 2 h later. A non-selective cyclooxygenase inhibitor indomethacin (10 mg/kg i.p.), piroxicam (2 mg/kg i.p.), a more potent antagonist of constitutive cyclooxygenase (COX-1) and compound NS-398 (2 mg/kg i.p.), a selective inhibitor of inducible cyclooxygenase (COX-2) given 30 min before LPS (1 mg/kg i.p.) significantly diminished both the LPS-induced ACTH and corticosterone secretion. COX-2 blocker was the most potent inhibitor of ACTH secretion (72.3%). Nomega-nitro-L-arginine methyl ester (L-NAME 2 and 10 mg/kg i.p.), a non-selective nitric oxide synthase (NOS) blocker given 15 min before LPS did not substantially alter plasma ACTH and corticosterone levels 2 h later. Aminoguanidine (AG 100 mg/kg i.p.), a selective inducible nitric oxide synthase (iNOS) inhibitor, considerably enhanced ACTH and corticosterone secretion induced by a lower dose (0.5 mg/kg) of LPS and did not significantly alter this secretion after a larger dose (1 mg/kg) of LPS. L-NAME did not markedly affect the indomethacin-induced inhibition of ACTH and corticosterone response. By contrast, aminoguanidine abolished the indomethacin-induced reduction of ACTH and corticosterone secretion after LPS. These results indicate an opposite action of PG generated by cyclooxygenase and NO synthesized by iNOS in the LPS-induced HPA-response.     

Possible involvement of 5-HT and 5-HT2 receptors in acceleration of gastrointestinal transit by escin Ib in mice

We have reported previously that escin Ib accelerated gastrointestinal transit (GIT) in mice, and that its effect may be mediated by the release of endogenous prostaglandins (PGs) and nitric oxide (NO). In this study, the possible involvement of 5-HT and 5-HT receptors in the GIT acceleration of escin Ib was investigated in mice. The acceleration of GIT by escin Ib (25 or 50 mg/kg, p.o.) was attenuated by pretreatment with ritanserin (0.5-5 mg/kg, s.c., a 5-HT(2A/2C/2B) receptor antagonist), but not with MDL 72222 (1 and 5 mg/kg, s.c.) and metoclopramide (10 mg/kg, s.c.) (5-HT3 receptor antagonists) or tropisetron (1 and 10 mg/kg, s.c., a 5-HT(3/4) receptor antagonist). Furthermore, pretreatment with ketanserin (0.05-5 mg/kg, s.c.), haloperidol (1-5 mg/kg, s.c.) and spiperone (0.5-5 mg/kg, s.c.) (5-HT2A receptor antagonists), as well as a bolus of dl-p-chlorophenylalanine methyl ester (PCPA, 1000 mg/kg, p.o., 1, 6 or 24 h before administration of the sample) (an inhibitor of 5-HT synthesizing enzyme tryptophan hydroxylase) and reserpine (5 mg/kg, p.o.) (a 5-HT depletor), but not 6-hydroxydopamine (80 mg/kg, i.p., a dopamine depletor) or repeated PCPA (300 mg/kg x2, p.o., 72 and 48 h before administration of the sample), also attenuated the effects of escin Ib. It is postulated that escin Ib accelerates GIT, at least in part, by stimulating the synthesis of 5-HT to act through 5-HT2, possibly 5-HT2A receptors, which in turn causes the release of NO and PGs.     

Antipsychotic action of selective group II metabotropic glutamate receptor agonist MGS0008 and MGS0028 on conditioned avoidance responses in the rat

The present study was designed to investigate the antipsychotic-like effects of selective group II metabotropic glutamate receptor (mGluR) agonists, 5-[2-[4-(6-fluoro-1H-indole-3-yl) piperidin-1-yl]ethyl]-4-(4-fluorophenyl)thiazole-2-carboxylic acid amide (MGS0008) and (1R, 2S, 5S, 6S)-2-amino-6-fluoro-4-oxobicyclo[3.1.0]hexane-2,6-dicarboxylic acid monohydrate (MGS0028) on conditioned avoidance responses in rats. MGS0008 (1, 3 and 10 mg/kg, p.o.) and MGS0028 (0.3, 1 and 3 mg/kg, p.o.) significantly and reduced conditioned avoidance responses in a dose-dependent fashion. Similar effects were seen with LY418426 (0.3, 1 and 3 mg/kg, p.o.), but not with LY354740 (3, 10 and 30 mg/kg, p.o.), both of which are selective agonists for group II mGluR. Since this effect is seen with a wide range of antipsychotics, such as haloperidol and clozapine [Life Sciences 71 (2002) 947], group II mGluR agonists deserve further attention for possible antipsychotic activity.     

Central antidopaminergic properties of 2-bromolisuride, an analogue of the ergot dopamine agonist lisuride

2-Bromolisuride (2-Br-LIS), a derivative of the ergot dopamine (DA) agonist lisuride, was investigated in rodents in comparison with the DA antagonist haloperidol with regard to its influence on DA related behaviour, cerebral DA metabolism and prolactin (PRL) secretion. 2-Br-LIS produced catalepsy in mice (ED50 3.3 mg/kg i.p.), antagonized apomorphine-induced stereotypies in mice (ED50 0.4 mg/kg i.p.), antagonized DA agonist-induced stereotypies in rats (0.1-1.56 mg/kg i.p.), inhibited locomotor activity in rats (0.025-6.25 mg/kg i.p.), antagonized the hyperactivity produced by various DA agonists in rats (0.025-6.25 mg/kg i.p.) and inhibited the apomorphine-induced hypothermia in mice (0.05-0.78 mg/kg i.p.). 2-Br-LIS (0.03-10 mg/kg i.p.) stimulated DA biosynthesis and DOPAC formation in the striatum and DA rich limbic system of rats, but had no effect on serotonin turnover. In striatum and limbic forebrain of gamma-butyrolactone-pretreated rats 2-Br-LIS reversed the apomorphine-induced inhibition of DOPA accumulation. 2-Br-LIS (0.03 - 3 mg/kg) enhanced PRL secretion in intact male rats. These findings indicate DA antagonistic properties of 2-Br-LIS presumably due to blockade of central pre- and postsynaptic DA receptors being of approximately the same order of potency as haloperidol. 2-Br-LIS is the first ergot compound with definite antidopaminergic properties suggesting its potential usefulness as a neuroleptic.     

Experience with a naphthylmedetomidine – ketamine – hyaluronidase combination in inducing immobilization in anthropoid apes

Background The aim of the study was to compare the effect of naphthylmedetomidine to medetomidine on the behavior of orangutans and chimpanzees. Methods The immobilization was performed as part of a medical examination in five chimpanzees and three orangutans. Following pre‐medication with midazolam (0.70–1.20 mg/kg p.o.), naphthylmedetomidine (50–70 μg/kg), or medetomidine (20–30 μg/kg) was given with ketamine (3 mg/kg) and hyaluronidase (150 M.U.) into musculus deltoideus. Results We observed the distinct anti‐aggressive effect of naphthylmedetomidine. The immobilization with naphthylmedetomidine was shallower and the influence on cardiac frequency less substantial compared to medetomidine. The overall sedative effect of naphthylmedetomidine lasted for less time, and its effect was incompletely antagonized with atipamezole in comparison to medetomidine. Conclusions Naphthylmedetomidine could replace medetomidine for inducing immobilization and sedation. A combination of naphthylmedetomidine–ketamine is suitable for relocating animals to other cages or for painless medical examinations.     

Attenuation of cocaine-induced conditioned place preference by Polygala tenuifolia root extract

A recent investigation indicated that Polygala tenuifolia Willdenow extract (PTE) possesses a potential antipsychotic effect. In this study, we examined the effects of PTE on the cocaine-induced changes in locomotor activity, conditioned place preference (CPP), fos-related antigen-immunoreactivity (FRA-IR), and activator protein (AP)-1 DNA binding activity. Cocaine-induced behavioral effects (hyperlocomotion and CPP) occurred in parallel with increases in FRA-IR and AP-1 DNA binding activity in the nucleus accumbens. These responses induced by cocaine were consistently attenuated by concurrent treatment with PTE (25 mg or 50 mg/kg/day, i.p. x 7). The adenosine A2A receptor antagonist, 1,3,7-trimethyl-8-(3-chlorostyrl)xanthine (0.5 or 1.0 mg/kg, i.p.), reversed the PTE-mediated pharmacological action in a dose related manner; neither the adenosine A(1) receptor antagonist, 8-cyclopentyl-1,3-dimethylxanthine (0.5 or 1.0 mg/kg, i.p.) nor the A2B receptor antagonist, alloxazine (1.5 or 3.0 mg/kg, i.p.) significantly affected this pharmacological action. Our results suggest that PTE prevents cocaine-induced behavioral effects, at least in part, via the activation of the adenosine A2A receptor.     

Stress- and Yohimbine-Induced Release of Cholecystokinin in the Frontal Cortex of the Freely Moving Rat: Prevention by Diazepam but Not Ondansetron

Abstract: The in vivo release of cholecystokinin (CCK)-like material (CCKLM) was measured in the frontal cortex of freely moving rats using the microdialysis technique combined with a sensitive radioimmunoassay. Local perfusion of K⁺ (100 m M )-enriched artificial CSF resulted in a 10-fold increase in CCKLM outflow, as compared with that occurring under basal resting (K⁺ = 3.0 m M ) conditions, and this effect could be completely prevented by removal of Ca²⁺ in the perfusing fluid. Chromatographic analyses demonstrated that CCK-8S contributed to 70% of CCKLM. Stressful stimuli such as a 2-min exposure to diethyl ether and a 30-min restraint produced a marked but transient increase in cortical CCKLM release. In addition, anxiety-like behavior induced by the systemic administration of yohimbine (5 mg/kg i.p.) was associated with a long-lasting enhancement in the peptide outflow. Pretreatment with the potent anxiolytic drug diazepam (5 mg/kg i.p., 5 min before each condition), which exerted no effect on its own, completely prevented CCKLM overflow due to diethyl ether, restraint, or yohimbine administration. In contrast, neither the systemic injection (0.1 mg/kg i.p.) nor the local application (100 µ M through the microdialysis probe) of the serotonin 5-HT₃ antagonist ondansetron affected the increased release of CCKLM in rats restrained for 30 min or treated with yohimbine. These results indicate that cortical CCKergic neurotransmission is increased during stress or anxiety-like behavior in rats. Prevention of this effect by diazepam suggests that an inhibitory influence of benzodiazepines on cortical CCKergic neurons might participate in the anxiolytic action of these drugs.     

Inhibition of peripheral adrenergic neurotransmission by lergotrile in spontaneously hypertensive rats

Intraperitoneal injection of lergotrile (0.5 mg/kg) produced arterial hypotension and bradycardia for 120 and 90 minutes, respectively, in anesthesized spontaneously hypertensive rats (SHR). During this time frame, lergotrile (0.5 mg/kg, i.p.) greatly attenuated diastolic blood pressure and cardiac rate responses to electrical stimulation (0.062-4 Hz) of the sympathetic outflow in pithed SHR, but had no significant effect on comparable increments in pressure and rate produced by exogenous norepinephrine (0.01–10 μg/kg, i.v.). Pretreatment of SHR with haloperidol (2 mg/kg, i.p.) prevented lergotrile-induced hypotension and partially reversed its inhibitory effect on neurogenic vasoconstrictor responses. Haloperidol alone had no significant effect on baseline arterial blood pressure or responses to sympathetic nerve stimulation. Administration of hexamethonium (20 mg/kg, i.v.) to SHR antagonized the hypotensive response to lergotrile (0.5 mg/kg, i.p.), although hydralazine (2 mg/kg, i.p.) still produced a marked reduction in pressure.These results suggest that lergotrile produces arterial hypotension and bradycardia primarily by inhibiting peripheral sympathetic nerve function through a dopaminergic mechanism. The probable site of action of lergotrile is at presynaptic (neuronal) dopamine receptors which are known to be inhibitory to neurogenic release of norepinephrine.