Social competition in rats: a test sensitive to acutely administered anxiolytics

Male Wistar rats were housed in groups of three (triads) and given brief sessions during which sweetened milk was available in a drinking bottle. The rats showed intense competition to obtain access to the milk and in many groups a stable rank order was formed of a dominant, an intermediate and a subordinate rat, when assessed as the amount of access to the drinking tube. When the subordinate rats were injected with the anxiolytic drugs chlordiazepoxide (1.25-20mg/kg), buspirone (0.3-5.0mg/kg) and alpidem (2.5-20mg/kg) and low doses of the hypnotic, zolpidem (0.125-2.0mg/kg) they increased their access to the milk. These increases were generally at the expense of the dominant rats whose access decreased. The effect of alpidem (5mg/kg) was antagonized by flumazenil (10mg/kg). Increases in access in subordinate rats were not seen after haloperidol (0.025-0.2mg/kg), imipramine (5, 10mg/kg) or morphine (2.5-10mg/kg). As the anxiolytic drugs were active at relatively low doses this test of social competition may provide a particularly sensitive and selective procedure for detecting and evaluating the actions of drugs from this class.     

Effects of carbamazepine, valproate calcium, clonazepam and piracetam on behavioral test methods for evaluation of memory-enhancing drugs

The effect of three anticonvulsants on several test methods for evaluation of memory-enhancing drugs have been studied in rats and mice. The results were compared to the results obtained from the nootropic piracetam and from imipramine. In an active avoidance test (pole jumping), repeated administration of carbamazepine (5 mg/kg i.p.) and piracetam (300 mg/kg p.o.) protected against impairment of learning rate caused by repeated application of an electroconvulsive shock. Valproate calcium (repeated administration of 30 mg/kg i.p.) was only weakly active, while clonazepam (repeated administration of 0.3 mg/kg i.p.) decreased the learning rate even more. Drugs were given in dosages which have no anticonvulsive activity in this test. The impairment of learning rate caused by repeated application of ethanol was prevented by carbamazepine (5 mg/kg i.p.), valproate calcium (30 and 100 mg/kg i.p.) and piracetam (100 mg/kg i.p.). Clonazepam (0.3 and 1 mg/kg i.p.) had a worsening effect on learning rate. In Porsolt's behavioral despair test, carbamazepine (5, 10 and 30 mg/kg i.p.) and valproate calcium (30 and 100 mg/kg i.p.) shortened the duration of immobility, which indicates an increased psychomotor activity. Clonazepam was ineffective. Results obtained with carbamazepine are similar to those obtained with piracetam. The data are discussed in view of the so-called psychotropic effects of carbamazepine in clinical trials.     

Comparison of the Relative Inhibition of Acetylcholinesterase and Neuropathy Target Esterase in Rats and Hens Given Cholinesterase Inhibitors

Inhibition of neuropathy target esterase (NTE, neurotoxic esterase)and acetylcholinesterase (AChE) activities was compared in brainand spinal cords of adult While Leghorn hens and adult maleLong Evan rats 4–48 hr after admiriistration of tri-ortho-tolylphosphate (TOTP po, 50–500 mg/kg to hens; 300–1000mg/kg to rats), phenyl saligenin phosphate (PSP im 0.1–2.5mg/kg to hens; 5–24 mg/kg to rats), mipafox (3–30mg/kg ip to hens and rats), diisopropyl phosphorofluoridate(DFP sc, 0.25–1.0 mg/kg to hens; 1–3 mg/kg to rats),dichlorvos (5–60 mg/kg ip to hens; 5–30 mg/kg torats), malathion (75–300 mg/kg po to hens; 600–2000mg/kg to rats), and carbaryl (300–560 mg/kg ip to hens;30–170 mg/kg to rats). Inhibitions of NTE and AChE weredose-related after administration of all compounds to both species.Hens and rats given TOTP, PSP, mipafox, and DFP demonstrateddelayed neuropathy 3 weeks later, with spinal cord lesions andclinical signs more notable in hens. Ratios of NTE/AChE inhibitionin hen spinal cord, averaged over the doses used, were 2.6 afterTOTP, 5.2 after PSP, 1.3 after mipafox, and 0.9 after DFP, whichcontrast with 0.53 after dichlorvos, 1.0 after malathion, and0.46 after carbaryl. Rat NTE/AChE inhibition ratios were 0.9after TOTP, 2.6 after PSP, 1.0 after mipafox, 0.62 after DFP,1.3 after dichlorvos, 2.2 after malathion, and 1.1 after carbaryl.The lower NTE/AChE ratios in rats given dosages of the fourorganophosphorus compounds that caused delayed neuropathy interferredwith survival, an effect that was not a problem in hens. Thisobservation, along with the absence of overt and specific clinicalsigns and the restricted presence of neuropathological lesionsin rats, suggests that the hen remains the animal of choicefor testing for organophosphorus-induced delayed neuropathy.     

Involvement of µ-opioid receptors in the antitussive effects of pentazocine

Summary The effect of pentazocine on the capsaicininduced cough reflex in rats was investigated. Intraperitoneal injection of pentazocine, in doses from 1 to 10 mg/kg, significantly decreased the number of coughs in a dose-dependent manner. The antitussive effect of pentazocine (10 mg/kg, i.p.) was significantly reduced by prior injection of naloxone (0.3 mg/kg, i.p.), but it was unaffected by Mr-2266 BS (5 mg/kg, i.p.), an antagonist of -opioid receptors. The antinociceptive potency of pentazocine (30 mg/kg, i.p.), as determined by the formalin test, was significantly reduced by pretreatment with Mr-2266 BS (5 mg/kg, i.p.), whereas naloxane (0.3 mg/ kg, i.p.) had no significant effect on the antinociceptive effect of pentazocine. The antitussive effects of pentazocine (3 mg/kg) and morphine (0.1 mg/kg) were significantly enhanced in rats treated chronically with naloxone (5 mg/kg/day, 5 days), whereas the antitussive effect of U-50,488 H (1 mg/kg, i.p.), a selective -opioid agonist, was not enhanced in these rats. By contrast, the antinociceptive effect of morphine (0.01 mg/kg, i.p.) was significantly enhanced in rats that had been pretreated chronically with naloxone. However, the antinociceptive effects induced by pentazocine (3 mg/kg, i.p.) and U-50,488 H (1 mg/kg, i.p.) were unchanged. These results suggest that pentazocine-induced antitussive effects in rats are mediated via stimulation of µ-opioid receptors. Send offprint requests to J. Kamei at the above address     

Antidepressant properties of rotigotine in experimental models of depression

Limited clinical data are available on the use of dopamine agonists for the control of motor function and also for the treatment of depression. This study was performed to evaluate the potential effects of the dopamine receptor agonist rotigotine in rat models of anxiety and depression. After repeated administration at doses of 0.05, 0.5, 1, and 5 mg/kg, rotigotine increased spontaneous motor activity at the 5 mg/kg dose after 3-5 days of treatment. At lower doses, the drug had no effect on locomotor activity. After a single administration, rotigotine had no anxiolytic activity in rats during the elevated plus-maze test or the Geller-Seifter conflict test. In the behavioral despair test (also known as the forced swim test), the 5 mg/kg dose of rotigotine enhanced the mobility of rats. Rotigotine (0.5, 1, and 5 mg/kg/day for 5 days) reversed the active avoidance deficit of helpless rats in the learned helplessness test, as shown by a significant decrease in escape failures after 3 to 4 days (0.5 mg/kg/day), 5 days (1 mg/kg/day), and 3 to 5 days (5 mg/kg/day) of treatment. During open-field testing of rats subjected to olfactory bulbectomy and given a 14-day schedule of rotigotine (0.3 mg/kg every 2 days), hyperactivity reversed according to a U-shaped dose-response curve. These results suggest that rotigotine may have antidepressant properties at doses of 1 mg/kg and lower. Potential effects at doses of 5 mg/kg and higher may be masked by an effect of the compound whereby general locomotor activity is enhanced.     

Studies on the role of serotonin receptor subtypes in the effect of sibutramine in various feeding paradigms in rats.

The effect of the 5-hydroxytryptamine (5-HT) and noradrenaline (NA) reuptake inhibitor sibutramine was studied in food deprived, neuropeptide Y (NPY)- or muscimol-injected rats. Sibutramine dose-dependently reduced feeding caused by food-deprivation (ED50 = 5.1+/-0.8 mg kg(-1)) or by NPY injection into the paraventricular nucleus of the hypothalamus (ED50 = 6.0+/-0.5 mg kg(-1)). The increase in food intake caused by muscimol injected into the dorsal raphe was not modified by sibutramine (1-10 mg kg(-1)). The hypophagic effect of 5.1 mg kg(-1) sibutramine in food-deprived rats was studied in rats pretreated with different serotonin receptor antagonists. Metergoline (non-selective, 0.3 and 1.0 mg kg(-1)), ritanserin (5-HT2A/2C, 0.5 and 1.0 mg kg(-1)) and GR127935 (5-HT1B/1D), 0.5 and 1.0 mg kg(-1)) did not modify the hypophagic effect of sibutramine, while SB206553 (5-HT2B/2C, 5 and 10 mg kg(-1)) slightly but significantly reduced it (Fint(2.53) = 3.4; P<0.05). The reduction in food intake caused by 6.0 mg kg(-1) sibutramine in NPY-injected rats was not modified by GR127935 (1.0 mg kg(-1)). The results suggest that, with the possible exception of a partial involvement of 5-HT2B/2C receptors in sibutramine's hypophagia in food-deprived rats, 5-HT1 and 5-HT2 receptor subtypes do not play an important role in the hypophagic effect of sibutramine, at least in the first 2 h after injection.     

The anxiolytic-like effect of the selective 5-HT6 receptor antagonist SB-399885: the impact of benzodiazepine receptors

The effect of lesion of 5-hydroxytryptamine (5-HT) neurons, produced by p-chloroamphetamine (p-CA; 2 × 10 mg/kg), and the influence of the benzodiazepine receptor antagonist flumazenil (10 mg/kg) on the anticonflict action of N-[3,5-dichloro-2-(methoxy)phenyl]-4-(methoxy)-3-(1-piperazinyl)benzenesulfonamide (SB-399885), a selective 5-HT₆ receptor antagonist, were investigated in the Vogel conflict drinking test in rats. In addition, the interaction between SB-399885 (0.3 mg/kg) and diazepam (2.5 mg/kg) was evaluated in that test. All the compounds tested were administered intraperitoneally. The anticonflict activity produced by SB-399885 (3 mg/kg) was not modified in p-CA-pretreated rats, but it was totally blocked by flumazenil. Combined administration of non-active doses of SB-399885 (0.3 mg/kg) and diazepam (2.5 mg/kg) produced a pronounced anticonflict effect in rats. The present results suggest that the anticonflict activity of SB-399885 is not conditioned by the integrity of 5-HT neurons, and that benzodiazepine receptors are indirectly involved in its effect, possibly due to a functional interaction between 5-HT₆ receptors and the γ-aminobutyric acid (GABA)/benzodiazepine system.     

Studies on the behavioural effects of tryptophan and rho-chlorophenylalanine.

The inhibitor of 5-hydroxytryptamine synthesis, p-chlorophenylalanine (150 mg/kg), decreased brain 5-hydroxytryptamine and increased activity in grouped rats during the light period. In a novel environment, however, activity was reduced. l-Tryptophan (150 mg/kg) restored brain 5-hydroxytryptamine to its original concentration and also reversed the effect of p-chlorophenylalanine on activity of grouped animals. l-Tryptophan (100 mg/kg) caused a partial reversal, while 25 mg/kg had no effect. In control rats, l-tryptophan increased the 5-hydroxytryptamine concentration and turnover, but had no effect on activity. Tryptophan led to a significantly greater increase of 5-hydroxytryptamine and a significantly smaller increase of 5-hydroxyindoleacetic acid in p-chlorophenylalanine-treated than in control rats.Although the dopamine antagonist, pimozide, (0·3 and 1 mg/kg) significantly reduced or blocked the hyperactivity produced by (+(-amphetamine (2 mg/kg), it did not block the effect of p-chlorophenylalanine on activity. Pimozide also did not block the hyperactivity caused by tranylcypromine plus l-tryptophan though it markedly reduced toxicity. A higher dose (2 mg/kg) of pimozide blocked the effect of p-chlorophenylalanine on activity.The results specifically implicate decreased 5-hydroxytryptamine synthesis in a behavioural effect of p-chlorophenylalanine and provide evidence against direct involvement of dopamine receptors. The results are discussed in relation to functional and non-functional 5-hydroxytryptamine and to the postulated defect of 5-hydroxytryptamine in depression.     

Effects of selective serotonergic agonists on aggressive behavior in rats

The effects of the relatively specific serotonergic agonists 8-OH-DPAT (5-HT_1A), TFMPP (5-HT_1B), and DOB (S-HT₂) were studied on defensive aggressive behavior in rats using the water competition test. 8-OH-DPAT (up to 0.25 mg/kg) and TFMPP (up to 1 mg/kg) were found to be ineffective, whereas DOB (up to 0.4 mg/kg) significantly reduced aggressive behavior in this test as well as in the offensive aggression test of the resident-intruder model. These results, combined with those from other studies, suggest that stimulation of 5-HT_1A, 5-HT_1B, and 5-HT₂ receptors reduces offensive aggression, whereas defensive aggression is only decreased by 5-HT₂ stimulation.     

D1/D2 dopamine and N-methyl-d-aspartate (NMDA) receptor participation in experimental catalepsy in rats

Mixed D₁/D₂ dopamine (DA) antagonists, perphenazine (5 mg/kg) and haloperidol (2 mg/kg) induced catalepsy in rats. SCH 23390 (1 mg/kg), a D₁ DA antagonist, also produced catalepsy. Co-administration of perphenazine (0.5 mg/kg) and SCH 23390 (0.1 mg/kg), at low doses, produced a marked increase in cataleptic response. B-HT 920, a D₂ agonist, reversed the cataleptogenic effects of perphenazine, haloperidol and SCH 23390. SKF 38893 (5 mg/kg) reduced the cataleptogenic effect of SCH 23390 but failed to reverse haloperidol- or perphenazine-induced catalepsy. SKF 38393 (10 mg/kg), however, protected the animals against perphenazine- induced catalepsy. Combined administration of B-HT 920 (0.1 mg/kg) and SKF 38393 (5 mg/kg) enhanced the protective effect of B-HT 920 in SCH 23390-treated animals but not in animals treated with haloperidol or perphenazine. MK-801 (0.025–0.5 mg/kg), a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, reduced the cataleptogenic effects of perphenazine, haloperidol as well as SCH 23390. The anticataleptic action of MK-801 was enhanced by scopolamine (0.1 mg/kg) but not by bromocriptine (1 mg/kg) or clonidine (0.05 mg/kg) in perphenazine-treated rats. Unlike B-HT 920 (0.1 mg/kg), SKF 38393 (5 mg/kg) potentiated the anticataleptic effect of MK-801 (0.01 mg/kg) against SCH 23390-induced catalepsy. The above data suggests D₁/D₂ interdependence in catalepsy and a modulatory role of D₁ and D₂ DA receptor stimulation on the anticataleptic effect of MK-801.     

Buspirone improves the anti-cataleptic effect of levodopa in 6-hydroxydopamine-lesioned rats

In Parkinson's disease (PD), prolonged exposure to L-3,4-dihydroxyphenylalanine (L-DOPA) results in motor fluctuations, such as the on-off phenomenon, and L-DOPA-induced dyskinesia. Previously, we found that activation of 5-HT(1A) in the substantia nigra pars compacta (SNc) decreased catalepsy in parkinsonian rats. In the current investigation, we attempted to evaluate the effect of buspirone on the anti-cataleptic effect of L-DOPA in 6-hydroxydopamine (6-OHDA)-lesioned male Wistar rats. Catalepsy was induced by the unilateral infusion of 6-OHDA (8 μg/2 μl/rat) into the central region of the SNc. After a 3-week recovery period, rats received L-DOPA intraperitoneally (ip; 15 mg/kg) twice daily for 20 days, and the anti-cataleptic effect of L-DOPA was assessed by the bar test at days 5, 10, 15 and 20. The results showed that L-DOPA had an anti-cataleptic effect only until day 15, and its effect was abolished on day 20. On day 21, these rats were co-treated with three different doses of buspirone (0.1, 0.5 and 2.5 mg/kg, ip) and L-DOPA (15 mg/kg, ip). At a dose of 0.5 mg/kg, buspirone improved the anti-cataleptic effect of L-DOPA. Furthermore, the effect of buspirone (0.5 mg/kg, ip) on the anti-cataleptic effect of L-DOPA (15 mg/kg, ip) was reversed by 1-(2-methoxyphenyl)-4-(4-phthalimidobutyl)piperazine hydrobromide (NAN-190; 0.5 mg/kg, ip), a 5-HT(1A) receptor antagonist. From these results, it may be concluded that buspirone improves the anti-cataleptic effect of L-DOPA in a 6-OHDA-induced animal model of PD through the activation of 5-HT(1A) receptors. In this regard, further investigations should be undertaken to clarify the exact mechanism of the interaction between 5-HT(1A) and dopaminergic neurons.     

Effects of p-chlorophenylalanine (p-CPA) on sleep in olfactory bulb lesioned rats.

The effect of p-CPA and 5-HTP followed by p-CPA on sleep was studied in rats with olfactory bulb lesions (O.B. lesioned rats). In these rats, electrodes were chronically implanted to record the EEG (frontal cortex and dorsal hippocampus), the cervical electromyogram and eye movements. The REM sleep stage was selectively decreased from 24 to 32 hours after 200 mg/kg of p-CPA in the sham lesioned rats, whereas both the slow wave sleep and REM sleep stages were markedly decreased by the same dose of p-CPA in the O.B. lesioned rats. In both sham and O.B. lesioned groups, the slow wave sleep and REM sleep stages decreased from 24 to 32 hours after 400 mg/kg of p-CPA and the percentage of decrease in the slow wave sleep stage was much larger with 400 mg/kg of p-CPA than with 200 mg/kg and 400 mg/kg of p-CPA. In the O.B. lesioned rats, the insomnia produced by 200 mg/kg and 400 mg/kg of p-CPA disappeared with 5-HTP (5 mg/kg). On the other hand, the insomnia produced by 200 mg/kg of p-CPA did not recur with 5-HTP in the sham lesioned rats, but with 400 mg/kg there was a recurrence. These results suggest that the enhanced effect of p-CPA and 5-HTP followed by p-CPA in the O.B. lesioned rats is due to changes in the sensitivity of the serotonergic system in the brain.     

Differential effect of buspirone and diazepam on negative contrast in one-way avoidance learning

The main aim of the present work was to investigate the effect of buspirone, a 5-HT_1A receptor agonist, on successive negative contrast in one-way avoidance learning. Successive negative contrast was induced by shifting rats from a large reward (30 s spent in the safe compartment) to a small reward (1 s). Acute administration of buspirone (0.25, 0.5, 0.75 and 1.0 mg/kg i.p.) did not attenuate the contrast effect, as opposed to that observed for diazepam (1 mg/kg i.p.). The highest dose of buspirone used, however, did interfere with the learning of the avoidance response itself. Chronic buspirone (20 days, 0.5 and 0.75 mg/kg i.p.) did not have any effect on successive negative contrast either. Overall, these results could suggest that the 5-HT_1A receptor is not involved in the negative contrast effect studied, quite different to that observed for the γ-aminobutyric acid (GABA) system. The findings are compared to results obtained with animal models selectively sensitive to some anxiolytic drugs, as are the so-called ‘conflict models’.     

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

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

延胡索甲素与左旋延胡索乙素抗吗啡躯体依赖和精神依赖的作用研究

目的 观察并比较延胡索甲素(corydaline,Cor)与左旋延胡索乙素(l-tetrahydropalmatine,l-THP)抗吗啡躯体依赖和精神依赖的作用。方法 SD大鼠随机分为对照组、模型组、Cor组、l-THP组。连续递增sc吗啡9 d后,纳洛酮促瘾,制备吗啡依赖大鼠催促戒断模型,促瘾前30 min ip Cor(40、80 mg/kg)或l-THP(5.0、10.0 mg/kg),观察大鼠戒断症状和体质量的降低;应用旷场实验,观察Cor(5、10 mg/kg)和l-THP(2.5、5.0 mg/kg)对吗啡诱导的大鼠自发活动的影响、对吗啡连续递增给药致大鼠行为敏化效应的影响,以及Cor(10、20、40 mg/kg)和l-THP(2.5、5.0、10.0 mg/kg)对大鼠自发活动的影响。结果 Cor(40、80 mg/kg)、l-THP(5.0 mg/kg)对吗啡催促戒断症状无显著改善作用,10 mg/kg l-THP显著改善大鼠戒断症状(P<0.05);Cor和l-THP对吗啡降低大鼠体质量效应有改善趋势,但差异不显著;Cor 40 mg/kg以下剂量、l-THP 10 mg/kg以下剂量对大鼠自发活动无显著影响;Cor(5、10 mg/kg)和l-THP(2.5、5.0 mg/kg)均可显著降低吗啡诱发的大鼠高活动性行为、行为敏化的形成(P<0.05、0.01)。结论 Cor和l-THP对吗啡所致的大鼠躯体依赖和精神依赖均有不同程度的调节作用,l-THP的起效剂量明显低于Cor。     

Spinal alpha 1- and alpha 2-adrenoceptors mediate facilitation and inhibition of spinal motor transmission, respectively

The role of descending noradrenergic fibers in the spinal motor systems was investigated using spinal reflexes in acutely spinalized rats. In rats pretreated with the MAO inhibitor clorgyline-HCl (1 mg/kg, i.v.), L-3,4-dihydroxyphenylalanine (L-dopa) (5 mg/kg, i.v.), a precursor of dopamine and noradrenaline, markedly potentiated the mono- (MSR) and polysynaptic reflexes (PSR). Selective blockade of alpha 1-adrenoceptors by pretreatment with prazosin-HCl abolished these facilitatory effects on the MSR and the PSR and revealed the inhibitory effect of L-dopa on the PSR. The depression of PSR was antagonized by the alpha 2-antagonist piperoxan. Clonidine-HCl (0.05 mg/kg, i.v.), a so-called alpha 2-agonist, and tizanidine-HCl (0.1 mg/kg, i.v.) decreased the MSR and the PSR in rats pretreated with prazosin. These inhibitions were antagonized by piperoxan. These results suggest that alpha 1- and alpha 2-adrenoceptors mediate facilitation and attenuation of motor transmission in the rat spinal cord, respectively.     

Effects of combined administration of 5-HT1A and/or 5-HT1B receptor antagonists and paroxetine or fluoxetine in the forced swimming test in rats

Clinical data suggest that coadministration of pindolol, a 5-HT1A/5-HT1B/beta-adrenoceptor antagonist, and selective serotonin reuptake inhibitors (SSRIs) may shorten the time of onset of a clinical action and may increase beneficial effects of the therapy of drug-resistant depression. Effects of combined administration of SSRIs and 5-HT receptor ligands are currently evaluated in animal models for the detection of an antidepressant-like activity; however, the obtained results turned out to be inconsistent. The aim of the present study was to investigate effects of a 5-HT1A antagonist (WAY 100635), 5-HT1B antagonists (SB 216641 and GR 127935) or pindolol, given in combination with paroxetine or fluoxetine (SSRIs), in the forced swimming test in rats (Porsolt test). When given alone, paroxetine (10 and 20 mg/kg), fluoxetine (10 and 20 mg/kg), WAY 100635 (0.1 and 1 mg/kg), SB 216641 (2 mg/kg), GR 127935 (10 and 20 mg/kg) and pindolol (4 and 8 mg/kg) did not shorten the immobility time of rats in that test. Interestingly, SB 216641 administered alone at a dose of 4 mg/kg produced a significant reduction of the immobility time in that test. A combination of paroxetine (20 mg/kg) and WAY 100635 or pindolol failed to reveal a significant interaction; on the other hand, when paroxetine was given jointly with SB 216641 (2 mg/kg) or GR 127935 (10 and 20 mg/kg), that combination showed a significant antiimmobility action in the forced swimming test in rats. The active behaviors in that test did not reflect increased general activity because combined administration of both the 5-HT1B antagonists and paroxetine failed to alter the locomotor activity of rats, measured in the open field test. Coadministration of fluoxetine and all the antagonists used did not affect the behavior of rats in the forced swimming test. The obtained results seem to indicate that blockade of 5-HT1B receptors, but not 5-HT1A ones, can facilitate the antidepressant-like effect of paroxetine in the forced swimming test in rats. No interaction was observed between fluoxetine and 5-HT1A/5-HT1B receptor antagonists.     

Modification of behavioral responses to methamphetamine evoked by the stimulant's metabolite p-hydroxynorephedrine in rats

The central effect of p-hydroxynorephedrine (OH-NE), one of the p-hydroxylated metabolites of methamphetamine (MAP) and amphetamine (AMP), was investigated in rats. Locomotion and stereotypy were examined after SC injections of 0.5-5 mg/kg of MAP or 0.02-0.5 mg/kg of apomorphine (APO) in animals treated with either saline or 5-50 mg/kg of OH-NE IP 20 hr before behavioral assessment. The locomotor stimulating effect of both 0.5-2 mg/kg of MAP and 0.2 mg/kg of APO was enhanced by 5 mg/kg of OH-NE. On the other hand, 30 mg/kg of OH-NE severely suppressed the stimulating effect of MAP but had no influence on that induced by 0.2 mg/kg of APO. The stereotypy induced by 5 mg/kg of MAP or 0.5 mg/kg of APO was enhanced and prolonged in the OH-NE-treated rats. Subsequently, examinations were performed to determine whether OH-NE had any effect on the dopaminergic mechanism. Hypomotility induced by 0.02 mg/kg of APO was alleviated by 5 mg/kg of OH-NE, but was aggravated by 30 mg/kg. These results suggest that OH-NE administered prior to SC injections of MAP or APO influences their behavioral effects via the dopaminergic mechanism. The possibility that other neural mechanisms may be involved in this OH-NE-induced behavioral modification is also discussed.     

Effects of serotonin (5-HT)2 receptor ligands on depression-like behavior during nicotine withdrawal

A pronounced withdrawal syndrome including depressed mood prevents cigarette smoking cessation. We tested if blockade or activation of serotonin (5-HT)₂ receptors affected the time of immobility (as an indirect measure of depression-like behavior) in naïve animals and in those withdrawn from chronic nicotine in the forced swim test (FST). The antidepressant imipramine was used as a control. In the FST, the selective 5-HT_2A receptor antagonist M100,907 (1-2 mg/kg, but not 0.5 mg/kg), the selective 5-HT_2C receptor antagonist SB 242,084 (0.3-1 mg/kg, but not 0.1 mg/kg), the 5-HT_2C receptor agonists Ro 60-0175 (10 mg/kg, but not 3 mg/kg) and WAY 163,909 (1.5-10 mg/kg, but not 0.75 mg/kg) as well as imipramine (30 mg/kg, but not 15 mg/kg) decreased the immobility time while the non-selective 5-HT₂ receptor agonist DOI (0.1-1 mg/kg) was inactive in naïve rats. We found an increase in immobility time in rats that were withdrawn from nicotine exposure after 5 days of chronic nicotine treatment. This effect increased from day 1 until day 10 following withdrawal of nicotine, with maximal withdrawal effects on day 3. M100,907 (1 mg/kg), SB 242,084 (0.3 mg/kg), Ro 60-0175 (3 mg/kg), WAY 163,909 (0.75-1.5 mg/kg) and imipramine (15-30 mg/kg) shortened the immobility time in rats that had been removed from nicotine exposure for 3 days. Locomotor activity studies indicated that the effects of SB 242,084 might have been non-specific, as we noticed enhanced basal locomotion in naïve rats. This data set demonstrates that 5-HT_2A receptor antagonist and 5-HT_2C receptor agonists exhibited effects similar to antidepressant drugs and abolished the depression-like effects in nicotine-withdrawn rats. These drugs should be considered as adjuncts to smoking cessation therapy, to ameliorate abstinence-induced depressive symptoms.     

Interaction of Viagra with the NO donors molsidomine and RE 2047 with regard to antithrombotic and blood pressure lowering activities.

After p.o. administration to rats in doses up to 30 mg/kg, Viagra showed no antithrombotic effect. However, it enhanced the inhibition of thrombus formation by RE 2047 from 9% to 17% (5 + 5 mg/kg) or 19% to 27% (10 + 10 mg/kg) in arterioles. This effect was even more obvious in venules where an inhibition of 9% (5 + 5 mg/kg) or 15% (10 + 10 mg/kg) was seen whereas the individual drugs had no effect. The antithrombotic activity of molsidomine was not altered. The blood pressure (b.p.) of spontaneously hypertensive rats was reduced by the combination of Viagra and RE 2047 (5 + 5 mg/kg) to 94% of normal after 2 h while the individual drugs had no effect at this dose. The coadminstration of 10 mg/kg of each drug reduced the b.p. to 87% of normal. The combination of Viagra with molsidomine decreased b.p. to 84% (5 + 5 mg/kg) or 79% (10 + 10 mg/kg), respectively.