Role of central nicotinic and β-adrenergic receptors in the onset and further development of tail-tremor induced by repeated nicotine administration to rats

The effects of nicotinic and β-adrenergic receptor antagonists on tail-tremor induced by repeated nicotine administration were investigated in rats. The daily administration of nicotine (0.5mg/kg/day, s.c.) for 8 days resulted in an augmentation of tail-tremor. However, repeated administration of dimethyl phenyl piperazinium iodide (1mg/kg/day, s.c.) for 8 days did not cause tail-tremor. Mecamylamine (0.5mg/kg, i.p), administered before the nicotine injection on each day, abolished the tail-tremor. After discontinuation of the mecamylamine treatment, nicotine injections caused tail-tremor augmentation. Propranolol (20mg/kg, i.p.), administered before the nicotine on each day, suppressed the appearance of tail-tremor. After the discontinuation of propranolol treatment, the degree of tail-tremor induced by a single injection of nicotine on day 9 was much greater in the propranolol-treated group than in the saline-treated control group. Neither carteolol (20mg/kg, i.p.) nor metoprolol (20mg/kg, i.p.) treatment showed such effects. Intraspinal injection of 6-hydroxydopamine markedly enhanced the tail-tremor induced on the first day of nicotine injection. This effect became more intense on subsequent administration of nicotine. The enhanced tail-tremor following 6-hydroxydopamine treatment was abolished by mecamylamine (0.5 and 1mg/kg, i.p.), and was suppressed by propranolol (5–20mg/kg, s.c.) in a dose-dependent manner. These results suggest that central nicotinic receptors are essential for the onset and for the further development of tail-tremor induced by the repeated administration of nicotine, and that β₂-adrenoceptors are associated with the tremor mechanism. Moreover, spinal noradrenergic mechanisms may be involved in the manifestation of this phenomenon. Received: 18 June 1996 / Accepted: 15 December 1996     

Haloperidol-induced vacuous chewing in rats: suppression by alpha-methyl-tyrosine.

Chronic treatment of rats with haloperidol (1 mg/kg twice daily for 4 weeks) induced repetitive vacuous chewing movements (VC), that persisted for over 72 h after haloperidol withdrawal. Haloperidol-induced VC were inhibited by the s.c. administration of the specific dopamine D1, receptor antagonist, SCH 23390 (0.025-0.100 mg/kg), in a dose-dependent manner, and were totally suppressed by an acute challenge with haloperidol (2 mg/kg i.p.) and by the dopamine synthesis inhibitor, alpha-methyl-tyrosine (AMT) (200 mg/kg i.p.). In AMT-treated rats, VC were reinstated by the administration of the selective D1 agonist, SKF 38393. The results support the hypothesis that chronic haloperidol-induced VC are mediated by dopamine acting selectively upon D1 receptors.     

Effects of morphine and met-enkephalin analogue on gastric lesions induced by indomethacin

The effects of morphine HCl and a synthetic met-enkephalin analogue [D-Ala2,MePhe4,Met(O)5ol]enkephalin (FK 33-824) on gastric damage produced by the intraperitoneal administration of indomethacin (10 mg/kg i.p.) have been investigated. Rats intraperitoneally pretreated with morphine HCl (10 mg/kg i.p.) and FK 33-824 (1 mg/kg i.p.) showed a statistically significant reduction both of the number and intensity of lesions induced by indomethacin. This protection was reversed by naloxone HCl (2 mg/kg i.p.). The protective effect was not related to a reduction of gastric secretion since the antisecretory drug cimetidine (25 mg/kg i.p.) and methscopolamine bromide (10 mg/kg i.p.) did not significantly prevent mucosal damage under the same experimental conditions.     

NMDA antagonists block restraint-induced increase in extracellular DOPAC in rat nucleus accumbens

The effects of the N-methyl-D-aspartate (NMDA) receptor antagonists CPP, TCP, PK 26124 and ifenprodil, and of the minor tranquillizer diazepam on stress-induced changes of dopamine metabolism in the nucleus accumbens were investigated in the rat. Dopamine metabolism was assessed by measuring the extracellular levels of 3,4-dihydroxyphenylacetic acid (DOPAC) by means of in vivo differential pulse voltammetry with electrochemically pretreated carbon fiber electrodes. Physical immobilization of the rats for 4 min caused a marked and long-lasting increase in extracellular DOPAC levels in the nucleus accumbens. A similar, though shorter-lasting, augmentation of extracellular DOPAC was observed in the nucleus accumbens after systemic administration of the anxiogenic agent methyl-beta-carboline-3-carboxylate (beta-CCM) (10 mg/kg s.c.). Pretreatment with CPP (1 mg/kg i.p.), TCP (3 mg/kg i.p.), PK 26124 (3 mg/kg i.p.), ifenprodil (3 mg/kg i.p.) or diazepam (2 mg/kg i.p.) totally antagonized the immobilization-induced increase in extracellular DOPAC in the nucleus accumbens. Diazepam and the benzodiazepine (omega 1-2) receptor antagonist flumazenil (30 mg/kg i.p.), but not ifenprodil, also antagonized the beta-CCM-induced activation of dopamine metabolism in the nucleus accumbens. Finally, systemic administration of haloperidol (25 micrograms/kg i.p.) increased the extracellular concentrations of DOPAC in the nucleus accumbens, but pretreatment with ifenprodil (3 mg/kg i.p.) did not modify this response. These data indicate that NMDA receptor antagonists prevent the activation of dopamine metabolism in the nucleus accumbens caused by immobilization stress but not by beta-CCM-induced anxiogenic stimulation. These results suggest that NMDA receptor antagonists may possess an anxiolytic-like action in the rodent, which is exerted via neuroanatomical circuits distinct from those acted upon by diazepam.     

The involvement of nitric oxide in the antinociception induced by cyclosporin A in mice

Cyclosporin A (CsA) and other immunophilin-binding agents are known to inactivate neuronal nitric oxide synthase (nNOS). Nitric oxide (NO) is involved in the nociception at the spinal level. We evaluated the effect of acute intraperitoneal (i.p.) administration of CsA on the tail-flick response in mice and the involvement of NO and opioid receptors in this effect. CsA (5, 10, 20 and 50 mg/kg i.p.) induced a significant increase in tail-flick response. Nitric oxide synthase (NOS) inhibitor N(G)-nitro-L-arginine (LNNA; 10, 40 and 80 mg/kg i.p.) significantly potentiated the CsA-induced (5 mg/kg) increase in tail-flick latency (TFL). While NOS substrate L-arginine (100, 200, 400 mg/kg i.p.) inhibited the CsA-induced (20 mg/kg) antinociception completely and in a dose-dependent manner. Concomitant administration of L-NNA and L-arginine blocked the inhibition exerted by the latter on the CsA-induced antinociception. The opioid receptor antagonist naloxone (4 mg/kg i.p.) did not alter the CsA effect. These results indicate that acute administration of CsA induces an antinociceptive effect that involves the L-arginine-NO pathway but is not mediated by opioid receptors.     

Effects of antidepressant drugs on a quickly-learned conditioned-suppression response in mice

Mice experienced to electric shock, exhibited a marked suppression of motor activity when placed in the same cage 24 hr after administration of shocks. Acute administration of imipramine-HCl (10 mg/kg, i.p.), desipramine-HCl (5 and 10 mg/kg, i.p.) and amitriptyline-HCl (5 and 10 mg/kg, i.p.) caused marked reduction of the conditioned suppression of shocked mice, but reduced the motor activity of the non-shocked mice. Maprotiline, mianserin and dimetacrine did not cause reduction of the conditioned suppression. Nialamide (100 mg/kg, i.p.) and pargyline-HCl (100 and 200 mg/kg, i.p.)caused marked reduction of the conditioned suppression but did not increase the motor activity of the non-shocked mice, and tranylcypromine-HCl (10 and 20 mg/kg, i.p.) did not cause reduction of the conditioned suppression. Diphenhydramine-HCl (10 and 20 mg/kg, i.p.) reduced the conditioned suppression of shocked mice in a dose-related manner. Chronic administration of imipramine-HCl (1 and 5 mg/kg, i.p.) for 14 days significantly reduced the conditioned suppression but did not influence the motility rate of the non-shocked mice. Also, chronic administration of amitriptyline (1 mg/kg, i.p.), desipramine (5 mg/kg, i.p.) and dimetacrine (10 mg/kg, i.p.), for 10 days, significantly reduced the conditioned suppression, but did not influence the motility rate of the non-shocked mice. Chronic administration of maprotiline reduced the conditioned suppression. On the other hand, chronic administration of mianserin (5 mg/kg, i.p.) and diphenhydramine (10 mg/kg, i.p.) did not cause a reduction of the conditioned suppression.     

The effect of nootropics on impared learning performance in a pole jumping test after repeated ethanol administration

The influence of ethanol administration (4 ml of 10% ethanol/d p.o.) for 6 and 13 d respectively, on learning behaviour of rats has been studied using an active avoidance reaction. While the formation of an active avoidance reaction was only insignificantly impaired by the application of ethanol for 6 d, the learning performance of rats showed a significant deficit after 13d of ethanol ingestion. Repeated nootropic pretreatment (d11 to 14 following first ethanol dose b.i.d.) resulted in an attenuation of learning deficits. The nootropics piracetam (100 mg/kg i.p.) methyl-glucamine orotate (225 mg/kg i.p.), meclofenoxate hydrochloride (100 mg/kg i.p.), pyritinol (100 mg/kg i.p.) and dihydroergotoxine mesilate (1 mg/kg i.p.) showed to be effective. The possible mechanism of action is discussed.     

Involvement of GABAA receptor sites in diazepam hypothermia

1. Intraperitoneal (i.p.) injection of diazepam (1.5-6 mg/kg) decreased the core body temperature (BT) of the rats. The effect was dose-dependent. 2. The hypothermia produced by diazepam (6 mg/kg, i.p.) was decreased in animals pretreated with high doses of bicuculline (BIC, 3 mg/kg, i.p.), while low doses of BIC (1.5 mg/kg, i.p.) potentiated the hypothermia. 3. Picrotoxin (PIC, 1 and 2 mg/kg, i.p.) pretreatment also decreased the hypothermic effect of diazepam. 4. Pretreatment of animals with atropine (AT, 10 mg/kg, i.p.) or propranolol (PRO, 10 mg/kg, i.p.) potentiated the hypothermic response of diazepam. Phenoxybenzamine (PHEN, 0.5 mg/kg, i.p.), methergoline (METH, 0.5 mg/kg, i.p.) or pimozide (PIM, 0.5 mg/kg, i.p.) did not change the diazepam hypothermia. 5. Single administration of BIC, PIC, PRO, PIM or METH also induced hypothermia. 6. One can postulate that diazepam hypothermia may be induced through GABAA receptor sites. However, further studies will clarify this hypothesis.     

Involvement of 5-hydroxytryptamine(1A) receptors in nicotine-induced tail tremor in rats

Involvement of the serotonergic system in tail tremor induced by repeated administration of nicotine was investigated in rats. Tail tremor induced by nicotine (0.5 mg/kg, s.c.) was suppressed by a 5-HT(1A) receptor antagonist, N-?2-[4-(2-methoxyphenyl)-1-piperazinyl-]ethyl?-N-(2-pyridinyl)cycloh exanecarboxamide trihydrochloride (WAY-100635; 0.3-3 mg/kg, i.p.), but not by a 5-HT(2) receptor antagonist, ketanserin (0.1-0.3 mg/kg, i.p). The 5-HT(1A) receptor agonists, buspirone (1-20 mg/kg, i.p.), gepirone (1-10 mg/kg, i.p.), tandospirone (1-10 mg/kg, i.p.) and (+/-)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.01-0.1 mg/kg, s.c.), enhanced the tail tremor. The enhancement of tail tremor by buspirone (10 mg/kg, i.p.) was blocked by WAY-100635 (0.3-3 mg/kg, i.p.). These findings suggest that nicotine-induced tail tremor is mediated by 5-HT(1A) receptors and that 5-HT(1A) receptor antagonists are effective in the treatment of tremor.     

Characteristics of the ambulation-increasing effect of the noncompetitive NMDA antagonist MK-801 in mice: assessment by the coadministration with central-acting drugs.

Characteristics of the ambulation-increasing effect of MK-801, a non-competitive NMDA antagonist, were assessed through the coadministration of MK-801 with various central-acting drugs in mice. The MK-801 (0.3 mg/kg, i.p.)-induced ambulation-increment with a slight ataxia was maximum at around 50 min, and ambulation returned to the control level at about 3 hr after the administration. At 1 mg/kg, the mouse's activity transiently increased, followed by a decrease due to a marked ataxia, which was due to neither stereotypy nor convulsion, for 20-50 min, and then increased again; the ambulation-increment continued even at 4 hr after the administration. Coadministration of MK-801 (0.3 mg/kg, i.p.) with either methamphetamine (2 mg/kg, s.c.), cocaine (20 mg/kg, s.c.), GBR-12909 (10 mg/kg, i.p.), scopolamine (0.5 mg/kg, s.c.), caffeine (10 mg/kg, s.c.) or morphine (10 mg/kg, s.c.) produced a significant enhancement of the effect. However, 0.1 mg/kg of MK-801 had no effect on the interaction with these drugs. On the other hand, the ambulation-increasing effect of MK-801 (0.3 mg/kg) was significantly reduced by haloperidol (0.3 and 0.1 mg/kg, s.c.), ceruletide (0.01 and 0.1 mg/kg, i.p.), reserpine (0.05 and 2 mg/kg, s.c., pretreatment 4 hr before) and nimodipine (1 and 3 mg/kg, i.p.), but it was scarcely modified by alpha-methyl-p-tyrosine (100 and 200 mg/kg, i.p., pretreatment 24 hr and 4 hr before), imipramine (20 mg/kg, i.p.), 6R-L-erythro-5,6,7,8-tetrahydro-biopterin (100 mg/kg, i.p.), pilocarpine (1 and 4 mg/kg, s.c.), N6-(L-2-phenylisopropyl)-adenosine (0.03 and 0.1 mg/kg, s.c.) and naloxone (1 and 5 mg/kg, s.c.).(ABSTRACT TRUNCATED AT 250 WORDS)     

Cocaine-induced hyperactivity and sensitization are dependent on GSK3

Glycogen synthase kinase 3 (GSK3) is a critical mediator of many intracellular signaling systems. The activity of GSK3 is regulated by several kinases, with inactivation occurring via phosphorylation of the inhibitory serine-21 (α-isoform) and serine-9 (β-isoform) residues. Here, we investigated whether acute cocaine administration regulates GSK3 activity and if inhibition of GSK3 by valproate or the selective GSK3 inhibitor SB 216763 would attenuate cocaine-induced behaviors in mice. Mice injected with cocaine (20 mg/kg, i.p.) showed a reduction in the phosphorylation of GSK3β in the caudate putamen, reflecting an increase in the activity of the kinase. To assess the role of GSK3 in cocaine-induced hyperactivity, mice were pretreated with valproate (50–300 mg/kg, i.p.), SB 216763 (0.25–7.5 mg/kg, i.p.), or the appropriate vehicle prior to saline or cocaine (20 mg/kg, i.p.). Valproate or SB 216763 produced significant dose-dependent reductions in cocaine-induced ambulatory and stereotypic activity. Repeated administration of cocaine can result in an augmentation of the locomotor-stimulatory effects of the drug, a phenomenon referred to as sensitization. Mice pretreated with SB 216763 (2.5 mg/kg, i.p.) prior to daily cocaine (20 mg/kg, i.p.) for 5 days showed a significant attenuation of the development of cocaine-induced behavioral sensitization following a cocaine challenge on day 13. These results indicate that cocaine activated GSK3β in the caudate putamen and that pharmacological inhibition of GSK3 reduced both the acute behavioral responses to cocaine and the long-term neuroadaptations produced by repeated cocaine, therefore suggesting a role for GSK3 in the behavioral and neurochemical manifestations associated with cocaine exposure.     

The dopaminergic system plays a role in the effect of lithium on inhibitory avoidance memory in mice

The effects of dopaminergic drugs on the inhibitory avoidance memory affected by lithium were examined in the Naval Medical Research Institute (NMRI) mice using a single-trial step-down inhibitory (passive) avoidance task. The results showed that post-training administration of lithium (10 mg/kg, i.p.) decreased the step-down latency on the test day, which was fully or partly reversed by pre-test administration of the same dose of the drug; suggesting state-dependent learning induced by lithium. Our results also showed that pre-test (i.p.) administration of the dopamine D1 receptor agonist SKF38393 and the dopamine D2 receptor agonist quinpirole by themselves and in combination with ineffective doses of lithium (0.3, 0.6 and 1.25 mg/kg) reversed the decrease of the step-down latency induced by post-training lithium. In contrast, pre-test administration of the dopamine D1 receptor antagonist SCH23390 (0.025, 0.05 and 0.1 mg/kg, i.p.) and the dopamine D2 receptor antagonist sulpiride (6.25 and 12.5 mg/kg, i.p.) alone or in combination with pre-test lithium (10 mg/kg), did not significantly alter the step-down latency on the test day, except for a higher dose of sulpiride (25 mg/kg) which by itself increased the step-down latency. Furthermore, pre-test administration of a lower dose of sulpiride (3 mg/kg) in combination with ineffective doses of lithium (03, 0.6 and 1.25 mg/kg) also reversed the decrease in the step-down latency induced by post-training lithium. In conclusion, the dopamine D1 and D2 receptor mechanism(s) may be involved, at least partly, in the effect of lithium on retrieval of the inhibitory avoidance memory influenced by the drug.     

Nitecapone and selegiline as effective adjuncts to L-DOPA in reserpine-induced catatonia in mice

Reserpine-induced catatonia is a widely accepted animal model of Parkinson's disease. In the present study, reserpine (5 mg/kg i.p.) and alpha-methylpara-tyrosine (AMPT) (200 mg/kg i.p.) induced catatonia in mice 20 h and 1 h before the experiment, respectively, as assessed using the rota-rod and bar tests after reserpine treatment. There was a significant decrease in fall-off time in the rota-rod test and a significant increase in time spent on the bar in the bar test as compared to the untreated control mice. Combination therapy with L-DOPA (100 mg/kg i.p.) and carbidopa (10 mg/kg i.p.) was less effective in reversing catatonia as compared to higher doses of L-DOPA (200 mg/kg i.p.) and carbidopa (20 mg/kg i.p.), which showed intense hyperactivity in reserpinized mice. Pretreatment with nitecapone (30 mg/kg i.p.), a COMT inhibitor, or selegiline (10 mg/kg i.p.), a MAO-B inhibitor potentiated the motor stimulant actions of subthreshold doses of the L-DOPA (100 mg/kg i.p.) and carbidopa (10 mg/kg i.p.) combination. Amantadine (40 mg/kg i.p.), but not bromocriptine, potentiated the effects of L-DOPA treatment. The NMDA antagonistic action of amantadine may have beneficial effects. It is concluded that COMT and MAO-B enzymes play an important role in the metabolism of dopamine and administration of a COMT or MAO-B inhibitor may prove to be a better adjunct to L-DOPA therapy than a dopamine receptor agonist in Parkinson's disease.     

Influence of ACTH on the effects of imipramine, desipramine and lithium on duration of immobility of rats in the forced swim test.

We examined the effects of adrenocorticotropic hormone (ACTH) on the immobilization of rats in the forced swim test with the administration of imipramine, desipramine, or lithium. A single administration of either imipramine (10-30 mg/kg, i.p.) or desipramine (30 mg/kg, i.p.) significantly decreased the duration of immobility in normal rats in a dose-dependent manner. Lithium (10-100 mg/kg, p.o.), however, had no affect on the performance of rats in the forced swim test. ACTH (100 microg/day), administered subcutaneously to rats for 1, 3, 7, and 14 days, had no apparent effect on the duration of immobility in this test. The immobility-decreasing effect induced by a single administration of either imipramine (10-30 mg/kg, i.p.) or desipramine (30 mg/kg, i.p.) was blocked by chronic administration of ACTH for 3-14 days. The reduction of immobility, induced by chronic administration of imipramine (10 mg/kg, i.p.) for 15 days, was blocked by treatment with ACTH for 14 days. When lithium (100 mg/kg, p.o.) was administered for 15 days concurrently with imipramine (10 mg/kg, i.p.), we observed a significant decrease in immobility in rats treated with ACTH for 14 days. We suggest that chronic treatment of rats with ACTH may prove to be an effective model of tricyclic antidepressants-treatment-resistant depression.     

Antagonism of methomyl-induced toxicosis by diphenhydramine in rats

The efficacy of diphenhydramine in the prevention and treatment of methomyl-induced toxicosis was evaluated in female rats. Diphenhydramine at 10 and 20 mg/kg subcutaneously (s.c.) given immediately after methomyl increased the LD(50) of methomyl (6.29 mg/kg intraperitoneally (i.p.)) in the rats by 71 and 75% respectively. Diphenhydramine at 20 mg/kg s.c. given immediately after methomyl (6 mg/kg i.p.) decreased the occurrence of cholinergic signs of toxicosis, and prevented convulsions, gasping and death by 100% in comparison with the control (methomyl-saline) group. Diphenhydramine administration at 2.5, 5 and 10 mg/kg s.c. 20 min before methomyl (8 mg/kg i.p.) significantly and dose-dependently decreased the number of convulsion episodes in rats in comparison with the control group. This effect was similar to those of atropine and diazepam pretreatments at 20 mg/kg s.c. Diphenhydramine and atropine at 20 mg/kg i.p. given 5 min after the methomyl administration (8 mg/kg i.p.) were close to each other in reducing the signs of cholinergic toxicity as well as the severity of toxicosis induced by methomyl in rats. Methomyl at 4 and 8 mg/kg i.p. significantly decreased erythrocyte (40 and 43%) and plasma (23 and 31%) cholinesterase activities in comparison with the control group. Diphenhydramine (10 mg/kg s.c.) injected 15 min before methomyl significantly decreased the inhibitory effect of methomyl (4 and 8 mg/kg i.p.) on erythrocyte cholinesterase to 17 and 27%, respectively. The inhibitory effect on plasma cholinesterase was not affected by the diphenhydramine pretreatment. The data suggest that diphenhydramine could be of therapeutic value in reducing the toxic effects of methomyl.     

Short-term erythrosine B-induced inhibition of the brain regional serotonergic activity suppresses motor activity (exploratory behavior) of young adult mammals

Previous studies showed that repeated ingestion of erythrosine B (artificial food color) developed behavioral hyperactivity, but nothing is known about its single administration effect as well as the neurochemical (s) involvement. The present study provides evidence that a single higher dosage (10, 100 or 200 mg/kg, p.o.) of erythrosine administration to young adult male rats reduced motor activity (MA) maximally at 2 h and brain regional (medulla-pons, hippocampus and hypothalamus) serotonergic activity (measuring steady-state levels of 5-HT and 5-HIAA, pargyline-induced 5-HT accumulation and 5-HIAA declination rate and 5-HT receptor binding) under similar experimental condition. The degree of erythrosine-induced inhibition of both MA and brain regional serotonergic activity was dosage dependent. Lower dosage (1 mg/kg, p.o.) did not affect either of the above. Erythrosine (100 or 200 mg/kg, p.o.)-induced MA suppression was also observed in the presence of specific MAO-A inhibitor, clorgyline (5 mg/kg, i.p.) or MAO-B inhibitor, deprenyl (5 mg/kg, i.p.); but their co-application (5 mg/kg, i.p., each) effectively prevented the erythrosine-induced motor suppression. Altogether these results suggest that a single higher dosage of erythrosine (10-200 mg/kg, p.o.) may reduce MA by reducing serotonergic activity with modulation of central dopaminergic activity depending on the brain regions.     

Psychopharmacological profile of the selective serotonin reuptake inhibitor, paroxetine: implication of noradrenergic and serotonergic mechanisms

The present study was designed to evaluate the psychopharmacological profile of the selective serotonin reuptake inhibitor paroxetine, and thus assess potential noradrenergic and/or serotonergic activity. Paroxetine dose-dependently increased mobility time in the mouse forced swimming test (8, 16, 32 and 64 mg/kg, i.p.) and reduced spontaneous locomotor activity when administered at a high dose (64 mg/kg, i.p.). Prior administration of 8-hydroxy-2-(di-n-propylamino)tetralin (1 mg/kg, i.p.), (+/-) pindolol (32 mg/kg, i.p.) or 5-methoxy-3-(1,2,3,6-tetrahydro-4-pyridyl)-1H-indole (RU 24969) (1 mg/kg, i.p.) potentiated the antidepressant-like effects of subactive doses of paroxetine (1, 2 and 4 mg/kg, i.p.) in the mouse forced swimming test. These effects were antagonized by prior administration of 1-(2-methoxyphenyl)-4-[-(2-phthalimido)butyl]piperazine) (0.5 mg/kg, i.p.). Complementary studies suggested that RU24969-induced anti-immobility effects were a result of an increase in locomotor activity; other interactions were without increase/decrease in locomotor activity. Acute administration of paroxetine (8, 16, and 32 mg/kg, i.p.) antagonized the hypothermia induced by the D2/D1 receptor agonist, apomorphine (16 mg/kg, s.c.), while repeated treatment with paroxetine (32 mg/kg) attenuated clonidine-induced (0.5 mg/kg, i.p.) hypothermia. Pre-treatment with the serotonergic neurotoxin, para-chlorophenylalanine attenuated the anti-immobility effects of low doses of paroxetine (8 and 16 mg/kg, i.p.) in the forced swimming test, whereas a higher dose of paroxetine remained active (32 mg/kg, i.p.). The results of the present study indicated that paroxetine displayed both noradrenergic-like and serotonergic-like activity in the pre-clinical psychopharmacological tests employed.     

两面针结晶8的解痉和镇痛作用研究

结晶-8,是从两面针提出的一种单体。当浓度为1×10^-6～1×10^-4g/ml对正常离体豚鼠回肠活动无影响,但对乙酰胆硷、匹鲁卡品、氯化钡及组织胺所致肠肌收缩有明显的松弛作用;结晶-8腹腔注射10 mg/kg有明显抑制小鼠扭体反应;8～20 mg/kg明显提高家兔及大鼠痛阈,200μg/kg脑室注射亦有明显提高大鼠痛阈。其镇痛作用不被丙烯吗啡(5 mg/kg)所拮抗,而被利血平(4 mg/kg)所对抗。表明结晶-8的解痉作用直接作用于肠平滑肌。而镇痛作用具有中枢性,与吗啡受体无直接关系,但与脑内单胺类介质有关。     

Imipramine-induced antinociception in the formalin test. Receptor mechanisms involved and effect of swim stress

This study concerned the effect of swim stress on imipramine-induced antinociception in mice. The data showed that intraperitoneal (i.p.) administration of different doses of imipramine (10-40 mg/kg) and 0.5-3 min of swim stress (17 degrees C) induced antinociception in the first and second phases of the formalin test. Low period of swim stress (10 s) with low doses of imipramine (2.5, 5 and 10 mg/kg i.p.), which did not have any effect by themselves, in combination showed antinociception in the second phase of the test. Either yohimbine (0.5 mg/kg i.p.) or naloxone (1 mg/kg i.p.) reversed the response induced by the combination of low doses of imipramine plus swim stress. Yohimbine (1 mg/kg i.p.) decreased the response of imipramine (20 mg/kg i.p.) but not that of 30 s swim stress in the second phase. However, naloxone (1 mg/kg i.p.) reduced the antinociception induced by imipramine (20 mg/kg i.p.) or 30 s swim stress in the second phase of the test, the combination of imipramine with swim stress was not altered by yohimbine or naloxone. Prazosin induced antinociception by itself in the first phase of the test and increased swim-stress-induced antinociception with no interaction. It is concluded that antinociception induced by imipramine in the second phase of formalin test may be mediated through alpha(2)-adrenoceptor antagonists. The results indicate that the responses of swim stress and imipramine may be mediated by an opioid mechanism, but the combination of both drugs induced higher antinociceptive effects.     

Protection by opioids against gastric lesions caused by necrotizing agents

The synthetic opioid met-enkephalin analog [D-Ala2, MePhe4, Met(0)5ol] enkephalin (DAMME) and the opiate morphine injected intraperitoneally to rats at doses of 0.5-2 and 5-20 mg/kg, respectively, showed a protective effect on gastric damage induced by oral administration of necrotizing agents (0.6 N HCl or 0.2 N NaOH solutions, 1 ml/rat). The protection was prevented by naltrexone (10 mg/kg s.c.), an opioid antagonist with long-lasting activity. Histological sections of mucosal samples from animals pretreated with morphine (10 mg/kg i.p.) and DAMME (1 mg/kg i.p.) showed less alteration of the columnar epithelium, with a normal glandular structure, than untreated rats. A mediation of prostaglandins is suggested, since indomethacin (10 mg/kg s.c.) significantly reduced the protective effects of opioids.