Beneficial effects of the sigma1 receptor agonists igmesine and dehydroepiandrosterone against learning impairments in rats prenatally exposed to cocaine

In utero cocaine (IUC) exposure results in offspring rats in complex neurochemical and behavioral alterations, particularly affecting learning and memory processes. We examined here the impact of IUC exposure on memory functions in male and female offspring rats and report that selective sigma₁ (σ₁) receptor agonists are effective in reversing the deficits. Dams received a daily cocaine, 20 mg/kg ip, injection between gestational days E17 to E20. Learning was examined in offspring between day P30 and P41 using delayed alternation in the T-maze, water-maze learning and passive avoidance. Both male and female rats prenatally exposed to cocaine showed delayed alternation deficits and impairments of acquisition of a fixed platform position in the water maze, as shown by higher acquisition latencies and diminutions of time spent in the training quadrant during the probe test. The acquisition of a daily changing platform position also demonstrated impaired working memory. Finally, passive avoidance deficits were observed. Pretreatment with the synthetic σ₁ agonist igmesine (0.1–1 mg/kg ip) or the neuroactive steroid dehydroepiandrosterone (DHEA 10–40 mg/kg ip) reversed the prenatal cocaine-induced learning deficits in offspring rats for each test. The σ₁ antagonist BD1063 (1 mg/kg ip) failed to affect performances alone but blocked the igmesine and DHEA effects, confirming the involvement of the σ₁ receptor. IUC exposure thus results in marked memory deficits, affecting spatial and nonspatial short- and long-term memories in juvenile male and female offspring rats. The activation of the σ₁ neuromodulatory receptor allows a complete behavioral recovery of the memory functions in prenatally cocaine-exposed rats.     

Involvement of sigma receptors in the behavioral effects of cocaine: evidence from novel ligands and antisense oligodeoxynucleotides

Pharmacological and molecular biological tools were used to validate the involvement of σ receptors in the actions of cocaine. Radioligand binding studies demonstrated significant levels of σ receptors in the brain and heart, where cocaine interacts preferentially with the σ₁ subtype. In behavioral pharmacological studies using mice, nine novel σ receptor antagonists significantly attenuated cocaine-induced convulsions, while structural analogs with weak interactions with σ receptors were ineffective. In contrast to the protection provided by the antagonists, a classical σ receptor agonist exacerbated the convulsive effects of cocaine. The antagonists also attenuated cocaine-induced lethality, with the best compound protecting against death even when administered as a post-treatment. At doses where the antagonists had no effect on baseline locomotor activity, they significantly attenuated the locomotor stimulatory effects of cocaine, suggesting their ability to block the psychomotor as well as the toxic effects of cocaine. To further validate that the anti-cocaine effects were achieved by interfering with cocaine’s access to σ receptors, antisense oligodeoxynucleotides against σ₁ receptors were shown to attenuate the convulsive and locomotor stimulatory effects of cocaine. Together, the studies support the involvement of σ receptors, particularly the σ₁ subtype, in the behavioral effects of cocaine.     

Stimulation of Sigma-1 receptor signaling by dehydroepiandrosterone ameliorates pressure overload-induced hypertrophy and dysfunctions in ovariectomized rats

Objective: Decreased dehydroepiandrosterone (DHEA) levels are associated with endothelial dysfunction and increased cardiovascular mortality in postmenopausal women. We investigated the role of DHEA, also known as sigma-1 receptor (Sig-1R) agonist, in myocardial hypertrophy, cardiac functional recovery and defined mechanisms of cardioprotective action. Methods: Wistar rats subjected to bilateral ovariectomy (OVX) were further treated with abdominal aortic stenosis. DHEA (15 and 30 mg/kg) was administered orally once a day for 14 days starting from 2 weeks after aortic banding. Results: Time course study indicated that left ventricle (LV) weight:body weight (BW) ratio increased time-dependently from 1 to 4 weeks after pressure-overload (PO) with significant inversed regulation of Sig-1R expression. Treatment with the Sig-1R agonist, DHEA, significantly attenuated PO-induced myocardial hypertrophy with increased expression of Sig-1R in the LV. DHEA also attenuated hypertrophy-induced impaired LV end diastolic pressure, LV developed pressure and LV contractility (± dp/dt_max). DHEA treatment significantly restored PO-induced impaired eNOS and Akt activity in the LV. Conclusion: We report, for the first time to our knowledge, the potential role of Sig-1R expression in the heart to attenuate PO-induced hypertrophy in ovariectomized rats. DHEA treatment protects against PO-induced cardiac injury via upregulation of Sig-1R and stimulation of Sig-1R-mediated Akt-eNOS signaling.     

Early‐life exposure to low levels of permethrin exerts impairments in learning and memory with the effects on neuronal and glial population in adult male mice

Permethrin, a pyrethroid chemical, is widely used as a pesticide because of its rapid insecticidal activity. Although permethrin is considered to exert very low toxicity in mammals, the effects of early, low‐level, chronic exposure on the adult central nervous system are unclear. In this study, we investigated the effects of low‐level, chronic permethrin exposure in early life on the brain functions of adult mice, using environmentally relevant concentrations. We exposed mice to the acceptable daily intake level of permethrin (0.3 ppm) in drinking water during the prenatal and postnatal periods. We then examined the effects on the central nervous system in adult male offspring. In the permethrin group, we detected behavior that displayed incomplete adaptation to a novel environment, as well as an impairment in learning and memory. In addition, immunohistochemical analysis revealed an increase in doublecortin‐ (an immature neuron marker) positive cells in the hippocampal dentate gyrus in the permethrin exposure group compared with the control group. Additionally, in the permethrin exposure group there was a decrease in astrocyte number in the hilus of the dentate gyrus, and remaining astrocytes were often irregularly shaped. These results suggest that exposure to permethrin at low levels in early life affects the formation of the neural circuit base and behavior after maturation. Therefore, in the central nervous system of male mice, low‐level, chronic permethrin exposure during the prenatal and postnatal periods has effects that were not expected based on the known effects of permethrin exposure in mature animals.     

Protective effects of icariin against learning and memory deficits induced by aluminium in rats

1. The present study examined the protective effects of icariin against the learning and memory deficits in aluminium-treated rats and its potential mechanisms of action. 2. Qualified rats were treated with 1600 p.p.m. AlCl(3) in drinking water for 8 months and the ability of spatial learning and memory was tested by the Morris water maze. In the place navigation test, aluminium administration significantly increased the mean escape latency and searching distance. In space probing test, aluminium markedly decreased the searching time and searching distance in the quadrant where the platform was originally located. All tests indicated deficits in rat spatial learning and memory induced by aluminium. Icariin treatment (60 and 120 mg/kg, by gavage for 3 months) dose-dependently protected against the development of aluminium-induced spatial learning and memory deficits. 3. To examine the mechanisms responsible for the protection afforded by icariin, the superoxide dismutase (SOD) activity and malondialdehyde (MDA) content in the hippocampus were assayed biochemically and the level of Abeta(1-40) in the hippocampus was determined immunohistochemically. Icariin treatment significantly increased SOD activity and decreased MDA and Abeta(1-40) content in the hippocampus of aluminium-intoxicated rats. 4. In conclusion, the present study demonstrates that icariin is effective in improving the spatial learning and memory of aluminium-intoxicated rats. The mechanisms responsible appear to be due, at least in part, to an increased anti-oxidant capacity and decreased lipid peroxidation and Abeta(1-40) levels in the rat hippocampus.     

The disruptive effects of the CB<Subscript>1</Subscript> receptor antagonist rimonabant on extinction learning in mice are task-specific

Rationale Disruption of CB₁ receptor signaling through the use of CB₁ (−/−) mice or the CB₁ receptor antagonist rimonabant (SR141716) has been demonstrated to impair extinction of learned responses in conditioned fear and Morris water maze tasks. In contrast, CB₁ (−/−) mice exhibited normal extinction rates in an appetitively motivated operant conditioning task. Objectives The purpose of this study was to test whether rimonabant would differentially disrupt extinction learning between fear-motivated and food-motivated tasks. Materials and methods Separate groups of C57BL/6J mice were trained in two aversively motivated tasks, conditioned freezing and passive avoidance, and an appetitively motivated operant conditioning task at a fixed ratio (FR-5) schedule of food reinforcement. After acquisition, the respective reinforcers in each task were withheld, and an intraperitoneal injection of vehicle or rimonabant was given 30 min before each extinction session. Results Rimonabant (3 mg/kg) treatment significantly disrupted extinction in both the conditioned freezing and passive avoidance tasks but failed to affect extinction rates in the operant conditioning task, whether using daily or weekly extinction sessions. Interestingly, rimonabant (3 mg/kg) prevented the significant increases in lever pressing (i.e., extinction burst) that occurred during the first extinction session of the operant conditioning task. Conclusions These results support the hypothesis that the CB₁ receptor plays a vital role in the extinction of aversive memories but is not essential for extinction of learned responses in appetitively motivated tasks.     

腺苷A_1受体阻断剂对大鼠海马BDNF蛋白表达及内质网的影响

目的探讨腺苷A1受体阻断对大鼠海马BDNF蛋白表达及内质网功能的影响。方法采用免疫组化技术观察腺苷A1受体特异性阻断剂8-环戊-1,3-二丙基黄嘌呤(DPCPX)对大鼠海马颗粒细胞BDNF蛋白表达的影响;采用透射电镜技术观察DPCPX对大鼠海马神经元内质网数量的影响。结果DPCPX(0.1 mg.kg-1,ip,15 d)可增加海马颗粒细胞BDNF蛋白表达阳性细胞的数目。DPCPX(0.5 mg.kg-1,ip,15 d)能增加BDNF蛋白在海马颗粒细胞的表达,使阳性细胞数目明显增加、染色加深;同时增加大鼠海马神经元中内质网的数量,使内质网密度增加。结论DPCPX可促进大鼠海马颗粒细胞内BDNF蛋白表达和诱导海马神经元内质网功能增强。     

Effects of second-generation histamine H1 receptor antagonists on the active avoidance response in rats

1. The aim of the present study was to establish a new schedule of active avoidance response in rats to estimate the central effects of second-generation histamine H1 receptor antagonists. 2. With the new schedule, a rat was placed into a dark room. A sliding door was opened after a delay of 5 s and, unless the animal moved into the lit room, an electric shock was delivered for 3 s. With the conventional schedule, the sliding door was opened immediately after the rat was placed into the dark room. 3. Ketotifen, at a dose of 50 mg/kg, showed no significant effect on the retrieval of active avoidance response with the conventional schedule. However, with the new schedule, the drug caused significant inhibition of retrieval of the response, even at a dose of 10 mg/kg. 4. Epinastine showed no significant effect on retrieval of the active avoidance response, even at a dose of 50 mg/kg with the new schedule. 5. Cetirizine, at a dose of 50 mg/kg, caused a significant effect, indicating that cetirizine, at this dose, markedly inhibits memory retrieval. 6. Both olopatadine and loratadine had potent effects; at doses of 20 and 50 mg/kg, respectively, these agents showed significant inhibitory effects on retrieval of the response. 7. In conclusion, we have developed a new schedule of active avoidance response that can be used to estimate the central effects of second-generation histamine H1 receptor antagonists.     

The anti-amnesic and neuroprotective effects of donepezil against amyloid beta25-35 peptide-induced toxicity in mice involve an interaction with the sigma1 receptor

BACKGROUND AND PURPOSE: The acetylcholinesterase inhibitor, donepezil, is also a high affinity sigma(1) receptor agonist. We examined the involvement of sigma(1) receptors in its anti-amnesic and neuroprotective properties against amyloid beta(25-35) peptide-induced toxicity in mice. EXPERIMENTAL APPROACH: Mice were given an intracerebroventricular (i.c.v.) injection of Abeta(25-35) peptide (9 nmol) 7-9 days before being tested for spontaneous alternation and passive avoidance. Hippocampal lipid peroxidation was measured 7 days after Abeta(25-35) injection to evaluate oxidative stress. Donepezil, the sigma(1) agonist PRE-084 or the cholinesterase (ChE) inhibitors tacrine, rivastigmine and galantamine were administered either 20 min before behavioural sessions to check their anti-amnesic effects, or 20 min before Abeta(25-35) injection, or 24 h after Abeta(25-35) injection and then once daily before behavioural sessions, to check their pre- and post-i.c.v. neuroprotective activity, respectively. KEY RESULTS: All the drugs tested were anti-amnesic, but only the effects of PRE-084 and donepezil were prevented by the sigma(1) antagonist BD1047. Only PRE-084 and donepezil showed neuroprotection when administered pre i.c.v.; they blocked lipid peroxidation and learning deficits, effects inhibited by BD1047. Post i.c.v., PRE-084 and donepezil showed complete neuroprotection whereas the other ChE inhibitors showed partial effects. BD1047 blocked these effects of PRE-084, attenuated those of donepezil, but did not affect the partial effects of the other ChE inhibitors. CONCLUSIONS AND IMPLICATIONS: The potent anti-amnesic and neuroprotective effects of donepezil against Abeta(25-35)-induced toxicity involve both its cholinergic and sigma(1) agonistic properties. This dual action may explain its sustained activity compared to other ChE inhibitors.     

Recent advances towards the discovery of ORL-1 receptor agonists and antagonists

Since their discovery a decade ago, remarkable progress has been made toward understanding the biological function and significance of the opioid receptor-like-1 (ORL-1) receptor and its endogenous peptide ligand, nociceptin. The human nociceptin receptor, herein referred to as ORL-1, but also known as OP4 (the fourth member of opioid peptide receptor family) or nociceptin/orphanin FQ peptide (NOP) receptor, was first identified as an orphan opioid receptor with close homology to the classical μ-, κ-, and δ-opioid receptors. ORL-1 does not bind endogenous ligands of the other opioid receptors with high affinity, but instead prefers the 17 amino acid peptide nociceptin. The obvious homologies of ORL-1 to opioid receptors, and its ligand nociceptin to opioid peptide ligands, led to a period of intense investigation that resulted in a number of significant reports describing the biology of the receptor and ligand. The emerging pharmacological evidence from these reports suggests that ORL-1 agonists may be clinically useful for treatment of stress, anxiety, substance abuse (opioid and alcohol), anorexia, cachexia, cough, asthma, and possibly neuropathic pain/allodynia. The peripheral effects of nociceptin suggest that agonists may have utility in the treatment of gastrointestinal motility disorders, water retention, and hypertension. ORL-1 antagonists may be useful in enhancing cognitive function and treating locomotor disorders such as Parkinsonism. In addition to research into the fundamental biology of ORL-1 and nociceptin, noteworthy advances have been made in the discovery of new peptide and non-peptide agonists and antagonists of the ORL-1 receptor leading to a better understanding of its involvement in a variety of biological processes. This review highlights the rationale for the development of ORL-1 ligands and recent progress made by different research groups towards the development of peptidic and non-peptidic ORL-1 agonists or antagonists over the last four years. To add perspective on the commercial potential of this research area, the development status of advanced new molecules is addressed together with any pharmacological characterisation of these entities.     

5-HT1A receptor agonists improve the performance of normal and scopolamine-impaired rats in an operant delayed matching to position task

A series of experiments examined the effects of 5-HT_1A ligands alone and in combination with the muscarinic antagonist scopolamine on short term working memory in the rat. The behavioural paradigm was a discrete trial, operant delayed matching to position task, with delays of 0, 5, 15 and 30 s. The 5-HT_1A ligands tested were the full agonist, 8-OH DPAT (0, 0.1, 0.3 and 1 mg/kg), the partial agonist, ipsapirone (0, 1, 3 and 10 mg/kg), and the purported antagonist, NAN 190 (0, 1, 2, and 4 mg/kg). 1-PP (0, 0.1, 0.3, 1 mg/kg), the major metabolite of ipsapirone, was also tested. The lowest dose of 8-OH DPAT significantly improved matching accuracy at the longest delay, whereas the highest dose impaired matching accuracy and increased the latency to respond. Ipsapirone also significantly improved the accuracy of performance at a dose of 3 mg/kg, but the doses of 1 and 10 mg/kg did not significantly affect performance. NAN-190, at the highest dose tested (4 mg/kg), impaired matching accuracy, whereas the two lower doses did not significantly affect performance. The highest dose also increased the latency to respond. 1-PP had no effect on performance. Scopolamine HBr (0.14 mg/kg) caused a delay dependent impairment in matching accuracy, and had no effect on missed trials or the latency to respond. Low doses of 8-OH DPAT (0.1 and 0.3 mg/kg) significantly attenuated the scopolamine induced accuracy impairment, whereas 1 mg/kg 8-OH DPAT potentiated the impairment. Ipsapirone (3 mg/kg) also significantly improved the performance of scopolamine impaired rats. NAN-190 increased the latency to respond and reduced the number of nose pokes made during the delays in scopolamine-treated rats, and tended to potentiate the scopolamine-induced accuracy impairment. 1-PP did not affect the performance of scopolamine treated rats. Taken together, these results suggest that modulation of 5-HT_1A receptors influences short term spatial working memory in the rat.     

Design and synthesis of an alpha1a-adrenergic receptor subtype-selective antagonist from BE2254

An alpha1a-adrenoceptor-selective antagonist has the potential to be a new benign prostatic hyperplasia drug with reduced side-effects. Modification of the non-selective antagonist BE2254 led to the development of a series of tetralin analogs. Evaluation of these compounds in cloned human alpha1-adrenoceptors resulted in the discovery of an analog that showed selectivity toward the human alpha1a-adrenergic receptor subtype. The compound also showed moderate potency to block human prostate muscle contraction.     

Alterations of nAChRs and ERK1/2 in the brains of rats with chronic fluorosis and their connections with the decreased capacity of learning and memory

In order to reveal the mechanism of the decreased ability of learning and memory induced by chronic fluorosis, nicotinic acetylcholine receptors (nAChRs) and the pathway of extracellular signal regulated protein kinase (ERK1/2) were investigated by using the rats fed with different concentrations of sodium fluoride for 6 months. Spatial learning and memory of the rats were evaluated by Morris Water Maze test. The expressions of nAChRs, ERK1/2 and mitogen-induced extracellular kinase (MEK1/2) at protein and mRNA levels were detected by Western blotting and real-time PCR, respectively. The results showed that as compared with controls, the learning and memory capacity in the rats with fluorosis was decreased. The protein expressions of α7 and α4 nAChR subunits in rat brains with fluorosis were decreased by 35% and 33%, whereas the corresponding receptor subunit mRNAs did not exhibit any changes. The increases of phospho- and total-ERK1/2 as well as phospho-MEK1/2 at the protein levels were found in the brains of rats with fluorosis as compared to controls, and no difference of ERK1/2 mRNA was found. In addition, the activation rate of phospho-ERK1/2 was decreased in the brains affected with fluorosis. The modifications of nAChRs and ERK1/2 pathway might be connected with the molecular mechanisms in the decreased capacity of learning and memory of the rats with fluorosis.     

知母皂苷元及其异构体对老年大鼠学习记忆和脑内M_1受体密度的影响

目的　观察知母皂苷元 (ZMS)及其异构体 (ZMR)对老年大鼠学习记忆和脑内M1受体密度的作用。方法　选择 2 4mon龄SD老年大鼠 ,将动物分为老年对照组、ZMS组和ZMR组 ,并以 3～ 4mon龄青年大鼠作为正常对照 ,用迷宫法测定学习记忆能力 ,采用放射配基结合分析法测定脑内M1受体密度。结果　用药组大鼠连续口服ZMS和ZMR 4 0d后 ,与老年对照组比较 ,其学习记忆能力明显增强 ,脑内M1受体密度升高。结论　知母皂苷元及其异构体对老年性痴呆的胆碱能系统功能渐进性退化有一定的预防和治疗作用     

Behavioral and biochemical effects of the 5-HT1A receptor agonists flesinoxan and 8-OH-DPAT in the rat.

The 5-HT_1A receptor agonists flesinoxan (0.2–3.2 mg kg⁻¹ s.c.) and 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (0.025–0.4 mg kg⁻¹ s.c.) produced (1) a dose-dependent facilitation of male rat ejaculatory behavior and (2) characteristic, dose-dependent effects on spontaneous motor activity. Thus, total locomotor activity and rearing activity were decreased. However, forward locomotion and peripheral locomotion were increased relative to the total horizontal activity. Furthermore, (3) 5-HTP accumulation, after inhibition of cerebral decarboxylase, was dose dependency decreased by both compounds in the ventral striatum and in the prefrontal cortex. There was a statistically significant decrease in DOPA accumulation in the ventral striatum after administration of a high dose of flesinoxan (3.2 mg kg⁻¹), and a tendency for 8-OH-DPAT to produce the same effect. The efficacy of the compounds to affect male rat sexual behavior, spontaneous motor activity in the open-field and forebrain 5-HT synthesis was approximately the same, whereas flesinoxan was about an order of magnitude less potent than 8-OH-DPAT.     

σ Receptor ligands and imidazoline secretagogues mediate their insulin secretory effects by activating distinct receptor systems in isolated islets

The effects of two potent σ receptor agonists (+)-3-PPP ((R)-3-(3-hydroxyphenyl)-N-(1-propyl)piperidine) and DTG (N,N′-di-(o-tolyl)guanidine) on the insulin secretory responses in rat islets of Langerhans were investigated. Both σ receptor ligands were able to potentiate the insulin secretory response of islets incubated at 6 mM glucose, in a dose-dependent manner and were also able to reverse the effects of diazoxide on insulin release. When islets were treated with efaroxan, a well-characterised imidazoline insulin secretagogue, and either (+)-3-PPP or DTG together, there was an unexpected and profound absence of stimulation of insulin release as compared to when islets were incubated with each compound alone. Experiments performed with islets where there was desensitization of DTG/σ receptor or efaroxan/imidazoline binding site mediated responses suggest that at least two distinct receptor systems appear to be involved. The complex interactions of these two classes of drug require further investigation.     

Growth retardation of fetal rats exposed to nicotine in utero: possible involvement of CYP1A1, CYP2E1, and P-glycoprotein

To elucidate the possible metabolic mechanism of intrauterine growth retardation induced by nicotine, this study determines the effects of prenatal nicotine exposure on fetal development and cytochrome P4501A1 (CYP1A1), CYP2E1, and P-glycoprotein (Pgp) expression in maternal liver and placenta. Pregnant rats were given 1.0 mg/kg nicotine subcutaneously twice a day from gestational day (GD) 8 to GD 15, 18, or 21. In nicotine-treated groups, fetal developmental parameters including body weight were significantly lower. The activities of CYP1A1 and CYP2E1 in maternal liver microsomes in nicotine-treated groups increased significantly with progressing gestation when compared with the corresponding control, but returned to the level similar to the control in late pregnancy. Nicotine-treated groups induced pathological changes and increased malondialdehyde (MDA) content in the placenta when compared with the control. The gene expressions of CYP1A1 and CYP2E1 in the placenta increased significantly in nicotine-treated groups on GD 15 and GD 18, but returned to the level similar to the corresponding control on GD 21. In nicotine group, there was a decrease of mdr1a expression on GD 15, GD 18, and GD 21, with the most significant decrease on GD 15. In contrast, no significant difference was found in mdr1b mRNA expression between the nicotine-treated animals and the corresponding control. In comparison with the corresponding control, the placental Pgp protein significantly decreased on GD 15 and GD 18. Our results showed that prenatal nicotine exposure resulted in inhibition of fetal growth significantly. The induction of CYP2E1 and CYP1A1 gene expression by nicotine in the maternal liver and placenta may be involved with the observed increase in oxidative stress and lipid peroxidation. The inhibition of the placental Pgp expression by nicotine may also contribute to an increased susceptibility of the fetus to environmental toxins.     

Antidepressant-like effects of endogenous histamine and of two histamine H1 receptor agonists in the mouse forced swim test

1. Effects of substances which are able to alter brain histamine levels and two histamine H₁ receptor agonists were investigated in mice by means of an animal model of depression, the forced swim test.
2. Imipramine (10 and 30 mg kg⁻¹, i.p.) and amitriptyline (5 and 15 mg kg⁻¹, i.p.) were used as positive controls. Their effects were not affected by pretreatment with the histamine H₃ receptor agonist, (R)-α-methylhistamine, at a dose (10 mg kg⁻¹, i.p.) which did not modify the cumulative time of immobility.
3. The histamine H₃ receptor antagonist, thioperamide (2–20 mg kg⁻¹, s.c.), showed an antidepressant-like effect, with a maximum at the dose of 5 mg kg⁻¹, which was completely prevented by (R)-α-methylhistamine.
4. The histamine-N-methyltransferase inhibitor, metoprine (2–20 mg kg⁻¹, s.c.), was effective with an ED₅₀ of 4.02 (2.71–5.96) mg kg⁻¹; its effect was prevented by (R)-α-methylhistamine.
5. The histamine precursor, L-histidine (100–1000 mg kg⁻¹, i.p.), dose-dependently decreased the time of immobility [ED₃₀ 587 (499–712) mg kg⁻¹]. The effect of 500 mg kg⁻¹ L-histidine was completely prevented by the selective histidine decarboxylase inhibitor, (S)-α-fluoromethylhistidine (50 mg kg⁻¹, i.p.), administered 15 h before.
6. The highly selective histamine H₁ receptor agonist, 2-(3-trifluoromethylphenyl)histamine (0.3–6.5 μg per mouse, i.c.v.), and the better known H₁ agonist, 2-thiazolylethylamine (0.1–1 μg per mouse, i.c.v.), were both dose-dependently effective in decreasing the time of immobility [ED₅₀ 3.6 (1.53–8.48) and 1.34 (0.084–21.5) μg per mouse, respectively].
7. None of the substances tested affected mouse performance in the rota rod test at the doses used in the forced swim test.
8. It was concluded that endogenous histamine reduces the time of immobility in this test, suggesting an antidepressant-like effect, via activation of H₁ receptors.

     

Effects of 5-HT1A receptor agonists,partial agonists and a silent antagonist on the performance of the conditioned emotional response test in the rat

In the present study, the effects of 5-HT_1A receptor ligands with varying degrees of intrinsic activity at the 5-HT_1A receptor were examined in the conditioned emotional response (CER) test and their effects compared to those of the benzodiazepine receptor agonists, diazepam and chlordiazepoxide. Diazepam (3.0 mg/kg) and chlordiazepoxide (3.0 mg/kg), and the 5-HT_1A receptor partial agonists, ipsapirone (10.0 mg/kg) and gepirone (3.0 mg/kg), alleviated conditioned suppression of lever pressing. The 5-HT_1A receptor partial agonist, buspirone (0.1–1.0 mg/kg), the 5-HT_1A receptor agonist, 8-OH-DPAT (0.01– 0.10 mg/kg), and the 5-HT_1A receptor antagonist, WAY-100635 (0.03–3.0 mg/kg), had no effects on conditioned fear. Neither enhancing the level of food deprivation nor pretreatment with the amnesic agent scopolamine induced anxiolytic-like effects in the present CER test. The anxiolytic-like effects of ipsapirone in this test were completely reversed by WAY-100635. These results indicate that 5-HT_1A agonist, but not antagonist actions, induce an anxiolytic effect in the CER test in rats. Received: 13 March 1996/Final version: 8 July 1996     

苯氧茚酮类衍生物的保护神经细胞和改善小鼠学习记忆作用

目的观察新型乙酰胆碱酯酶抑制剂苯氧茚酮类衍生物(YKY-1~7)对谷氨酸诱导PC12细胞神经毒性的保护作用和对Aβ25~35致痴呆小鼠学习记忆能力的改善作用。方法2mmol·L-1谷氨酸诱导PC12细胞兴奋毒性损伤,观察YKY-1~7对谷氨酸致PC12细胞兴奋毒性的保护作用;小鼠侧脑室注射(icv)凝聚态Aβ25~358μg制作痴呆模型,次日,igYKY-72·5、5、10mg·kg-1,连续10d,测试小鼠被动回避的学习记忆能力,大脑皮层、海马和血清中的乙酰胆碱酯酶(AChE)活性以及大脑皮层局部脑血流量。结果7个苯氧茚酮类衍生物中有6个对谷氨酸诱导的PC12细胞兴奋毒性损伤具有较好的保护作用,其中YKY-7的作用最强。YKY-7可明显改善Aβ25~35所致痴呆小鼠的学习记忆能力,对皮层和海马组织中AChE活性有相对较弱的选择性抑制作用,对皮层局部脑血流量也有一定的提高作用。结论所合成的多数苯氧茚酮类衍生物对神经细胞具有保护作用;对Aβ25~35icv致痴呆模型小鼠学习记忆功能有较大的改善作用,其作用可能与一定程度的选择性抑制大脑皮层和海马AChE活性有关。