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1.
Mediation of the antidepressant-like effect of 8-OH-DPAT in mice by postsynaptic 5-HT1A receptors. 总被引:1,自引:0,他引:1 下载免费PDF全文
G. P. Luscombe K. F. Martin L. J. Hutchins J. Gosden D. J. Heal 《British journal of pharmacology》1993,108(3):669-677
1. The 5-hydroxytryptamine (5-HT)1A agonist 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT) has been evaluated in a mouse model for detecting potential antidepressants (Porsolt test). The effects of various receptor antagonists, lesions of brain monoaminergic neurones and chronic drug treatments on this 8-OH-DPAT-induced response have also been determined. 2. 8-OH-DPAT (0.3-10.0 mg kg-1, s.c.) dose-dependently increased the mobility of mice in the Porsolt test. Other selective 5-HT1A receptor ligands (0.3-30 mg kg-1, s.c.) either mimicked the 8-OH-DPAT response (ipsapirone, at 10 and 30 mg kg-1, s.c.) or were inactive (buspirone and gepirone). However, each of these compounds (< or = 100 mg kg-1, p.o.) inhibited the response to 8-OH-DPAT (3 mg kg-1, s.c.) when given concurrently. 3. The putative 5-HT1A antagonists, spiroxatrine (1-30 mg kg-1, p.o.), (+/-)-pindolol (30 mg kg-1, p.o.) and methiothepin (3-10 mg kg-1, p.o.), each attenuated the 8-OH-DPAT (3 mg kg-1, s.c.)-induced increase in mobility. 4. The dopamine D1 receptor antagonist, SCH 23390 (3-10 mg kg-1, p.o.), weakly reversed the 8-OH-DPAT response.(ABSTRACT TRUNCATED AT 250 WORDS) 相似文献
2.
Sadananda M Natusch C Karrenbauer B Schwarting RK 《Pharmacology, biochemistry, and behavior》2012,101(2):258-264
In recent years, 50-kHz ultrasonic vocalizations of laboratory rats have become increasingly important behavioral measures in research on emotion and motivation, since these calls may help to study appetitive subjective states, for example in relation to addiction. Among others, 50-kHz calls occur when rats experience or expect rewards, including drugs of abuse, and it is assumed that these calls depend on dopamine function, especially in the meso-limbic system. One established means to induce 50-kHz calls is to challenge rats with d-amphetamine, a psychomotor stimulant, which acts largely by boosting dopamine and noradrenaline function in the brain. In a 1st experiment, we studied whether another psycho-stimulatory amphetamine, namely the derivative 3,4-methylene-dioxymethamphetamine (MDMA, Ecstasy), could also enhance 50-kHz calls by using an activity box and testing conditions, which had previously been found to be appropriate in case of d-amphetamine. In support of previous work, we found that MDMA (2.5, 5, 10 mg/kg, ip) dose-dependently increased locomotion and center time, together with decreases in rearing activity, but the drug did not elicit 50-kHz calls. Assuming that this lack of effect is due to the drug's substantial pro-serotonergic effects in the brain, which may inhibit 50-kHz calls, we performed a 2nd experiment where we tested the serotonin 5-HT1A receptor agonist 8-hydroxy-2-tetralin (8-OH-DPAT; 0.05, 0.5, 2.5 mg/kg, ip). This drug dose-dependently stimulates serotonin autoreceptors and heteroreceptors, can act in a psycho-stimulatory way and can enhance dopamine function. In the activity box, 8-OH-DPAT increased locomotor activity (0.5, 2.5 mg/kg) and decreased rearing (2.5 mg/kg); that is, the drug seemed to share some psycho-stimulatory effects with MDMA. Unlike MDMA, 8-OH-DPAT enhanced 50-kHz calls in a dose-dependent way, namely only with the 0.5 mg/kg dose. These results are discussed with respect to their possible neurochemical mechanisms, especially on 5-HT and dopamine in the brain. 相似文献
3.
Kitamura Y Kitagawa K Fujitani Y Shibata K Araki H Sendou T Gomita Y 《Biological & pharmaceutical bulletin》2007,30(1):117-120
We examined the influence of 8-hydroxy-2-di-n-propylamino tetralin (8-OH-DPAT), a serotonin 1A (5-HT1A) receptor full agonist, on the wet-dog shake response induced by the (+/-)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), a 5-HT2A receptor agonist, in adrenocorticotropic hormone (ACTH)-treated rats. Chronic ACTH (100 microg/rat, s.c.) treatment for 14 d increased the wet-dog shake response induced DOI. The 8-OH-DPAT inhibited the wet-dog shake response induced by DOI in rats with ACTH for 14 d. On the other hand, the 8-OH-DPAT-induced hypothermia and flat body posture were inhibited when ACTH was administered for 14 d. These findings suggest that chronic treatment with ACTH decreased the sensitivity of the 5-HT1A receptor system; however, the inhibitory effects from the 5-HT1A receptors to the 5-HT2A receptor system is not inhibited in ACTH-treated rats. 相似文献
4.
In the present study, the effects of prenatal manganese (Mn) intoxication on the anxiolytic-like effects of diazepam and the 5-HT1A receptor agonist R-(+)-8-hydroxy-dipropylaminotetralin (8-OH-DPAT) were examined. Wistar dams were exposed to MnCl2?4H2O at 5, 000 ppm in the drinking water for the duration of pregnancy. On the day of parturition, Mn was discontinued as an additive in the drinking water. Control rats were derived from dams that consumed tap water and had no exposure to Mn. Male offspring were tested at the age of 12 weeks. The anxiolytic-like effect was assessed in an elevated plus maze device and with the Vogel conflict test. The benzodiazepine anxiolytic diazepam (5 mg/kg, ip) increased the percentage of time spent in open arms in control rats (in comparison to saline treatment) (p < 0.05); no such effect was seen in Mn-exposed rats. Conversely, the serotoninergic 5-HT1A agonist 8-OH-DPAT (0.3 mg/kg, ip) increased the percentage of time spent in open arms in both experimental groups. In the Vogel drinking test, an anxiolytic-like effect was also observed in both test groups (in controls this was of borderline significance). In contrast, 8-OH-DPAT did not evoke an anxiolytic-like action in control or in Mn-exposed rats in the anticonflict test. In conclusion, findings indicate that gestational Mn exposure attenuated benzodiazepine-mediated anxiolytic-like effects but not those of the 5-HT1A receptor agonist 8-OH-DPAT. 相似文献
5.
The effects of antimanic agents, including lithium, carbamazepine, clonazepam and zotepine, on the postsynaptic 5-HT1A receptor-mediated behavioral and hypothermic responses induced by 8-OH-DPAT in rats, and on [3H]8-OH-DPAT binding to 5-HT1A receptors in the rat hippocampus were examined. Treatment with lithium (3 mEq/kg, IP) for 14 days enhanced forepaw treading, one component of the 5-HT behavioral syndrome induced by 8-OH-DPAT, and this enhancement by lithium was abolished by catecholamine depletion with reserpine or -methyl-p-tyrosine, but not by 5-HT depletion withp-chlorophenylalanine. These data suggest that lithium enhances 5-HT1A-mediated behavior via catecholaminergic systems. In contrast, chronic lithium treatment did not alter the hypothermic response to 8-OH-DPAT in untreated rats, as well as in rats treated with reserpine. These findings strengthen the suggestion that lithium has no direct influence on the postsynaptic 5-HT1A-mediated response. Other antimanic agents had no effect on either forepaw treading or hypothermia induced by 8-OH-DPAT. Radioligand binding studies using [3H]-8-OH-DPAT demonstrated that chronic lithium treatment, but not other antimanic agents, caused 5-HT1A receptor down-regulation in rat hippocampus. A discrepancy therefore exists between 5-HT1A receptor down-regulation and unaltered 5-HT1A-mediated behavioral and hypothermic responses in catecholamine-depleted rats after chronic lithium treatment. 相似文献
6.
These experiments assessed whether reported increases in food consumption and food-reinforced instrumental performance in undeprived rats by the 5-HT1A agonist 8-hydroxy-2(di-n-propylamino)tetralin (8-OH-DPAT) are due to an increment in the incentive value of foods. Against this hypothesis, we found that when undeprived rats were trained to lever press for the food pellets and then allowed to consume the pellets under 8-OH-DPAT, this reexposure decreased subsequent instrumental extinction performance regardless of test drug condition relative to reexposure under vehicle. Although both food consumption and reinforced lever press performance were incremented, 8-OH-DPAT was found generally to reduce instrumental extinction performance and lever pressing during a period when the reinforcer was delivered non-contingently. Rats injected with 8-OH-DPAT were, however, more sensitive to delay of reinforcement, and increased their lever press performance at a 3-s delay but decreased performance at 6-s and 12-s delays relative to animals injected with vehicle. These results are consistent with the hypothesis that 8-OH-DPAT modifies arousal processes in a manner similar to mild stress, thereby acting both to elevate rewarded instrumental performance and to increase sensitivity to the effects of non-reward. 相似文献
7.
Uphouse L Maswood S Jackson A Brown K Prullage J Myers T Shaheen F 《Pharmacology, biochemistry, and behavior》2002,72(3):533-542
Fischer and Sprague-Dawley ovariectomized rats were hormonally primed with estradiol benzoate (EB) and progesterone, and the ability of the 5-HT(1A) receptor agonist, (+/-) 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), to inhibit lordosis behavior was examined. Both strains showed rapid inhibition of lordosis behavior following either intraperitoneal or subcutaneous treatment with 8-OH-DPAT. Similarly, in both strains, pretreatment with EB (1 week prior to estrogen and progesterone priming) attenuated the lordosis-inhibiting effects of 8-OH-DPAT. However, Sprague-Dawley females showed a greater decline in lordosis behavior with a lower dose of 8-OH-DPAT than did Fischer females. The strain difference was present in females that had been preprimed with EB as well as in females receiving a single estrogen and progesterone priming. Moreover, strain differences were present across different priming doses of EB. Sprague-Dawley females were also more likely to show flat body posture after injection with 8-OH-DPAT so that the greater sensitivity of this strain to the 5-HT(1A) receptor agonist was not restricted to the drug's effect on lordosis behavior. These findings lead to the suggestion that, relative to Fischer rats, Sprague-Dawley females are more responsive to the 5-HT(1A) receptor agonist. Possible explanations for this strain difference are discussed. 相似文献
8.
Gea H. Dreteler Wout Wouters Pramond R. Saxena 《European journal of pharmacology》1990,180(2-3):339-349
The cardiovascular response to flesinoxan and 8-OH-DPAT (8-hydroxy-2-(di-N-propylamino)tetralin), 5-HT1A receptor agonists, has been investigated in anaesthetized Wistar rats and spontaneously hypertensive rats (SHR) and in conscious SHR. Flesinoxan and 8-OH-DPAT potently lowered blood pressure and heart rate in these models. In conscious SHR, atropine reversed the bradycardia induced by flesinoxan partially and that induced by 8-OH-DPAT completely. In pithed rats with vasopressin-raised blood pressure, neither flesinoxan nor 8-OH-DPAT lowered blood pressure or heart rate. Intracisternal administration of either flesinoxanor 8-OH-DPAT was less efficacious than intravenous administration. The cardiovascular responses to flesinoxan and 8-OH-DPAT in the anaesthetized Wistar were inhibited by the putative 5-HT1A antagonists methiothepin, buspirone, spiroxatrine and 8-MeO-C1EPAT (8-methoxy-2-(N-2-chloroethyl-N-n-propylamino)tetralin). 8-MeO-C1EPAT appeared to be the most suitable antagonist in this model. The 5-HT1C, 5-HT2 antagonist ritanserin or the 5-HT3 antagonist GR 38032F had no effect on the responses to flesinoxan or 8-OH-DPAT. In conscious SHR however, 8-MeO-C1EPAT did not antagonize these cardiovascular responses. This study confirms the involvement of central 5-HT1A receptors in the cardiovascular effects of flesinoxan and 8-OH-DPAT. 相似文献
9.
The effects of the putative 5-HT1A receptor antagonist NAN-190 on feeding and spontaneous locomotor activity in rats were examined. The drug elicited a robust, dose-dependent (0.01-10 mg/kg) increase in food consumption in free feeding animals. Microstructural analysis of feeding induced by NAN-190 (3 mg/kg) revealed that the drug increased the duration of feeding and number of feeding bouts but decreased the feeding rate. The increase in feeding induced by 3 mg/kg of NAN-190 was not apparent until 2-4 h after injection. This prolonged latency to onset of the feeding response appeared to be due to response competition. Thus, a 'neuroleptic-like' action of the drug on spontaneous motor activity was observed during the the initial 2 h following injection. A dopamine receptor antagonist action of NAN-190 was also indicated by the results of studies in which the drug was observed to block oral stereotypy induced by the dopamine receptor agonist apomorphine. In interaction studies, NAN-190 (0.1 and 10 mg/kg) failed to block the feeding response induced by the prototypical 5-HT1A receptor agonist 8-OH-DPAT (0.0625 and 1.0 mg/kg) and indeed, appeared to have an additive effect with 8-OH-DPAT on consummatory behaviour. These data suggest that NAN-190 may act as a partial agonist rather than an antagonist at the 5-HT1A receptor and also provide the first evidence that the drug has dopamine receptor antagonist properties in vivo. 相似文献
10.
Ovariectomized rats were primed with sesame oil or estradiol benzoate followed 48 h later by either sesame oil or progesterone. Four hours later, rats were treated with either saline or 0.25 mg/kg 8-hydroxy-2-9(di-n-propylamino)tetralin (8-OH-DPAT). Rats were allowed to eat for 4 h after this final treatment. Animals in all hormonal conditions showed hyperphagia following 8-OH-DPAT. However, the hyperphagia was significantly attenuated by pretreatment with estradiol benzoate. There was no effect of progesterone on the hyperphagic response. These results suggest that previous findings of an estrous cycle modulation of the hyperphagic response to 8-OH-DPAT arise from the modulatory effects of estradiol, and not progesterone, during the female reproductive cycle. 相似文献
11.
B Poeschla J Gibbs K J Simansky G P Smith 《Pharmacology, biochemistry, and behavior》1992,42(3):541-543
To investigate the dependence of the satiating action of cholecystokinin (CCK) on serotonergic action at central 5-HT receptors, we examined the effect of systemic pretreatment with 8-OH-DPAT (a 5-HT1A agonist that decreases central 5-HT synthesis and release via an action at somatodendritic autoreceptors in the brainstem raphe) on the suppression of food intake induced by systemic administration of cholecystokinin octapeptide (CKK-8). 8-OH-DPAT significantly attenuated the satiating action of CKK-8. This result is consistent with the hypothesis that peripherally acting CCK recruits central serotonergic processes to elicit normal satiety. 相似文献
12.
Li X Inoue T Abekawa T Weng S Nakagawa S Izumi T Koyama T 《European journal of pharmacology》2006,532(1-2):74-80
Evidence from preclinical and clinical studies has shown that 5-HT(1A) receptor agonists have anxiolytic actions. The anxiolytic actions of 5-HT(1A) receptor agonists have been tested by our previous studies using fear conditioning. However, little is known about the brain regions of anxiolytic actions of 5-HT(1A) receptor agonists in this paradigm. In the present study, we investigated the effects of bilateral microinjections of flesinoxan, a selective 5-HT(1A) receptor agonist, into the hippocampus, amygdala and medial prefrontal cortex on the expression of contextual conditioned freezing and the defecation induced by conditioned fear stress in rats. These results reveal that both intrahippocampal and intraamygdala injections of flesinoxan decreased the expression of conditioned freezing, while injections into the medial prefrontal cortex did not. In addition, intraamygdala injection of flesinoxan attenuated the increased defecation induced by conditioned fear, but injections into the hippocampus and medial prefrontal cortex failed. These results suggest that flesinoxan exerts its anxiolytic actions in the fear conditioning through stimulations of the postsynaptic 5-HT(1A) receptors in the hippocampus and amygdala. 相似文献
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15.
Kitamura Y Araki H Shibata K Gomita Y Tanizaki Y 《European journal of pharmacology》2003,481(1):75-77
We examined the effect of adrenocorticotropic hormone (ACTH) on the immobilization of rats in the forced swim test after administration of the 5-HT(1A) receptor agonist, 8-hydroxy-2-di-n-propylamino tetralin (8-OH-DPAT). Imipramine (3-30 mg/kg, i.p.) or 8-OH-DPAT (0.1-1 mg/kg, s.c.) significantly decreased the duration of immobility in normal rats. The immobility-decreasing effect of imipramine was blocked when ACTH was administered for 14 days. On the other hand, the immobility-decreasing effect induced by 8-OH-DPAT was not blocked by chronic administration of ACTH for 14 days. These findings indicate that 8-OH-DPAT can be useful in an animal model of depressive conditions resistant to antidepressant treatment. 相似文献
16.
Summary Human serotonin (5-hydroxytryptamine, 5-HT)-1A receptors have been transfected in NIH-3T3 cells, and their coupling to adenylyl cyclase was analysed depending on (1) the number of receptor expressed, (2) the experimental conditions used, (3) the nature of the agonists. Two monoclonal cell lines were used, expressing low (45 fmol/mg) and high (500 fmol/mg) levels of 5-HT1A receptor. Two methods were tested to study the negative coupling of the transfected 5-HT1A receptors to adenylyl cyclase: (1) measurement of CAMP production in intact cells, (2) measurement of adenylyl cyclase activity in vitro on membrane preparations. Studies on intact cells revealed that an increase in the receptor concentration was followed by (1) an increase in the efficacies of 5-HT, 5-CT (5-carboxamidotryptamine) and 8-hydroxy2-(di-n-propylamino)tetralin (8-OH-DPAT), (2) a 2 to 3-fold increase in the potency of 5-CT and 8-OH-DPAT, but no change in the potency of 5-HT. In membrane preparations, 8-OH-DPAT dose-response curve was shifted leftwards when the receptor concentration became higher whereas the corresponding shift was smaller for 5-HT and absent for 5-CT. Surprisingly, on membrane preparations, 8-OH-DPAT was a partial agonist relative to 5-HT. The relative efficacy of 8-OH-DPAT was lower in the clone expressing the lowest level of receptor. This partial agonist behavior of 8-OH-DPAT could be modulated by the ionic conditions under which the adenylyl cyclase activity was measured. When physiological intracellular concentrations of Na+, Mg2+ and K+ were used, 8-OH-DPAT became an almost full agonist relative to 5-HT.These data indicate that (1) the classical pharmacological models do not exactly fit with characteristics of the negative coupling between transfected 5-HT1A receptors and adenylyl cyclase; (2) on membranes, the experimental procedures (ionic conditions) can modify this coupling differently depending on the nature of the agonist.Abbreviations 5-HT
5-hydroxytryptamine (serotonin)
- 8-OHDPAT
8-hydroxy-2-(di-n-propylamino)-tetraline
- 5-CT
5-carboxamidotryptamine
- IBMX
isobutyl methyl xanthine
- BSA
bovine serum albumine
- EC50
half maximal efficacy
- DXM
dexamethasone
- PTX
Bordetella pertussis toxin
- G protein
GTP-binding protein
Correspondence to A. Varrault at the above address 相似文献
17.
In the rat shock-induced ultrasonic vocalization test, the anxiolytic effects of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) obtained after systemic (IP) and intracerebral injection into the dorsal raphe nucleus (DRN) were selectively abolished by pretreatment with the 5-HT1A receptor antagonist WAY-100635 [N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-N-(2-pyridinyl) cyclo-hexanecarboxamide trihydrochloride]. This blockade was demonstrated both after systemic and DRN application of WAY-100635. Therefore, it is concluded that the anxiolytic effects of 8-OH-DPAT are mediated by activation of somatodendritic 5-HT1A receptors. 相似文献
18.
Wolfgang Löscher Ulrike Witte Gabriele Fredow Jörg Traber Thomas Glaser 《Naunyn-Schmiedeberg's archives of pharmacology》1990,342(3):271-277
Summary In pigs, behavioural responses were examined after administration of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a full agonist at 5-hydroxytryptamine (5-HT) receptors of the 5-HT1A subtype, and the pyrimidinylpiperazine derivatives ipsapirone and Bay Vq 7813 (2-[4-(2-pyrimidinyl)-1-piperazinylpropyl]-1,2-benzisothiazol-3(2H)one-1,1-dioxide), which act as partial agonists at 5-HT1A receptors. The most prominent behavioural response examined after 8-OH-DPAT, 0.5 mg/kg i. m., ipsapirone, 2–5 mg/kg i.m., and Bay Vq 7813, 0.5–2 mg/kg i.m. or i.v., were head shakes. The potency of the three drugs to induce this behaviour correlated with their activity at 5-HT1A receptors as determined by inhibition of forskolin-stimulated adenylate cyclase, substantiating that the head shake response has potential as a quantitative probe of in vivo receptor function. The 5-HT2/5-HT1C receptor antagonist ritanserin did not counteract the head shakes induced by ipsapirone, suggesting that neither 5-HT2 nor 5-HT1C receptors are involved in mediation of this response to this 5-HT1A receptor agonist in pigs. Once daily administration of Bay Vq 7813 or ipsapirone for 3–5 days led to a reduction in the head shake response. 1-Pyrimidinylpiperazine (1-PP), a pharmacologically active metabolite shared by ipsapirone, Bay Vq 7813, and related pyrimidinylpiperazine derivatives, did not induce behavioural alterations in pigs. The data provide further evidence that marked species differences exist in functional responses to 5-HT receptor ligands.
Send offprint requests to W. Löscher at the above address 相似文献
19.
Suppression of lordosis behavior by the putative 5-HT receptor agonist 8-OH-DPAT in the rat 总被引:1,自引:0,他引:1
S Ahlenius A Fernandez-Guasti S Hjorth K Larsson 《European journal of pharmacology》1986,124(3):361-363
The administration of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), inhibited the lordosis induced by estradiol benzoate or estradiol benzoate plus progesterone in ovariectomized rats. There was no facilitation of lordosis by 8-OH-DPAT in animals pretreated with a threshold dose of estradiol benzoate. The results are consistent with the view that 8-OH-DPAT is an agonist at 5-HT receptors and provide further support for an inhibition role of central 5-HT in the mediation of lordosis behavior. 相似文献
20.
Circadian rhythm in the behavioral responsiveness to the selective 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was studied in rats. Rats were subcutaneously injected with 8-OH-DPAT at one of the following times of day: 0000, 0400, 0800, 1200, 1600, 2000 hours. The postsynaptic 5-HT1A receptor behavioral syndrome, that is, forepaw treading, head weaving, and flat body posture, were measured after the administration of 8-OH-DPAT. Circadian rhythms were found in each of the behavioral responses to 8-OH-DPAT. Peak responses were observed in the mid-dark phase (1200 hours) while the weakest responses were observed in the midlight phase (0000 hours). In a subsequent experiment, 8-OH-DPAT was administered intracerebroventricularly during the mid-dark phase and the mid-light phase. The behavioral responses to the drug in the middark phase were significantly higher than those in the mid-light phase. These results suggest that the function of central postsynaptic 5-HT1A receptor exhibits circadian rhythm. 相似文献