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  • 1
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Activation of 5-HT1B receptors is thought to play an important role in the inhibitory influence of serotonin on feeding behaviour and body weight in mammals. Earlier studies have shown that 5-HT1B-knockout (KO) mice eat more and are heavier than wild-type (WT) controls and that the selective 5-HT1B receptor agonist CP-94,253 reduces food intake in food-deprived mice. Here we characterize the behavioural effects of both CP-94,253 and the selective 5-HT1B receptor antagonist SB224289 on feeding and other behaviours within the behavioural satiety sequence, and also report a c-fos mapping study using CP-94,253. CP-94,253 produced a dose-dependent suppression of food intake with a profile consistent with a selective effect on feeding behaviour. These effects were absent or reduced in 5-HT1B-KO mice and in WT mice pretreated with SB224289. SB224289 administered alone enhanced food intake consistent with impaired satiation; a similar effect was apparent in 5-HT1B-KO mice compared to WT. CP-94,253 induced c-fos in a range of structures previously implicated in the expression of feeding behaviour. These results suggest that the activation of 5-HT1B receptors is an important component of endogenous satiation mechanisms in the mouse.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Science, Ltd
    European journal of neuroscience 17 (2003), S. 0 
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Although null mutant (‘knockout’) mice have provided valuable animal models to complement traditional approaches to psychopharmacology, such animals may also show complex adaptations to the induced mutation. Here we demonstrate that serotonin1B (5-HT1B) receptor knockout (KO) mice show adaptations in serotonin2C (5-HT2C) receptor-mediated functions. They show smaller reductions in food intake and locomotor activity in response to administration of 5-HT2C receptor agonists that are not accounted for by altered drug disposition. These effects are not mimicked by pretreatment of wildtype (WT) mice with a 5-HT1B receptor antagonist showing that they result from a longer term adaptation to the loss of 5-HT1B receptor function and not from a short-term interaction between 5-HT1B- and 5-HT2C-mediated functions. In addition, we show that 5-HT1B receptor KO mice have a lowered hypothalamic c-fos response to the administration of 5-HT2C receptor agonists. These results demonstrate that compensatory adaptations to the constitutive loss of 5-HT1B receptors may be an important determinant of the altered response of 5-HT1B KO mice to a variety of pharmacological challenges.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-2072
    Keywords: Anxiety ; Elevated zero-maze ; Rat ; Diazepam ; Chlordiazepoxide ; mCPP ; 8-OH-DPAT ; Ondansetron ; Head dips ; Stretched attend postures
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The elevated “zero-maze” is a modification of the elevated plus-maze model of anxiety in rats which incorporates both traditional and novel ethological measures in the analysis of drug effects. The novel design comprises an elevated annular platform with two opposite enclosed quadrants and two open, removing any ambiguity in interpretation of time spent on the central square of the traditional design and allowing uninterrupted exploration. Using this model, the reference benzodiazepine anxiolytics, diazepam (0.125–0.5 mg/kg) and chlordiazepoxide (0.5–2.0 mg/kg) significantly increased the percentage of time spent in the open quadrants (% TO) and the frequency of head dips over the edge of the platform (HDIPS), and reduced the frequency of stretched attend postures (SAP) from the closed to open quadrants. In contrast, the anxiogenic drugm-chlorophenyl-piperazine (mCPP; 0.25–1.0 mg/kg) induced the opposite effects, decreasing %TO and HDIPS, and increasing SAP. The 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.001–0.1 mg/kg) had no effects on either %TO or HDIPS, but did decrease SAP at 0.01 mg/kg although not at higher or lower doses. Similarly, the 5-HT3 receptor antagonist, ondansetron (0.0001–1.0 mg/kg) decreased SAP and increased %TO at 0.01 mg/kg, but not at other doses. The present data suggest that a combination of the novel “zero-maze” design and a detailed ethological analysis provides a sensitive model for the detection of anxiolytic/anxiogenic drug action.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-2072
    Keywords: Key words WAY100135 ; 8-OH-DPAT ; Fluoxetine ; 5-HTP ; 5-HT1A receptor ; Ethanol intake ; Food intake ; Alcohol-preferring rats
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Selective serotonin reuptake inhibitors (SSRIs) or serotonin precursors inhibit ethanol and food intake by increasing the synaptic availability of 5-HT in the central nervous system. However, these agents can also increase 5-HT levels at somatodendritic 5-HT1A autoreceptors, with negative effects on serotonergic transmission. (+)WAY100135 [N-ter-butyl 3-4-(2-methoxy-phenyl) piperazin-1-yl-2-phenylpropa-namide dihydrochloride] is a selective antagonist both at pre-and post-synaptic 5-HT1A receptors. The present study investigated the effect on ethanol and food intake of (+)WAY100135, given alone or coadministered with the SSRI fluoxetine or the 5-HT precursor 5-hydroxytryptophan (5-HTP) in genetically selected alcohol-preferring rats. Blockade of presynaptic 5-HT1A receptors after injection of (+)WAY100135, 0.1 or 1 μg/rat, into the dorsal raphe did not significantly modify ethanol, food or total fluid intake. The same doses of (+)WAY100135 did not modify the inhibition of ethanol and food intake induced by intraperitoneal (IP) injection of fluoxetine, 5 mg/kg. Subcutaneous (SC) administration of (+)WAY100135 (1 or 10 mg/kg) did not affect the 3-h, or the overnight intake of ethanol, food or total fluids. Given together with IP fluoxetine (5 mg/kg) or SC 5-HTP (100 mg/kg plus carbidopa, 12.5 mg/kg), the same SC doses of (+)WAY100135 did not modify their inhibitory effect on ethanol and food consumption. Present findings suggest that blockade either of pre-or of pre-and postsynaptic 5-HT1A receptors does not potentiate the inhibitory effect of fluoxetine or 5-HTP on ethanol and food intake.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-2072
    Keywords: Chronic administration ; Drinking ; Locomotor activity ; Piribedil ; Tolerance ; Thirst
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Low doses of piribedil (0.25–5.0 mg/kg) administered acutely produced reliable decrements in locomotor activity in thirsty and non-thirsty animals, the greatest effect occurring at the highest dose. A sequence of ten daily injections of piribedil produced indications of the development of tolerance, at the two highest doses (2.5 and 5.0 mg/kg) in thirsty animals. The smallest doses used, given either acutely or chronically, produced a weak enhancement of drinking behaviour within the first 15 min of a drinking test, as shown by a reduction in latency to drink and an increase in the amount of water consumption. Tolerance did develop with respect to drinking behaviour; animals treated chronically with piribedil displayed higher levels of drinking at several dose levels when compared with acutely treated subjects. The tolerance displayed at the two highest doses could have a close affinity with that shown with regard to locomotor activity.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-2072
    Keywords: Phenelzine ; Deuterium substitution ; Behaviour ; Potentiation ; Monoamine oxidase inhibition ; Antidepressant
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Phenelzine in the rat induced biphasic behavioural stimulation, which was profoundly potentiated by deuterium substitution. Doses of 12.5 or 25.0 mg/kg phenelzine had little or no effect on spontaneous activity, whereas the same doses of deuterated phenelzine produced hyperactivity, wetdog shakes, forepaw padding, splayed hind limbs, backward walking, sniffing and stereotyped grooming 2–12 h after injection. Similarly, the behavioural response induced by 50.0 mg/kg phenelzine was strongly potentiated by deuterium substitution. It appears likely that the increased behavioural response induced by deuterated phenelzine may be due to its greater potency as a monoamine oxidase inhibitor compared to undeuterated phenelzine. Since phenelzine is an antidepressant that is particularly efficacious in the treatment of severe anxiety, a deuterated analogue of the drug seems likely to be clinically useful.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1432-2072
    Keywords: Key words d-Fenfluramine ; 5-HT2C receptor ; Serotonin ; Mouse ; Feeding ; Satiety
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract   Rationale: d-Fenfluramine stimulates the release of serotonin (5-HT) and is a potent inhibitor of the re-uptake of 5-HT into nerve terminals. Administration of d-fenfluramine suppresses food intake in both animals and humans. Objective: We have investigated the role of the 5-HT2C receptor in mediating the effect of d-fenfluramine on mouse food intake and the behavioural satiety sequence. Methods: Mutant mice lacking serotonin 5-HT2C receptors and wild-type animals were habituated to a daily presentation of wet mash. Animals were non-deprived and received d-fenfluramine (3–30 mg/kg) 30 min prior to being assessed for the presence of stereotypy and presented with wet mash. The behaviour of animals was observed for the subsequent 40 min and food intake was recorded. Results: d-Fenfluramine dose-dependently inhibited the consumption of a palatable wet mash by the mice. d-Fenfluramine (3 mg/kg) significantly reduced the amount of wet mash consumed by wild-type mice and induced a temporal advance in the behavioural satiety sequence consistent with an enhancement of satiety. Mutant mice were less sensitive to the satiating effects of 3 mg/kg d-fenfluramine. Hence, this dose of d-fenfluramine had a reduced effect on both food consumption and the behavioural satiety sequence in the 5-HT2C mutant mice. In contrast, mutant mice showed an increased sensitivity to the stereotypy induced by high doses of d-fenfluramine (10, 30 mg/kg) compared to that of wild-type littermates. Conclusion: These data demonstrate a role for the 5-HT2C receptor in mediating d-fenfluramine-induced satiety.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-2072
    Keywords: 8-OH-DPAT ; Feeding ; Chewing ; Liquid diet ; Choice test ; Rat ; 5-HT1A receptors
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract There have been recent claims that the 5-HT1A agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) elicits chewing and eating of solid but not liquid foods. Therefore, the effects of 8-OH-DPAT and another 5-HT1A agonist gepirone on the consumption of a liquid chow diet, by free feeding male rats, were examined. Both drugs produced a dose-dependent increase in the consumption of liquid diet during a 2 h test. The doses of 8-OH-DPAT and gepirone which increased liquid diet intake in this study were in the same range as those which were found previously to increase food pellet consumption by free feeding rats. The effects of 8-OH-DPAT were also examined in a feeding choice test in which free feeding animals were allowed to choose between food pellets and a liquid chow diet. In this test, 8-OH-DPAT significantly increased total food intake (liquid plus pellet) but had no significant effect on the consumption of either liquid or pellet diets when analysed separately. Thus, there were large individual differences in diet choice after 8-OH-DPAT injection. However, rats did not consistently choose to eat food pellets rather than the liquid diet, as would be predicted if the drug elicited chewing rather than eating. These results provide strong evidence that 8-OH-DPAT elicits a behaviourally specific hyperphagia and not chewing or gnawing.
    Type of Medium: Electronic Resource
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