Anxiolytic-like effects observed in rats exposed to the elevated zero-maze following treatment with 5-HT2/5-HT3/5-HT4 ligands (original) (raw)
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Behavioural Brain Research, 2007
Animal models of anxiety remain a useful tool for evaluating the anxiolytic-like effect of new treatments. Even though many tests are similarly based on exploration tasks, using more than one animal model is all the more recommended since there are qualitative differences between such tests. Furthermore, although many tests are excellent tool for detecting benzodiazepines/GABA compounds, inconsistent results have been reported for 5-HT ligands. Here, two animal models have been chosen, the elevated plus maze (EPM) based on the natural aversion of rodents for open spaces and the four-plates test (FPT) a models involving the animal's conditioned response to stressful events. In a recent study, we have demonstrated that the 5-HT 2A/2C agonist DOI and the 5-HT 2B agonist BW 723C86 were shown to produce an anxiolytic-like effect in both tests. This study aimed to evaluate a putative interaction between benzodiazepine and 5-HT 2 ligands in the FPT and the EPM. Indeed, close distribution of GABA A and 5-HT 2 receptors was found in brain structures leading to functional interrelation. In the FPT, sub-active doses of alprazolam and diazepam were strongly potentiated by DOI. BW 723C86, also potentiated the anxiolytic-like effect of the two benzodiazepines with a weaker effect. In the same way, DOI and benzodiazepines administration induced an increase in the anxiolytic-like parameters in the EPM with a strongest effect observed with alprazolam. Regardless of anxiety models used in this study, 5-HT 2A ligands exerted facilitatory influence upon GABAergic system. Therefore, the FPT and the EPM might implicate the same kind of anxiety.
Anxiolytic-like effects of 5-HT2 ligands on three mouse models of anxiety
Behavioural Brain Research, 2003
The behavioural effects of 5-HT(2) receptor agonists, 5-HT(2A) and 5-HT(2C) receptor antagonists were investigated in the mouse four plates test (FPT), light/dark paradigm (L/D) and the elevated plus maze (EPM), in order to elucidate the role of the 5-HT(2) receptor subtypes in these models and to address the inconclusive results previously reported using rat psychopharmacological models. All compounds were administered intraperitoneally 30 min before each test. DOI, a preferential 5-HT(2A) agonist (0.5-8 mg/kg) and BW 723C86, a 5-HT(2B) agonist (8 and 16 mg/kg) provoked an anxiolytic-like response in the FPT. In the EPM, an anxiolytic-like effect was observed for DOI (0.5, 1 and 2 mg/kg), BW 723C86 (0.5, 4, 8 and 16 mg/kg), RO 60-0175 a 5-HT(2C) agonist (4 mg/kg) and the non-selective 5-HT(2) receptor agonist mCPP (0.25 mg/kg.). Ketanserin, a 5-HT(2A/2C) non-selective receptor antagonist (0.015 and 0.03 mg/kg), induced an anxiogenic-like effect in the L/D paradigm. The 5-HT(2C) antagonists (RS 10-2221, SDZ SER082 and SB 206553) were without effect in all three tests. These behavioural results are indicative of an anxiolytic-like action of 5-HT(2) receptor agonists, an anxiogenic-like effect of 5-HT(2A) receptor antagonism, whereas the blockade of 5-HT(2C) receptors are without effect in the mouse models studied.
1996
The purpose of this study was to determine the roles of the presynaptic 5-hydroxytryptamine 1A (5-HT 1A ) receptors in the median raphé nucleus (MRN) and of the postsynaptic 5-HT 1A receptors in its projection area of the dorsal hippocampus in the social interaction and elevated plus-maze tests of anxiety. Direct administration of the 5-HT 1A receptor agonist (Ϯ)-8hydroxy-dipropylaminotetralin (8-OH-DPAT, 200 ng) into the MRN had significant anxiolytic effects in all three test situations examined (social interaction, plus-maze trials 1 and 2). These anxiolytic effects were antagonized by a silent dose (200 ng) of the 5-HT 1A receptor antagonist WAY 100635, confirming that they were mediated by 5-HT 1A receptors. In contrast, after bilateral administration to the dorsal hippocampus, 8-OH-DPAT (100 ng) had significant anxiogenic effects in the social interaction test and in plus-maze trial 2. These anxiogenic effects were antagonized by silent doses of 5-HT 1A receptor antagonists [(ϩ)WAY 100135, 10 mg/kg s.c., and intrahippocampal (Ϯ)tertatolol, 3 g, respectively], confirming mediation by 5-HT 1A receptors. In rats naive to the plus-maze, neither 8-OH-DPAT (50, 100, or 200 ng) nor the 5-HT 1A receptor antagonist (Ϯ)tertatolol (3 g) had any significant effect when administered to the dorsal hippocampus. This demonstrates that previous experience of a rat in the plus-maze has a major effect on the sensitivity of dorsal hippocampal 5-HT 1A receptors, as we have demonstrated previously for the 5-HT 1A receptors in the dorsal raphé nucleus. Overall, our results provide evidence that stimulation of the presynaptic 5-HT 1A receptors in the MRN results in an anxiolytic action, whereas stimulation of the post-synaptic 5-HT 1A receptors in its projection area results in an anxiogenic effect. These results are consistent with an overall reduction in 5-HT neurotransmission in the dorsal hippocampus having an anxiolytic effect, and they explain the relatively weak anxiolytic profile detected when 5-HT 1A receptor agonists are given systemically.
Psychopharmacology, 1993
The introduction of buspirone for the treatment of anxiety, together with the eventual suggestion of a mode of action involving the serotonin (5-HT)I A receptor subtype, has generated considerable research activity and renewed interest in the potential role of 5-HT in anxiety. The further identification of multiple 5-HT I receptors, coupled with the possibility that these subtypes potentially are involved in discrete biobehavioral regulation and pathophysiological conditions, has greatly expanded the search for tools capable of probing these receptors and has raised hopes for a new generation of more specific compounds to treat other disorders associated with the 5-HT system such as depression, aggression, and sleep and eating distmbances. The involvement of 5-HT in anxiety has prompted a careful reevaluation of several traditional areas of research. This has included those methods used in the in vivo evaluation of drugs in preclinical animal test procedures used to assess potential anxiolytic activity, as well as the mechanisms associated with adaptive changes occurring during long-term drug administration. The proliferation of various procedures for studying the anxiolytic effects of 5-HT drugs has not always been accompanied by systematic behavioral and pharmacological validation. At the present time, this area of research is characterized by numerous inconsistent findings. Procedures that are objective and impartial to the behavioral effects of drugs provide distinct advantages for addressing some of these issues, as will the results from carefully controlled clinical studies. The main objective of this article is to provide an overview of the recent developments in research involving the 5-HT system and anxiety. The emphasis will be on the 5-HT1 receptor system and a review of the results in the predominant animal models used to evaluate these drugs, as well as an overview of the mechanisms currently believed to be responsible for the therapeutic activity of this class of compounds. Studies with the pigeon are reviewed, since this species appears distinctly sensitive to the anxiolytic-Correspondence to: J.E. Barrett like effects of 5-HT1A drugs in conflict procedures. Although chronic administration of 5-HT1A drugs appears necessary for clinical anxiolytic and antidepressant activity, the most noteworthy neuropharmacological effects in animals seem to occur in 5-HT2 and, perhaps, 5-HT 3 receptors which are downregulated. Studies summarizing the activity of drugs interacting with 5-HTlc/2 and 5-HT 3 receptor sites are also discussed as they too may be involved in anxiety or the actions of anxiolytic drugs. The growing evidence suggesting an interaction between 5-HT receptor types, particularly between 5-HT1A and 5-HT~c/2 receptors, is reviewed, since drugs with these combined properties appear to be particularly efficacious in animal models of anxiety and warrant further detailed analyses. The development of drugs targeted specifically at multiple receptors may provide distinct therapeutic advantages for disorders such as anxiety and depression that appear to involve multiple neurotransmitter systems.
Pre- or postsynaptic activity of 5-HT1A compounds in mice depends on the anxiety paradigm
Pharmacology Biochemistry and Behavior, 1996
BEHAV 54(4) 677-686, 1996.-The purpose of the present study was to compare the contribution of pre and postsynaptic S-HT,, receptors to the anxiolytic effects of serotonergic IA compounds in two animal models of anxiety. To this aim, the 5-HT,, ligands buspirone, ipsapirone, indorenate, and 8.OH-DPAT were tested in the burying behavior test and the avoidance exploratory behavior paradigm in control, pCPA-treated, and 5,7-DHT-lesioned mice. p-CPA and S.7-DHT treatments did not modify the burying behavior per se, while 5-HTIA agonists produced a significant reduction in this behavior in both p-CPA-and 5,7-DHT-lesioned animals. In the exploratory behavior paradigm, p-CPA per se but not 5,7-DHT increased the black/white transitions, interpreted as an antianxiety action. The ICV injection of 5,7-DHT blocked such effect of the S-HTjA compounds in the avoidance exploratory behavior test. Data suggest that the effect of 5-HTIA compounds in the burying behavior test is mediated via the stimulation of postsynaptic receptors, while in the avoidance exploratory behavior paradigm these compounds act through the stimulation of the presynaptic site. Discussion is based on the differences between the animal models of anxiety.
Neuropharmacology, 1997
The highly selective 5-HT4 receptor antagonists, SB 204070A (0.001-0.1 mg/kg s.c., 30 tin pretest) and SB 207266A (0.01, 1 and 10 mg/kg p.o., 1 hr pre-test), increased time spent in social interaction without affecting locomotor activity, in a rat 15 min social interaction test under high light, unfamiliar conditions. At 1 and 10 mg/kg s.c., SB 204070A was no longer active. These results are consistent with the profile expected of anxiolytic treatments in this procedure. In a rat 5 tin elevated x-maze test, SB 204070A (0.01 and 1 mg/kg s.c., 30 tin pre-test) significantly increased the percentage of time spent on the open arms. SB 204070A (0.01 mg/kg s.c.) and SB 207266A (1 mg/kg p.o., 1 hr pre-test) also increased percentage entries to the open arms. Neither compound affected locomotion at any dose tested in the procedure. The effects of both compounds in this procedure are also consistent with anxiolysis. Neither SB 204070A (O.1 or 1 mg/kg s.c., 30 min pre-test) nor SB 207266A (0.1 or 1 mg/kg p.o., 1 hr pre-test) affected either unpunished or punished responding, in a rat Geller-Seifter conflict model of anxiety. The maximal efficacy of both SB 204070A and SB 207266A in the rat social interaction test was similar to that of the benzodiazepine anxiolytic chlordiazepoxide (5 mg/kg S.C.or p.o.) used as a positive control, but was considerably less in the elevated x-maze procedure. The results suggest that 5-HT4 receptor antagonists may have modest anxiolytic-like actions in rats.
The Pharma Innovation Journal, 2013
The serotonergic system of brain is well understood to play a crucial role in emotional processing in human and animals. 5-HT3 receptor, the ion channel type of receptor is involved in mood, anxiety, depression, learning and memory. Objective of the present work was to investigate the anxiolytic potential of a novel 5-HT3 receptor antagonist (4-phenylpiperazin-1-yl) (quinoxalin-2-yl) methanone (4a) in mice. Different behavioral test paradigms for anxiety like elevated plus maze, open field test, light-dark model and hole board test were used for assessing the effect. Diazepam 2 mg/kg i.p. served as a reference standard. From the results it was found that 4a dose dependently at 2 and 4 mg/kg i.p. attenuated the behavioral alterations in the anxiety models in mice. The exact mechanism of 5HT3 receptor antagonist for anxiolytic potential is still ill understood. Our further studies will deal with mechanisms at molecular levels for anxiolytic potential of 4a. Keyword: 5-HT3 Receptor, An...