Anxiolytic-like effects of 5-HT2 ligands on three mouse models of anxiety (original) (raw)
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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 At 1 and 10 mg/kg s.c., SB 204070A was no longer active.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.
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.
Scientific Reports, 2014
The present study examined the effects of administering selective 5-HT antagonists and agonists to rats tested in the elevated zero-maze (EZM) model of anxiety. The EZM paradigm has advantages over the elevated plus-maze (EPM) paradigm with respect to measuring anxiety, yet has been utilized less frequently. Three experiments were conducted each with a diazepam control (0.25, 0.5 and 0.75 mg/kg). In the first experiment, we administered the 5-HT 2C antagonist RS 102221 (0.5, 1.0, and 2.0 mg/kg) and 5-HT 2C agonist MK-212 (0.25, 0.5 and 0.75 mg/kg); in the second experiment, we administered the 5-HT 3 antagonist Y-25130 (0.1, 1.0 and 3.0 mg/kg) and 5-HT 3 agonist SR 57227A (0.1, 1.0 and 3.0 mg/kg), and in the third experiment, we administered the 5-HT 4 antagonist RS 39604 (0.01, 0.1, 1.0 mg/kg) and 5-HT 4 agonist RS 67333 (0.01, 0.1 and 0.5 mg/kg). The administration of 5-HT 2/3/4 subtype antagonists all generated behavioral profiles indicative of anxiolytic-like effects in the EZM, which was apparent from examination of both traditional and ethological measures. While little effect was observed from 5-HT 2 and 5-HT 3 agonists, the 5-HT 4 agonist RS 67333 was found to produce a paradoxical anxiolytic-like effect similar to that produced by the 5-HT 4 antagonist RS 39604. We conclude by discussing the implications of these findings.
Preclinical evidence for the anxiolytic activity of 5-HT3 receptor antagonists: A review
Stress Medicine, 1992
From ancient history to present times, mankind has sought for anxiolytics, and various medications have been found and consequently used, at present culminating in heavy benzodiazepine use. Side-effects such as dependence and tolerance have always induced the need, and accordingly the search, for new and better treatments. The 5-HT,, receptor agonists like buspirone are an example of such new therapeutic agents. Whether or not those compounds will indeed be better as well remains to be seen. Recently another new class of putative anxiolytics has been proposed, the 5-HT3 receptor antagonists. The present article reviews the evidence for anxiolytic activity of this new class of compounds in animal models of anxiety. Compared to the established anxiolytics (benzodiazepines and, to a lesser extent, 5-HT,, receptor agonists) 5-HT, receptor antagonists have a different anxiolytic profile.
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.
Effect of 5-HT2C receptor antagonist RS 102221 on mouse behavior
Bulletin of Experimental Biology and Medicine, 2006
Injection of RS 102221 (selective antagonist of serotonin 5-HT 2C receptors) in a dose of 2 mg/kg reduced anxiety of mice in the light-darkness test and decreased the amplitude of the startle reflex. RS 102221 in a dose of 1 mg/kg reduced prestimulus inhibition of the startle reflex. No behavioral changes in Porsolt test and motor activity in the open field test were detected. Hence, RS 102221 is characterized by selective anxiolytic activity, and 5-HT 2C receptors are involved in the mechanisms of anxiety and startle reflex formation.
Behavioural pharmacology of 5-HT3 receptor ligands
Neuroscience & Biobehavioral Reviews, 1992
pharmacology of5-HT s receptor hgands NEUROSCI BIOBEHAV REV 16(1) 107-113, 1992 --Extensive studms have ascribed a role for the central 5-HT 3 receptor m the modulation of behavtour Much of the work stems from the actions of potent and selective 5-HTa receptor antagomsts, these agents reduce mcsohmblC dopamme lnmated hyperactwity, release suppressed behaviour, reduce the reinforcing properties and withdrawal symptoms of drugs of abuse, enhance cognmve performance and modulate appetite. This article reviews the prechmcal and chmcal evidence lmphcatmg the 5-HT 3 receptor m these indications and d~scusses the potential neurochemlcal mechanisms underlying the behavloural changes 5-HT 3 receptor Psychosis Anxmty Drugs of abuse Cognmon Appetite Socml encounters
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.
Behavioural Brain Research, 2018
5-HT7 receptors have been suggested to play a role in the regulation of psychiatric disorders. The experimental literature however is not fully consistent on this possibility. Two selective 5-HT7 receptor antagonists, DR-4004 and SB-269970, were evaluated in mouse models used to detect drugs used to treat anxiety, depression, or schizophrenia. A 5-HT-induced hypothermia assay was used to define the doses of DR-4004 and SB-269970 predicted to impact 5-HT7 receptors in the brain in vivo. 5-HT induced hypothermia in wildtype mice by either i.p. or i.c.v. routes but did not in 5-HT7 receptor knockout mice. 5-HT-induced hypothermia was not attenuated by drugs selectively blocking alpha1 or 5-HT1A receptors. Doses of DR-4004 and SB-269970 that blocked 5-HT-induced hypothermia, did not display significant anxiolytic-like (elevated plus maze; vogel conflict) or antidepressant-like efficacy (tail-suspension test) in mouse models. These compounds did demonstrate some antipsychotic-like properties in the PCP-induced hyperactivity assay and anxiolytic/anti-stress effects in the stress-induced cGMP assay. Negative findings were substantiated by positive control drugs that were active in each assay system. We conclude that 5-HT-induced hypothermia can be used to estimate blockade of central 5-HT7 receptors. Effects of DR-4004 and SB-269970 in animal models are generally consistent with the experimental literature that the evidence is mixed or not robust regarding the potential efficacy of 5-HT7 receptor antagonism in the treatment of anxiety, depression, or schizophrenia.
Neuropharmacology, 2001
oxy]-5-pyridyl]carbamoyl]-6-trifluoromethylindoline hydrochloride) is a new, selective 5-hydroxytryptamine (5-HT) 2C receptor inverse agonist. SB-243213 has high affinity for the human 5-HT 2C receptor (pK i 9.37) and greater than a 100-fold selectivity over a wide range of neurotransmitter receptors, enzymes and ion channels. In in vitro functional studies, SB-243213 acted as an inverse agonist at the human 5-HT 2C receptor with a pK b of 9.8. In in vivo studies, SB-243213 was a potent inhibitor of central 5-HT 2C receptor-mediated function in rats, blocking meta-chlorophenylpiperazine-induced hypolocomotion with an ID 50 of 1.1 mg/kg p.o. and a long duration of action (Ͼ8 h). In rats, SB-243213 exhibited anxiolytic-like activity in both the social interaction and Geller-Seifter conflict tests. Importantly, unlike diazepam, chronic administration of SB-243213 did not result in the development of either tolerance to the anxiolytic-like effects or withdrawal anxiogenesis. Furthermore, in rodents, SB-243213 did not affect seizure threshold, did not increase body weight or induce catalepsy, but attenuated the haloperidol-induced catalepsy. SB-243213 did not affect amphetamine-, MK-801-or phencyclidine-induced hyperactivity. In conclusion, SB-243213 may possess an improved anxiolytic profile compared to benzodiazepines. SB-243213 also modulates dopaminergic transmission, lacks pro-psychotic properties and may have utility in the treatment of schizophrenia and motor disorders.