Characterization of 5HT 1A/1B−/− mice: An animal model sensitive to anxiolytic treatments (original) (raw)
Related papers
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2018
Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are first-line antidepressants, but require several weeks to elicit their actions. Chronic SSRI treatment induces desensitization of 5-HT1A autoreceptors to enhance 5-HT neurotransmission. Mice (both sexes) with gene deletion of 5-HT1A autoreceptors in adult 5-HT neurons (1AcKO) were tested for response to SSRIs. Tamoxifen-induced recombination in adult 1AcKO mice specifically reduced 5-HT1A autoreceptor levels. The 1AcKO mice showed a loss of 5-HT1A autoreceptor-mediated hypothermia and electrophysiological responses, but no changes in anxiety- or depression-like behavior. Sub-chronic fluoxetine (FLX) treatment induced an unexpected anxiogenic effect in 1AcKO mice in the novelty suppressed feeding (NSF) and elevated plus maze tests, as did escitalopram in the NSF test. No effect was seen in wild-type (WT) mice. Sub-chronic FLX increased 5-HT metabolism in prefrontal cortex, hippocampus and raphe of 1AcKO but not WT mice, sugges...
Pharmacology Biochemistry and Behavior, 2015
More effective treatments for major depression are needed. We studied if the selective 5-HT 3 receptor antagonist ondansetron can potentiate the antidepressant potential of the selective serotonin (5-HT) reuptake inhibitor (SSRI) paroxetine using behavioral, neurochemical and electrophysiological methods. Flinders Sensitive Line (FSL) rats, treated with ondansetron, and/or a sub-effective dose of paroxetine, were assessed in the forced swim test. The effects of an acute intravenous administration of each compound alone and in combination were evaluated with respect to 5-HT neuronal firing rate in the dorsal raphe nucleus (DRN). Effects of s.c. administration of the compounds alone and in combination on extracellular levels of 5-HT were assessed in the ventral hippocampus of freely moving rats by microdialysis. The results showed that ondansetron enhanced the antidepressant activity of paroxetine in the forced swim test. It partially prevented the suppressant effect of paroxetine on DRN 5-HT neuronal firing and enhanced the paroxetine-induced increase of hippocampal extracellular 5-HT release. These findings indicate that 5-HT 3 receptor blockade potentiates the antidepressant effects of SSRIs. Since both paroxetine and ondansetron are used clinically, it might be possible to validate this augmentation strategy in depressed patients.
Journal of Neurochemistry, 2009
Selective serotonin reuptake inhibitors (SSRIs) increase extracellular serotonin (5-HT) levels through inhibition of the carrier responsible for the reuptake of 5-HT into serotonergic neurons . Secondary to this effect 5-HT receptors, including those involved in negative feedback regulation of 5-HT neuronal activity, become increasingly activated. This is supported by single cell recordings in rats, showing that 5-HT reuptake inhibition decreases serotonergic cell firing through the activation of 5-HT 1A autoreceptors ( Fornal et al. 1999). This secondary effect of SSRIs, which counteracts their primary action on the 5-HT carrier, has prompted Artigas (1993) to propose a clinical augmentation strategy to improve onset of action and therapeutic efficacy of SSRIs by simultaneously blocking the 5-HT 1A autoreceptors with pindolol. under the curve; SERT, serotonin transporter; SSRI, selective serotonin reuptake inhibitor.
The International Journal of Neuropsychopharmacology, 2001
The possible role of 5-HT "A and 5-HT #C receptors in the anxiety induced by fear, acute treatment with SSRI antidepressants or the 5-HT receptor agonist m-CPP were tested in the social interaction anxiety test in male Sprague-Dawley rats. Fluoxetine (2n5-10 mg\kg, i.p.), sertraline (15 mg\kg, i.p.) and m-CPP (0n5-2n0 mg\kg, i.p.) all had an anxiogenic-like profile (decrease in time of total social interaction and increase in self-grooming compared to vehicle) under low-light, familiar arena test conditions. All these effects were reversed by pretreatment with the highly subtype-selective 5-HT #C receptor antagonist, SB-242084 at doses of either 0n05 or 0n2 mg\kg, i.p. In contrast, the selective 5-HT "A receptor antagonist WAY-100635 (0n05 and 0n2 mg\kg, s.c.) failed to reverse SSRI-induced decrease in time of total social interaction, further, it augmented selfgrooming response. SB-242084 (0n2 mg\kg) and WAY-100635 (0n05 and 0n2 mg\kg) reversed hypolocomotion caused by the SSRI antidepressants. SB-242084, tested alone against vehicle under highlight , unfamiliar arena test conditions associated with fear, caused significant anxiolysis at 0n2 mg\kg and higher doses. These results suggest that increased anxiety in rodents, and possibly, also in humans (e.g. agitation or jitteriness after SSRIs and panic after m-CPP), caused by acute administration of SSRI antidepressants or m-CPP, are mediated by activation of 5-HT #C receptors. Blockade of 5-HT "A autoreceptors may exacerbate certain acute adverse effects of SSRI antidepressants. Both 5-HT "A and 5-HT #C receptors are involved in the SSRIinduced decrease in locomotor activity. In addition, our studies confirm data that subtype-selective 5-HT #C receptor antagonists have strong anxiolytic actions.
Elevated anxiety and antidepressant-like responses in serotonin 5-HT 1A receptor mutant mice
Proceedings of the National Academy of Sciences, 1998
The brain serotonin (5-hydroxytryptamine; 5-HT) system is a powerful modulator of emotional processes and a target of medications used in the treatment of psychiatric disorders. To evaluate the contribution of serotonin 5-HT 1A receptors to the regulation of these processes, we have used gene-targeting technology to generate 5-HT 1A receptor-mutant mice. These animals lack functional 5-HT 1A receptors as indicated by receptor autoradiography and by resistance to the hypothermic effects of the 5-HT 1A receptor agonist 8-hydroxy-2-(di- n -propylamino)tetralin (8-OH-DPAT). Homozygous mutants display a consistent pattern of responses indicative of elevated anxiety levels in open-field, elevated-zero maze, and novel-object assays. Moreover, they exhibit antidepressant-like responses in a tail-suspension assay. These results indicate that the targeted disruption of the 5-HT 1A receptor gene leads to heritable perturbations in the serotonergic regulation of emotional state. 5-HT 1A recepto...
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.
Pharmacology Biochemistry and Behavior, 1999
Chronic fluoxetine in tests of anxiety in rat lines selectively bred for differential 5-HT 1A receptor function . PHARMACOL BIOCHEM BEHAV 62 (4) 695-701, 1999.-Selective breeding for high and low sensitivity to the hypothermic response induced by the 5-HT 1A receptor agonist 8-OH-DPAT has established two lines of rat (HDS and LDS, respectively) whose behavior differs in a model of depression and in the social interaction test of anxiety. The HDS line has a higher level of anxiety and, furthermore, does not display the usual anxiogenic response to intrahippocampal administration of 8-OH-DPAT. It was therefore hypothesized that this line of rat might be a useful model of high trait anxiety with a susceptibility to depression. We thus investigated whether chronic treatment with fluoxetine would result in an anxiolytic effect in the social interaction test in the LDS and HDS lines of rat. In both lines, acute fluoxetine (10 mg/kg) produced an anxiogenic effect in the social interaction test; when rats were tested 24 h after 14 days of fluoxetine treatment there were no anxiolytic effects in either line. In the social interaction test, chronic fluoxetine treatment did not change either the anxiogenic effect of 8-OH-DPAT (100 ng) injected bilaterally into the dorsal hippocampus in the LDS line or the lack of response in the HDS line. In the elevated plus-maze, chronic fluoxetine treatment resulted in a significant anxiogenic effect in the HDS line, but was without effect in the LDS line. Intrahippocampal 8-OH-DPAT was without effect in the plus-maze in either line. These results suggest that chronic treatment with fluoxetine did not modify the hippocampal 5-HT 1A receptor in either line. The anxiogenic effects observed in the plus-maze in the HDS line after chronic fluoxetine might relate to line differences in 5-HT 1A receptors in other brain regions.
Neuropsychopharmacology, 2005
The addition of low doses of atypical antipsychotic drugs, which saturate 5-HT 2A receptors, enhances the therapeutic effect of selective serotonin (5-hydroxytryptamine; 5-HT) reuptake inhibitors (SSRIs) in patients with major depression as well as treatment-refractory obsessive-compulsive disorder. The purpose of the present studies was to test the effects of combined treatment with a low dose of a highly selective 5-HT 2A receptor antagonist (M100907; formerly MDL 100,907) and low doses of a SSRI using a behavioral screen in rodents (the differential-reinforcement-of low rate 72-s schedule of reinforcement; DRL 72-s) which previously has been shown to be sensitive both to 5-HT 2 antagonists and SSRIs. M100907 has a B100-fold or greater selectivity at 5-HT 2A receptors vs other 5-HT receptor subtypes, and would not be expected to appreciably occupy non-5-HT 2A receptors at doses below 100 mg/kg. M100907 increased the reinforcement rate, decreased the response rate, and shifted the inter-response time distributions to the right in a pattern characteristic of antidepressant drugs. In addition, a positive synergistic interaction occurred when testing low doses of the 5-HT 2A receptor antagonist (6.25-12.5 mg/kg) with clinically relevant doses of the SSRI fluoxetine (2.5-5 mg/kg), which both exerted minimal antidepressant-like effects by themselves. In vivo microdialysis study revealed that a low dose of M100907 (12.5 mg/kg) did not elevate extracellular 5-HT levels in the prefrontal cortex over those observed with fluoxetine alone (5 mg/kg). These results will be discussed in the context that the combined blockade of 5-HT 2A receptors and serotonin transporters (SERT) may result in greater efficacy in treating neuropsychiatric syndromes than blocking either site alone. Neuropsychopharmacology (2005) 0, 000-000.