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Implication of 5-HT2A subtype receptors in DOI activity in the four-plates test-retest paradigm in mice
Nadège Ripoll1, Martine Hascoët, Michel Bourin
1Research Group, EA 3256, Neurobiologie de l'anxiété et de la dépression, Faculté de Médecine, BP 53508, 1 rue Gaston Veil, F44035 Nantes Cedex 01, France.
Abstract:
The four-plates test (FPT) is an animal model of anxiety which allows the detection of anxiolytic effect not only of benzodiazepines (BZDs) but also of other non-BZDs anxiolytic compounds such as antidepressants (ADs). Furthermore, DOI, a 5-HT(2A/2C) agonist, has been shown to exert an anxiolytic-like effect in this model. Retesting mice in animal models of anxiety (test-retest paradigm) induces an anxiogenic-like and a loss of anxiolytic-like effects in response to BZDs and ADs. On the contrary, DOI has been reported to oppose the fear potentiation induced by trial 1 in the FPT. Despite DOI is considered as one of the most selective 5-HT(2A) available, it acts as agonist at all three 5-HT(2) receptor subtypes (5-HT(2A), 5-HT(2B) and 5-HT(2C)). The aim of this study was thus to investigate in the FPT test-retest paradigm, which 5-HT(2) receptor subtype(s) was involved in the DOI-induced effect in experienced mice. The effect of DOI (0.25-4 mg/kg) and the agonists, 5-HT(2B), BW 723C86 (1-16 mg/kg) and 5-HT(2C), RO 60-0175 (0.25-4 mg/kg) have also been studied. Then, antagonism studies were conducted combinating the 5-HT(2A) receptor antagonist SR 46349B, the 5-HT(2B/2C) receptor antagonist SB 206553 or the selective 5-HT(2C) receptor antagonist RS 10-2221 (at the doses of 0.1 and 1 mg/kg) with the DOI (1 mg/kg). Our study shows that the BW 723C86 had no effect on retesting mice, whereas it exerted an anxiolytic-like effect in naive mice. By contrast to DOI, the RO 60-0175 had no effect neither in naive nor experienced mice. Furthermore, only the SR 46349B antagonized the DOI-induced anti-punishment effect. Diazepam included as a positive control also increased in each case the number of punished passages in naive mice. Our findings altogether also suggest that DOI exerts its anxiolytic-like effect in the FPT test-retest paradigm through 5-HT(2A) receptors.
Insights
The four-plates test reveals DOI
Area of Science:
- Neuroscience
- Pharmacology
- Behavioral Science
Background:
- The four-plates test (FPT) is a validated animal model for assessing anxiolytic effects of various compounds.
- DOI, a 5-HT(2A/2C) agonist, exhibits anxiolytic-like effects in the FPT, but its specific receptor involvement in experienced animals is unclear.
- Repeated testing in anxiety models can alter drug responses, necessitating investigation into DOI's effects in this context.
Purpose of the Study:
- To elucidate the specific 5-HT(2) receptor subtype(s) mediating DOI's anxiolytic-like effect in the FPT test-retest paradigm.
- To compare the effects of selective agonists for 5-HT(2B) and 5-HT(2C) receptors with DOI in naive and experienced mice.
- To determine the role of 5-HT(2A), 5-HT(2B), and 5-HT(2C) receptors in DOI's anti-punishment effect using receptor antagonists.
Main Methods:
- Administered DOI, 5-HT(2B) agonist BW 723C86, and 5-HT(2C) agonist RO 60-0175 to naive and experienced mice in the FPT.
- Utilized receptor antagonists SR 46349B (5-HT(2A)), SB 206553 (5-HT(2B/2C)), and RS 10-2221 (5-HT(2C)) in combination with DOI.
- Assessed anxiolytic-like effects by measuring punished passages, with diazepam serving as a positive control.
Main Results:
- BW 723C86 showed anxiolytic-like effects in naive mice but not in retested (experienced) mice.
- RO 60-0175 did not produce anxiolytic-like effects in either naive or experienced mice.
- Only the 5-HT(2A) receptor antagonist SR 46349B successfully antagonized the anti-punishment effect of DOI in experienced mice.
Conclusions:
- The anxiolytic-like effect of DOI in the FPT test-retest paradigm is mediated primarily through 5-HT(2A) receptors.
- 5-HT(2B) and 5-HT(2C) receptors do not appear to play a significant role in DOI's anti-punishment effects in experienced mice.
- These findings contribute to understanding the neurobiological mechanisms underlying anxiety and the action of serotonergic compounds.
