Cortical 5-HT2A receptor signaling modulates anxiety-like behaviors in mice. Science

University of Lausanne, Lausanne, Vaud, Switzerland
Science (Impact Factor: 33.61). 08/2006; 313(5786):536-40. DOI: 10.1126/science.1123432
Source: PubMed


Serotonin [5-hydroxytryptamine (5-HT)] neurotransmission in the central nervous system modulates depression and anxiety-related behaviors in humans and rodents, but the responsible downstream receptors remain poorly understood. We demonstrate that global disruption of 5-HT2A receptor (5HT2AR) signaling in mice reduces inhibition in conflict anxiety paradigms without affecting fear-conditioned and depression-related behaviors. Selective restoration of 5HT2AR signaling to the cortex normalized conflict anxiety behaviors. These findings indicate a specific role for cortical 5HT2AR function in the modulation of conflict anxiety, consistent with models of cortical, "top-down" influences on risk assessment.

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    • "Inhibitory effects of 5-HT on GABA mIPSC frequency suggested that 5-HT receptors were acting presynaptically. Combining pharmacological tools with mice lacking 5-HT 2A receptors (5-HT 2A /- ; Weisstaub et al., 2006), we described inhibitory 5-HT 1A receptors at presynaptic terminals from 5-HT 2A -/-mice. The lower inhibitory effects of 5-HT 100 μM puff in VB neurons from WT mice suggested that 5-HT 2A receptors could counteract the inhibitory actions of 5-HT 1A. "
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    ABSTRACT: Serotonin receptors are targets of drug therapies for a variety of neuropsychiatric and neurodegenerative disorders. Cocaine inhibits the re-uptake of serotonin (5-HT), dopamine, and noradrenaline while caffeine blocks adenosine receptors and opens ryanodine receptors in the endoplasmic reticulum. We studied how 5-HT and adenosine affected spontaneous GABAergic transmission from thalamic reticular nucleus (TRN). We combined whole-cell patch clamp recordings of miniature inhibitory post-synaptic currents (mIPSCs) in ventrobasal (VB) thalamic neurons during local (puff) application of 5-HT in wild type (WT) or knockout mice lacking 5-HT2A receptors (5-HT2A -/-). Inhibition of mIPSCs frequency by low (10 μM) and high (100 μM) 5-HT concentrations was observed in VB neurons from 5-HT2A -/- mice. In WT mice, only 100 μM 5-HT significantly reduced mIPSCs frequency. In 5-HT2A -/- mice, NAN-190, a specific 5-HT1A antagonist, prevented the 100 μM 5-HT inhibition while blocking H-currents that prolonged inhibition during post-puff periods. The inhibitory effects of 100 μM 5-HT were enhanced in cocaine binge-treated 5-HT2A -/-. Caffeine binge treatment did not affect 5-HT-mediated inhibition. Our findings suggest that both 5-HT1A and 5-HT2A receptors are present in presynaptic TRN terminals. Serotonergic-mediated inhibition of GABA release could underlie aberrant thalamocortical physiology described after repetitive consumption of cocaine. This article is protected by copyright. All rights reserved.
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    • "Normal depressive-like behavior in the FST and TST Impaired facilitation of synaptic activity in PFC Weisstaub et al., 2006; Beique et al., 2007 -Decreased anxietylike behavior TPH2 Tryptophan hydroxilase 2 Kim et al., 2009 Tph2 À / À ; "
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    • "In general, these studies support the notion that early life adverse experience is a major risk factor for anxiety development (Benekareddy et al. 2011). Serotonergic neurotransmission is known to be related to anxiety (Gross and Hen 2004), and serotonin type 2 (5-HT2) receptors have been implicated as possible targets to modulate anxiety behavior (Weisstaub et al 2006). "
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