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WEISSTAUB Noelia Victoria

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Título:

Contribution of cortical 5-HT2a receptors signaling to the modulation of anxiety-like behaviors in mice

Autor/es:

WEISSTAUB, NOELIA

Lugar:

Scottdale, Arizona, USA

Reunión:

Congreso; Annual Meeting of ACNP; 2008

Institución organizadora:

American College of Neuropharmacology

Resumen:

Behavioral responses to environmental stimuli result from complex interactions between different brain structures. Anxiety is a potentially adaptive response to uncertainties and stressors that are often present in the environment. Papez in 1937 made the first attempt to identify the basic circuitry underlying the emotional response to anxiety and with time a more complex circuitry has emerged implicating cortical areas, hippocampus, amygdala, medial preoptic area, hypothalamus, ventral striatum, periaqueductal gray and their interconnected structures. Several neurotransmitters are involved in mediating anxiety-related behaviors including GABA, noradrenaline, and serotonin (5-HT). 5-HT producing cells of the dorsal and median raphe nuclei (DRN and MRN respectively) project widely to the brain regions involved in anxiety and serotonergic compounds act as anxiolytics in humans and animals. Various 5-HT receptors have been postulated to mediate the effects of 5-HT on anxiety states including HTR1A, HTR2 among others. In particular pharmacological evidence suggested that 5-HT2A, which is expressed in most of these anxiety-related brain regions, might be important in modulating anxiety responses at different levels of the circuit. We further investigated the role of 5-HT2A receptors in the control of anxiety states using a genetic mouse model. Given that 5-HT signaling exerts pro-anxiety effects on behavior, if the HTR2As are involved in mediating this effect, loss of HTR2A signaling capacity should result in disinhibition of behavior. Methods: Mice lacking HTR2As (2AKO) were engineered. These mice were exposed to a battery of behavioral test to address their response in conflict situations. Also their response in fear and depression related test was measured. In order to identify the population of 5-HT2A receptors involved in the regulation of anxiety states, we utilized a second genetic line that allowed us to gain spatial control over the expression of 5-HT2A receptors. These rescue mice were exposed to a similar battery of behavioral paradigms. Results: 2AKO mice exhibited more disinhibited or risky behaviors compared to their wild type littermates, however, no differences in their response in depression or fear related test were recorded, suggesting that 5-HT2A receptor signaling is required for the normal response to novel conflict situations. In order to identify which subpopulations of HTR2As were involved in this low-anxiety phenotype of the global knockout, we restored the expression of HTR2As in the cortex while leaving other HTR2A-expressing regions inactivated. We found that restoration of cortical signaling was sufficient to normalize the anxiety behaviors of the 2AKO mice. Discussion: This study found that 5-HT2A signaling is required for the normal expression of behavioral responses to novel conflict situations. Also we established a key role of cortical HTR2A signaling in mediating anxiety-related behaviors.

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