5-HT1A receptor knockout mice and mice overexpressing corticotropin-releasing hormone in models of anxiety

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Abstract

Pharmacological experiments have implicated a role for serotonin (5-HT)1A receptors in the modulation of anxiety. More recent is the interest in corticotropin-releasing hormone (CRH) system as a potential target for the treatment of anxiety disorders. However, selective pharmacological tools for the CRH system are limited, hampering research in this field. Gene targeting is a relatively new approach to study mechanisms underlying anxiety disorders. 5-HT1A receptor knockout (1AKO) mice have been created on three different background strains, and two different lines of mice, overexpressing CRH (CRH-OE), have been generated. In the present review, behavioural and physiological findings reported for 1AKO mice and CRH-OE mice will be reviewed. As behavioural phenotyping is often limited to one or two approach avoidance paradigms, we extended these observations and also tested 1AKO and CRH-OE mice in a conditioned fear paradigm. This paradigm reflects essentially different aspect of anxiety than approach avoidance paradigms. 1AKO mice on a 129/Sv background strain showed similar freezing as wild-type (WT) mice. In CRH-OE mice, less freezing was observed than in the corresponding wild-type mice. The fact that the anxious phenotype of these genetically altered mice seems less clear than initially reported will be discussed. Rather than studying the direct consequences of alterations in the targeted gene, 1AKO and CRH-OE mice seem very valuable to study compensatory processes that seem to have taken place in reaction to life-long changes in gene expression.

Introduction

The brain γ-aminobutyric acid (GABA)-ergic system is the neurotransmitter system most strongly linked to anxiety. Since their introduction in the early 1960s, benzodiazepines are still the most widely prescribed compounds in the treatment of anxiety disorder. Over the years, other neurotransmitter systems have received much attention as potential targets in the search for new anxiolytics with fewer side effects. The serotonergic (5-HT) system is one of the neurotransmitter systems associated with anxiety (Griebel, 1995). Research has focussed especially on the 5-HT1A receptor subtype, but so far, this has resulted in only few clinically effective compounds. More recent is the interest in the neuropeptide corticotropin-releasing hormone (CRH). This neuropeptide is known to be a key modulator of behavioural, autonomic, and neuroendocrine responses to stress (Dunn and Berridge, 1990). Persistent changes in central nervous system CRH may underlie the development of mood and anxiety disorders (Heim and Nemeroff, 1999). However, lack of highly selective agonists and antagonists for both CRH receptor subtypes has hampered research into the role of CRH in anxiety. In the last decade, genetically altered mice have been generated to further study the role of neurotransmitter systems in fear and anxiety (for reviews, see Belzung, 2001, Holmes, 2001). By selective inactivation of specific genes, knockout mice can be created, whereas adding extra genes to the genome results in the overexpression of a specific gene product. In this way, the function of a specific gene can be investigated. In the present paper, behavioural and physiological findings obtained with 5-HT1A knockout (1AKO) mice and mice overexpressing CRH (CRH-OE) will be reviewed, and new data from our research group will be presented.

Section snippets

Serotonin and 5-HT1A receptors

The serotonergic neurotransmitter system has one endogenous ligand, 5-HT, but is rather complex because of the existence of at least 14 5-HT receptor subtypes (Hoyer et al., 1994). The 5-HT1A receptor has been well characterized pharmacologically, thanks to the availability of selective and potent agonists and antagonists. Both agonists and antagonists modulate anxiety behaviour in animals and, importantly, 5-HT1A receptor agonists also modulate anxiety in humans. The partial 5-HT1A receptor

CRH and anxiety

CRH is involved in regulating adaptive responses to stress. CRH not only activates the hypothalamic pituitary adrenal axis and the autonomic nervous system, but also modulates behavioural responses to a wide range of stressful stimuli. Central CRH administration has arousing effects, including increases in heart rate and blood pressure, and increases in locomotion and acoustic startle response (Koob et al., 1993). This profile of behavioural activation shifts to enhanced suppression of

Conclusions

The present review shows that reports on anxiety behaviour in 1AKO and CRH-OE mice are not conclusive. Some research groups observed enhanced anxiety behaviour in approach avoidance paradigms, but this could not always be replicated in other approach avoidance studies or in other laboratories. Anxiety tests modelling other aspects of anxiety, like stress-induced hyperthermia, which is independent of locomotor activity, and fear conditioning both yielded negative results in 1AKO mice as well as

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