Interactions between corticotropin-releasing hormone and serotonin: implications for the aetiology and treatment of anxiety disorders.

The amount of evidence for a role of aberrant serotoninergic neurotransmission in the aetiology of anxiety disorders, such as generalised anxiety and panic disorder, has been increasing steadily during the past several years. Although the picture is far from complete yet--partly due to the large number of serotonin (5-HT) receptors and the often-disparate effects of receptor agonists and antagonists in animal models of anxiety--SSRIs and the 5-HT1A agonist buspirone have now earned their place in the treatment of anxiety disorders. However, these drugs show--as they do in depressed patients--a delayed onset of improvement. Therefore, new therapeutical strategies are being explored. Corticotropin-releasing hormone (CRH), which plays a key role in the autonomic, neuroendocrine and behavioural responses to stress, is a strong anxiogenic neuropeptide and a promising candidate for therapeutical intervention in anxiety disorders. The neuroanatomical localisation of CRH, its congeners (the urocortins) and their receptors within the serotoninergic raphé nuclei suggests that interactions between the CRH system and 5-HT may play a role in fear and anxiety. In this chapter, I will discuss studies from my own and other laboratories showing that CRH and the urocortins influence several aspects of serotoninergic neurotransmission, including the firing rate of 5-HT neurones and the release and synthesis of this monoamine. Moreover, the interactions between CRH and 5-HT during psychologically stressful challenges will be discussed. Finally, I will review data showing that long-term alterations in the CRH system lead to aberrant functioning of serotoninergic neurotransmission under basal and/or stressful conditions. From this growing set of data the picture is emerging that the CRH system exerts a vast modulatory influence on 5-HT neurotransmission. An aberrant cross-talk between CRH and 5-HT may be of crucial importance in the neurobiology of anxiety disorders and represents, therefore, a promising goal for therapeutical intervention in these psychiatric diseases.