CNS & Neurological Disorders - Drug Targets, 2006, 5, 135-145 135 1871-5273/06 $50. 00+. 00 © 2006 Bentham Science Publishers Ltd. Neuropeptides in Psychiatric Diseases: An Overview with a Particular Focus on Depression and Anxiety Disorders C. Belzung *,1 , I. Yalcin 1 , G. Griebel 2 , A. Surget 1 and S. Leman 1 1 EA3248, Psychobiologie des émotions, UFR Sciences et techniques, Parc Grandmont, 37200 Tours, France 2 Sanofi-Aventis, CNS Research Department, 31 avenue Paul Vaillant-Couturier, 92220 Bagneux, France Abstract: This paper aimed at reviewing the involvement of neuropeptides in various psychiatric diseases, particularly in depression, and anxiety disorders. General features of neuropeptides are first described, including the history of their discovery, their definition, classification, biosynthesis, transport, release, inactivation, as well as their interaction with specific neuronal receptors. The differences with classical neurotransmitters are mentioned, as well as the different patterns of co-transmission. Finally, different mechanisms, both at the cellular and at the systemic level, are proposed that may explain the involvement of these molecules in various psychiatric diseases. Indeed, at the cellular level, a neuropeptide can be involved in a psychiatric disease, either because it is co-localized with a classical neurotransmitter involved in a disease, or because the neuropeptide-containing neuron projects on a target neuron involved in the disease. At the systemic level, a neuropeptide can play a direct role in the expression of a symptom of the disease. This is illustrated by different exemples. Keywords: Neuropeptide, psychiatric diseases, depression, anxiety. INTRODUCTION In the past decades, there has been increasing interest and, consequently, active and dynamic research on neuropeptides. This has been facilitated by the development of biochemical, immunohistochemical and in situ hybridization techniques. Neuropeptides regulate physiological processes throughout all phases of development. They act as neurohormones, neurotransmitters, and/or neuromodulators, maintain homeostasis and influence cognitive, emotional and behavioural functions, including hunger, thirst, sex drive, pleasure and pain. As they are synthesized and bind to specific targets within brain areas involved in psychiatric conditions and are sometimes colocalized in neurons synthesizing classical neurotransmitters that are related to some of these diseases, compounds interfering with neuropeptide functions have been developed as pharmacological tools intending to treat a variety of mental diseases, including schizophrenia, major depression, anorexia nervosa or addiction. This paper is divided into two parts: a first one describing some very general features of these molecules (history, definition, biosynthesis, transport, biodistribution, differences and interactions with classical neurotransmitters), and a second part, based on various examples, describing putative mechanisms of action of neuropeptides in particular psychiatric diseases such as anxiety disorders and depression. The first part is not aimed at providing novel data on neuropeptide biosynthesis or interactions with classical transmitters, but presents general features of these molecules, with the hope that they may help a non specialized reader within this field. *Address correspondence to this author at the EA3248, Psychobiologie des émotions, UFR Sciences et techniques, Parc Grandmont, 37200 Tours, France; E-mail: catherine.belzung@univ-tours.fr I- GENERAL FEATURES History The term neuropeptide was initially coined by de Wied (1925-2004) at the end of the sixties. He formulated the hypothesis that peptides localized within neurons may directly influence brain function and consequently human and animal behaviour [1,2]. In fact, de Wied began research in this field at the end of the fifties when he was studying the behavioural effects of pituitary hormones on rodents confronted with an avoidance learning paradigm in a shuttle box. At this time, he showed that stress hormones such as arginine vasopressin (AVP) and adrenocorticotropic hormone (ACTH) could act directly on the brain, an effect that was independent of their endocrine function. This led to the "neuropeptide concept”, a concept that encompasses the physiological functions of neuropeptide at the cellular level (its effects on neural communication) and at the integrative level (its effects on the modulation of brain activity, cognitive functions and behaviour). Definition According to Holmgren and Jensen [3], “A neuropeptide is a peptide that can be released from a neurone as a signalling molecule. This signalling molecule will have an effect as a transmitter or a modulator on other excitable cells (and sometimes on its own cell, actually).” It is important here to note that a neuropeptide is not only a peptide being present in neurons; it should also be involved in cellular communication, that is, elicits effects on another cell via high affinity binding to specific targets (receptors). These molecules are expressed in the central nervous system (CNS) as well as in the peripheral nerves (for example sensory and motor nerves); however, in this review of involvement of neuropeptides in psychiatric conditions, we will focus on neuropeptides expressed in the CNS. Indeed, when a given peptide is involved in a psychiatric disease, this generally