CNS & Neurological Disorders - Drug Targets - Volume 5, Issue 2, 2006

The health burden of psychiatric disorders is rapidly increasing, whilst the range of available pharmacotherapies is limited and suboptimal with regard to efficacy and tolerability. Recent findings support a major role for neuropeptides in several of these conditions and thereby identify neuropeptide systems as potential novel therapeutic targets for the treatment of psychiatric disorders. In preclinical models, pharmacological and/or genetic manipulation of corticotropin-releasing factor (CRF), vasopressin, neuropeptide Y (NPY), galanin, bombesin, nociceptin and neurotensin alters anxiety-, depression- or schizophrenia-related responses. Recently, specific and highly potent small molecule neuropeptide receptor agonists and antagonists have been developed that can readily cross the blood-brain barrier. Clinical assessment of several compounds is currently underway. This issue will provide an overview of recent developments in this rapidly advancing field. The introductory paper by Catherine Belzung and colleagues [1] describes general features of neuropeptides, including the history of their discovery, their definition, classification, biosynthesis, transport, release, inactivation, as well as their interaction with specific neuronal receptors. It focuses more particularly on the involvement of neuropeptides in depression, and anxiety disorders. CRF is undoubtedly the most extensively studied neuropeptide, notably because of its well-known involvement in the regulation of the hypothalamo-pituitary-adrenal (HPA) stress axis, whose dysfunctioning has been directly linked to the development of stress-related disorders. Thomas Steckler and Frank Dautzenberg give a comprehensive update on the involvement of CRF and its receptor subtypes in affective disorders and drug abuse [2]. Since vasopressin has been shown to be critical for adaptation of the HPA axis during stress through its ability to potentiate the stimulatory effect of CRF, it has been hypothesized that this peptide may provide a good opportunity for pharmacological treatment of stress-related disorders. The availability of the first orally active non-nonpeptide V1b receptor antagonist, SSR149415, opened a new era for examining the role of vasopressin in stress-related disorders. Rainer Landgraf in his review [3] elegantly demonstrates that the capability of vasopressin to respond to both stressful stimuli and mediate genetic polymorphisms makes the central release of this peptide a key process for converging behavioral regulation related to stress disorders. Christina Carjaval and colleagues [4] review recent developments on the role of NPY in emotion and alcohol dependence and they examine the potential of the NPY system as a novel therapeutic strategy in the treatment of anxiety, depression and alcohol-related disorders. Although less studied within the CNS field than the previous peptides, gastrin-releasing peptides and their receptors are increasingly examined for their involvement in psychiatric and neurological diseases. Rafael Roesler and his colleagues [5] review this emerging idea. Becky Kinkead and Charles Nemeroff [6] discuss the idea that neurotensin receptor ligands may represent an innovative approach for the treatment of schizophrenia. There is now compelling evidence that the orphanin FQ/nociceptin (OFQ/N) system may represent a valuable target for the development of drugs treating a variety of psychiatric disorders. Rainer Reinscheid [7] discusses the recent development of OFQ/N ligands and their behavioral effects in animal studies. Our understanding of the role of the galanin system in modulating emotional behavior and drug withdrawal has progressed in recent years. Andrew Holmes and Marina Picciotto [8] summarize in their review current developments and scientific achievements that have been made to elucidate the functions of galanin in psychiatric disorders. In the last review article, Michael Cowen and Andrew Lawrence [9] discuss the potential of therapeutic strategies targeting neuropeptide systems implicated in aberrant alcohol-seeking behaviour. The search for novel treatment strategies for psychiatric disorders is driven by the growing medical need to enhance the response rate, efficacy and side-effect profile of existing drugs. Given the wealth of animal and human data supporting the role for neuropeptides in modulating behavioral responses, targeting these systems remains a highly promising avenue for the development of novel clinical entities in psychiatric disorders.

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.

Dysfunctioning of corticotropin-releasing factor (CRF) and its receptors (CRF1 and CRF2) has been linked to the development of stress-related disorders, such as affective disorders and drug abuse. The molecular characterization of CRF1 and CRF2 receptors and their splice variants has generated detailed information on their pharmacology, tissue distribution and physiology. In addition, the recent development of a small molecule CRF1 antagonist has provided important information on the contribution of this receptor to the development of stress-related diseases. Despite the high homology to the CRF1 receptor and the generation of peptide-based research tools, the physiological role of the CRF2 receptor is largely unclear. This is due to different expression patterns in rodents and primates and the lack of brainpenetrant CRF2-selective small molecule antagonists. However, the CRF2 receptor may be important for motivational types of behavior essential for survival, such as feeding and defense and impacts on cardiovascular function.

The neuropeptide arginine vasopressin (AVP) is released within distinct brain areas upon appropriate stimulation, including stressful challenges. Following its predominantly dendritic release, AVP triggers a variety of receptor-mediated effects related to behavioral and neuroendocrine regulation. Antagonist treatment together with other sophisticated loss-of-function and gain-of-function approaches provide evidence for a multiple involvement of V1a and V1b receptor subtypes in stress-related behavior and disorders, including anxiety disorders, comorbid depression and their neuroendocrine concomitants. Conversely, in the high versus low anxiety (HAB/LAB) rat model, the phenotype of extreme trait anxiety is associated with a polymorphism-driven overexpression of AVP in the hypothalamic paraventricular nucleus. This overexpression of AVP might be considered a final common pathway of anxiety-related behavior. The capability of both responding to stressful stimuli and mediating genetic polymorphisms makes the central release of AVP a key process for converging (i.e., environmentally and genetically driven) behavioral regulation. Polymorphisms in the promoter structures of the AVP gene and AVP receptor genes, underlying differences in gene expression, thus contribute to individual variation in behavior as well as to psychopathology, making genes of the brain AVP system and their products a promising target for therapeutic interventions.

Neuropeptide Y (NPY) is considered to be an important neuromodulator in the regulation of emotional behavior. For example, NPY is consistently involved in anxiety-related behaviors and there is increasing support for a role of this peptide in mood disorders such as depression. Furthermore, recent evidence suggests that NPY has a significant role in the neurobiological response to alcohol, including alcohol consumption, dependence, and withdrawal. In addition, NPY is beginning to emerge as an important modulator in the etiology of alcoholism that is independent from the addictive and reinforcing properties of the traditional system commonly associated with dopamine and instead, is strongly associated with innate emotionality. The recent developments elucidating the role of NPY in emotion and alcohol dependence are reviewed and the potential of the NPY system as a novel therapeutic strategy in the treatment of anxiety, depression and alcohol-related disorders is examined.

The mammalian bombesin (BB)-like peptide gastrin-releasing peptide (GRP) stimulates cell proliferation, displays a range of neuroendocrine activities, and acts as a growth factor in the pathogenesis of several types of human cancer. Several lines of evidence have indicated that GRP and its receptor (GRPR) might also be involved in the neurochemical alterations associated with psychiatric and neurological disorders. GRP and GRPR are distributed throughout the mammalian central nervous system (CNS). Altered levels of BB-like peptides have been found in the CNS of patients with schizophrenia and Parkinson's disease. Dysfunctions in GRPR-induced cellular calcium signaling have been reported in fibroblasts from patients with Alzheimer's disease. A translocation in the GRPR gene has been associated with autism. Pharmacological and genetic studies in rodents have shown that GRPRs in brain areas such as the dorsal hippocampus and amygdala are importantly involved in regulating synaptic plasticity and aspects of behavior that might be altered in disorders such as anxiety, schizophrenia, depression, autism and dementia. Behaviors modulated by the GRPR in rodents include grooming, food intake, stereotypy, social behavior, and emotionally-motivated learning and memory. Together, these findings support the view that the GRPR should be considered a therapeutic target for a subset of CNS diseases.

Evidence implicating neural circuits that utilize the neuropeptide transmitter neurotensin (NT) in the pathophysiology of schizophrenia and in the mechanism of action of antipsychotic drugs has previously been reviewed. The majority of evidence, taken together, supports the development of NT receptor agonists as novel antipsychotic drugs. This review comprehensively describes the NT receptor subtypes, discusses the development of NT receptor agonists and the behavioral effects of currently available NT receptor agonists. The compilation of data suggests that NT receptor agonists may represent a novel class of antipsychotic drugs for the treatment of schizophrenia.

Almost 10 years after the discovery of Orphanin FQ / Nociceptin (OFQ/N) a large number of synthetic small molecule agonists and antagonists have been developed and tested in various physiological assays. Together with the academic work on the physiological functions of OFQ/N, we now have compelling evidence that this neuropeptide system might represent a valuable target for the development of drugs treating a variety of psychiatric disorders. Most prominently, the anti-stress and anxiolytic effects of OFQ/N agonists have been investigated although clinical trials have not yet been launched. Other possible applications of OFQ/N agonists and antagonists include treatment of depression, anorexia and rewarding aspects of drug addiction. This paper will summarize current developments and highlight the scientific achievements that have been made to elucidate the functions of OFQ/N with respect to psychiatric disorders.

Galanin is a neuropeptide synthesized in many neuronal types including brainstem norepinephrine-producing cells of the locus coeruleus and the serotonin-producing neurons of the dorsal raphe nucleus. Galanin inhibits the firing of rodent norepinephrine, serotonin and dopamine neurons and reduces release of these neurotransmitters in forebrain target regions. The distribution of galanin and its receptors and its actions on monoamine signaling has fostered interest in this neuropeptide in the field of behavioral pharmacology and the potential role of galanin in the pathophysiology of neurological diseases such as Alzheimer's disease, epilepsy, stroke, and in psychiatric disorders such as anxiety, depression, and drug addiction, particularly withdrawal. In rodent models, expression of galanin in brain is altered by various stressors, while administration of galanin can modulate anxiety-like responses to stress. Emerging evidence further supports a role for galanin in the mediation of depression-related behaviors in rodents. Recently, galanin agonists have been shown to decrease behavioral signs of opiate withdrawal, which are thought to result from hyperactivation of brain stress pathways. Studies using genetically modified mice suggest that galanin normally plays a protective role against opiate reinforcement and withdrawal. The present article reviews current evidence on a potential role for galanin in modulating stress-related neural pathways and behaviors, and speculates on the therapeutic potential of targeting this galanin system for emotional disorders and opiate addiction.

As with other addictions, human alcoholism is characterised as a chronically relapsing condition. Consequently, the "holy grail" from a therapeutic viewpoint is the development of clinically effective, safe drugs that promote high compliance rates and prevent relapse. Here we discuss the potential of therapeutics targeting neuropeptide systems implicated in aberrant alcohol-seeking behaviour. Clearly, much of the data so far available comes from preclinical studies; however, one of the first effective therapeutic strategies for alcoholism (still in use today) was the use of non-selective opioid receptor antagonists, such as naltrexone (Revia™). In addition to opioid receptors, other neuropeptide receptors including those for corticotrophin releasing factor (CRF), neuropeptide Y and nociceptin may represent valid therapeutic targets to regulate alcohol consumption and the affective consequences of alcohol withdrawal.