Neuropeptide and Sigma Receptors as Novel Therapeutic Targets for the Pharmacotherapy of Depression

Abstract

Among the most prevalent of mental illnesses, depression is increasing in incidence in the Western world. It presents with a wide variety of symptoms that involve both the CNS and the periphery. Multiple pharmacological observations led to the development of the monoamine theory as a biological basis for depression, according to which diminished neurotransmission within the CNS, including that of the dopamine, noradrenaline (norepinephrine) and serotonin systems, is the leading cause of the disorder. Current conventional pharmacological antidepressant therapies, using selective monoamine reuptake inhibitors, tricyclic antidepressants and monoamine oxidase inhibitors, aim to enhance monoaminergic neurotransmission. However, the use of these agents presents severe disadvantages, including a delay in the alleviation of depressive symptoms, significant adverse effects and high frequencies of non-responding patients. Neuroendocrinological data of recent decades reveal that depression and anxiety disorders may occur simultaneously due to hypothalamus-pituitary-adrenal (HPA) axis hyperactivity. As a result, the stress-diathesis model was developed, which attempts to associate genetic and environmental influences in the aetiology of depression. The amygdala and the hippocampus control the activity of the HPA axis in a counter-balancing way, and a plethora of regulatory neuropeptide signalling pathways are involved. Intervention at these molecular targets may lead to alternative antidepressant therapeutic solutions that are expected to overcome the limitations of existing antidepressants. This prospect is based on preclinical evidence from pharmacological and genetic modifications of the action of neuropeptides such as corticotropin-releasing factor, substance P, galanin, vasopressin and neuropeptide Y. The recent synthesis of orally potent non-peptide micromolecules that can selectively bind to various neuropeptide receptors permits the onset of clinical trials to evaluate their efficacy against depression.

Differential Activity by Polymorphic Variants of a Remote Enhancer that Supports Galanin Expression in the Hypothalamus and Amygdala: Implications for Obesity, Depression and Alcoholism

“…Furthermore, polymorphisms in and around the GAL gene have been associated with panic disorder and anxiety in female patients (Unschuld et al, 2008(Unschuld et al, , 2010. As a result of its expression in the amygdala (Miller et al, 1993b;Planas et al, 1994a) and its known role in mood modulation (Crawley et al, 2002;Hobson et al, 2006;Karlsson and Holmes, 2006;Madaan and Wilson, 2009;Paschos et al, 2009;Rotzinger et al, 2009), GAL and its three receptors have received a great deal of attention by researchers attempting to understand the role of the galaninergic system in chronic anxiety and depression and to develop novel therapies. Indeed, a recent GWAS analysis demonstrated evidence for an association between polymorphisms close to the GAL gene locus and major depressive disorder (Wray et al, 2010).…”

Effect of Metabolic Syndrome on Depression in Mice

“…46,49,50 Paschos et al reported up-regulated of NE in the peripheral nervous system, and downregulation in the hippocampal region at times of depression. 51 Ferraro et al reported an increase in plasma NE in patients with type 1 diabetes. 52,53 While others have reported a decrease in thalamic NE in diabetic animals subjected to stress.…”

Challenges for PET Neuroimaging of Depressive Disorders

“…Thus, the complexity of both depression and PET sets limits on the interpretation of findings. Most PET studies of depressive disorders have been based on the monoamine hypothesis (Schildkraut et al 1968;Schildkraut and Kety 1967), despite the clear-cut need for exploring other strategies (Hindmarch 2002;Berton and Nestler 2006;Pittenger and Duman 2008;Paschos et al 2009;Covington, III et al 2010;Wegener and Volke 2010). Here, we first review recent molecular PET reports on depressive disorders in humans.…”

“…Some of the pathways that may be causally connected to depressive disorders include genes that encode presynaptic vesicular proteins, plasma membrane receptors, intracellular signaling molecules, proteins that regulate the actin cytoskeleton, and the transcriptional regulatory machinery (Covington, III et al 2010). Additional molecular pathways thought to be either causative or curative of depression include neuroplasticity, neuropeptides, and nitric oxide synthase (Pittenger and Duman 2008;Paschos et al 2009;Wegener and Volke 2010). Clearly, responding promptly to ever-changing notions on molecular pathways of depressive disorders constitutes a major challenge for PET neuroimaging.…”