Neuropeptide systems as novel therapeutic targets for depression and anxiety disorders

doi:10.1016/j.tips.2003.09.011

Trends in Pharmacological Sciences

Volume 24, Issue 11, November 2003, Pages 580-588

https://doi.org/10.1016/j.tips.2003.09.011 Get rights and content

Abstract

The health burden of stress-related diseases, including depression and anxiety disorders, is rapidly increasing, whereas the range of available pharmacotherapies to treat these disorders is limited and suboptimal with regard to efficacy and tolerability. Recent findings support a major role for neuropeptides in mediating the response to stress and thereby identify neuropeptide systems as potential novel therapeutic targets for the treatment of depression and anxiety disorders. In preclinical models, pharmacological and/or genetic manipulation of substance P, corticotropin-releasing factor (CRF), vasopressin, neuropeptide Y and galanin function alters anxiety- and depression-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, with antidepressant efficacy confirmed in double-blind, placebo-controlled trials of tachykinin NK₁ (substance P) receptor antagonists, and preliminary evidence of antidepressant activity in an open-label trial of a CRF₁ receptor antagonist.

Section snippets

Substance P

Since its discovery in the 1930s, SP has been one of the most extensively studied neuropeptides. SP is an 11 amino acid peptide belonging to the tachykinin family; it mediates its biological actions through G-protein-coupled tachykinin (NK₁) receptors. During decades of research to map the distribution of SP, there has been much speculation concerning its proposed physiological roles in inflammation, pain, gastrointestinal and respiratory function, stress responses and emesis. Only since the

Corticotropin-releasing factor

The 41 amino acid neuropeptide CRF initiates the hypothalamic–pituitary–adrenal (HPA) axis response to stress, and has been the subject of intense investigation in the pathophysiology and treatment of depression and anxiety disorders. In the mammalian brain, the CRF system comprises four CRF-related peptides (CRF, and urocortin 1, 2 and 3) and two G-protein-coupled CRF receptor subtypes {CRF₁ and CRF₂ receptors [with 2(a), 2(b) and 2(c) splice variants]}. In addition to a major projection from

Vasopressin

The nonapeptide vasopressin, synthesized in the PVN and supraoptic nucleus, is well known for its role on fluid metabolism. Vasopressin is also a key regulator of the HPA axis. Stress stimulates the release of vasopressin from the median eminence into the pituitary portal circulation where it strongly potentiates the effects of CRF on ACTH release [38].

Extrahypothalamic vasopressin-containing neurons have been characterized in the rat, notably in the medial amygdala and the bed nucleus of the

Neuropeptide Y

Neuropeptide Y (NPY) is the ancestor of a peptide family that in mammals also includes pancreatic polypeptide (PP) and peptide YY (PYY). In addition to a role as a sympathetic co-transmitter, NPY is abundantly expressed in numerous brain areas, including the locus coeruleus, hypothalamus, amygdala, hippocampus, nucleus accumbens, and neocortex (Figure 1c; Figure 2c). Central NPY colocalizes with noradrenaline, GABA, somatostatin and agouti-related protein [51]. Actions of NPY are mediated

Galanin

The 29–30 amino acid neuropeptide galanin coexists with noradrenaline in locus coeruleus neurons and with 5-HT in the DRN. The neuropeptide has been shown to act as an inhibitory neuromodulator of these (and other) neurotransmitters in the rodent brain 67, 68. Although its distribution appears to vary somewhat across species [69], galanin and its receptors are found in limbic regions, including the amygdala, BNST, hippocampus and hypothalamus of the rat brain 70, 71 (Figure 1d). The

Future directions

Figure 1 illustrates the high degree of anatomical overlap in the distribution of neuropeptide neurons in limbic regions of the rat brain. This raises the question of whether these neuropeptides exert common downstream effects on neural systems that mediate stress. Indeed, there is evidence of functional relationships between certain neuropeptides. The intimate relationship between vasopressin and CRF at the level of the HPA axis is probably the best example of this, but there has also been

Acknowledgements

A.H. is supported by the National Institute on Alcohol Abuse and Alcoholism and M.H. by grants from the Swedish Medical Research Council and the European Community.

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Citation Excerpt :
Previous studies have also shown that juvenile BPA exposure in rodents can inhibit the expression of glutamate receptors in the hippocampus and visual cortex (Chen et al., 2018; Hu et al., 2017). Under normal physiological conditions, BLA activity can be regulated by different neurotransmitters (e.g., glutamate, acetylcholine, and serotonin (5-HT)) released by projection neurons from other brain regions (Hasegawa et al., 2017; Holmes et al., 2003; Liu et al., 2020; Unal et al., 2015). In addition, receptors of hormone and neuropeptide, such as corticotropin-releasing factor (CRF), neuropeptide Y (NPY), are widely distributed in the whole amygdala and mediate depression and anxiety disorders by inducing or inhibiting BLA activity (Giesbrecht et al., 2010).
Bisphenol A (BPA) is a known endocrine disruptor and has been gradually replaced in industrial applications by other bisphenols, such as bisphenol S (BPS). However, whether these analogues are any safer for the central nervous system remains elusive. Here, we investigated behavioral impairments in mice after BPA and BPS exposure from postnatal days 21–49 (P21~P49). Results showed that BPA (0.1 and 1 mg/kg/d) and BPS (1 mg/kg/d) impaired emotion and social interaction of mice, while low dose exposure (0.1 mg/kg/d) induced no observable changes on emotion in mice. The behavioral deficits were accompanied by hyperactivation of the basolateral amygdala (BLA), i.e., dose-dependent increase in neuronal firing rates and local field potential power. In addition, glutamate receptors were up-regulated in the BLA, showing the same activation trend after exposure to different doses of BPA and BPS. Taken together, these findings imply that BPA and BPS cause behavioral impairments in juvenile mice by disrupting local neuronal activation in the BLA. Although BPS exerted less adverse effects on mice than BPA at the low dose, it does not appear to be a safe alternative to BPA in regard to brain function after prolonged high-volume exposure.

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Trends in Pharmacological Sciences

Neuropeptide systems as novel therapeutic targets for depression and anxiety disorders

Abstract

Section snippets

Substance P

Corticotropin-releasing factor

Vasopressin

Neuropeptide Y

Galanin

Future directions

Acknowledgements

Neuropsychopharmacology

Pharmacol. Ther.

Neuropharmacology

Brain Res.

Neuroscience

Eur. J. Pharmacol.

Behav. Brain Res.

Behav. Brain Res.

Brain Res.

Neuropsychopharmacology

Biol. Psychiatry

Neuropsychopharmacology

Peptides

J. Psychiatr. Res.

Regul. Pept.

Neuropsychopharmacology

Neurosci. Biobehav. Rev.

Life Sci.

Biol. Psychiatry

Neuropharmacology

Pharmacol. Biochem. Behav.

Neuropsychopharmacology

Trends Neurosci.

Neurosci. Lett.

Neuropsychopharmacology

Trends Pharmacol. Sci.

Prog. Neuropsychopharmacol. Biol. Psychiatry

Neurosci. Lett.

Neuropsychopharmacology

Life Sci.

Neurosci. Lett.

Bioorg. Med. Chem.

Peptides

Trends Neurosci.

Eur. J. Pharmacol.

Trends Neurosci.

Anxiolytics: past, present, and future agents

J. Clin. Psychiatry

Distinct mechanism for antidepressant activity by blockade of central substance P receptors

Science

Selective blockade of neurokinin-2 receptors produces antidepressant-like effects associated with reduced corticotropin-releasing factor function

J. Pharmacol. Exp. Ther.

Serotonin and substance P co-exist in dorsal raphe neurons of the human brain

Neuroreport

5-hydroxytryptamine (5-HT)1A autoreceptor adaptive changes in substance P (neurokinin 1) receptor knock-out mice mimic antidepressant-induced desensitization

J. Neurosci.

Substance P (neurokinin 1) receptor antagonists enhance dorsal raphe neuronal activity

J. Neurosci.

Substance P induces a cardiovascular defense reaction in the rat: pharmacological characterization

Circ. Res.

Comparison of the phenotype of NK1R−/− mice with pharmacological blockade of the substance P (NK1) receptor in assays for antidepressant and anxiolytic drugs

Behav. Pharmacol.

Comparison of the phenotype of NK1R−/− mice with pharmacological blockade of the substance P (NK₁) receptor in assays for antidepressant and anxiolytic drugs