Yvan Dumont

The neurocircuitry and receptor subtypes mediating anxiolytic-like effects of neuropeptide Y.

This review aims to give a brief overview of NPY receptor distribution and physiology in the brain and summarizes series of studies, test by test and region by region, aimed at identification receptor subtypes and neuronal circuitry mediating anxiolytic-like effects of NPY. We conclude that from four known NPY receptor subtypes in the rat (Y(1), Y(2), Y(4), Y(5)), only the NPY Y(1) receptor can be linked to anxiety-regulation with certainty in the forebrain, and that NPY Y(2) receptor may have a role in the pons. Microinjection studies with NPY and NPY receptor antagonists support the hypothesis that the amygdala, the dorsal periaqueductal gray matter, dorsocaudal lateral septum and locus coeruleus form a neuroanatomical substrate that mediates anxiolytic-like effects of NPY. The release of NPY in these areas is likely phasic, as NPY receptor antagonists are silent on their own. However, constant NPY-ergic tone seems to exist in the dorsal periaqueductal gray, the only brain region where NPY Y(1) receptor antagonists had anxiogenic-like effects. We conclude that endogenous NPY has an important role in reducing anxiety and serves as a physiological stabilizer of neural activity in circuits involved in the regulation of arousal and anxiety.

The molecular pharmacology of CGRP and related peptide receptor subtypes.

Calcitonin gene-related peptides (alpha and beta isoforms), better known as CGRPalpha and CGRPbeta, were isolated twenty years ago. In fact, these were the first peptides to be characterized using a molecular cloning strategy, which is not the traditional approach of biochemical extraction and purification. Paradoxically, progress in the characterization of CGRP receptor subtypes has been extremely slow as a result of difficulties in their cloning and the lack of selective receptor subtype agonists and antagonists. However, exciting progress has been made overthe pasttwo years and is briefly reviewed here.

Species differences in the expression and distribution of the neuropeptide Y Y1, Y2, Y4, and Y5 receptors in rodents, guinea pig, and primates brains

The respective distribution of neuropeptide Y Y1, Y2, Y4, and Y5 receptor subtypes was investigated in rodents (rat and mouse), guinea pig, and primates (marmoset and vervet monkeys and human) brains, representing three orders of mammals. [125I][Leu31,Pro34]PYY (total Y1‐like; Y1, Y4, and Y5) and [125I]PYY3–36 (total Y2‐like; Y2 and possibly Y5) binding sites were discretely but similarly distributed in the rat and mouse brain, each having its unique pattern. In contrast, surprisingly low levels of [125I]PYY3–36 binding sites were found in the guinea pig brain including in the hippocampal formation. [125I][Leu31,Pro34]PYY/BIBP3226‐insensitive binding sites (Y5‐like) were found in different areas of the rat and guinea pig brains. The primate brains also revealed a different distribution binding profile for these various NPY receptor subtypes. Although the human and vervet brains contained very low amounts of [125I][Leu31,Pro34]PYY sites (Y1‐like) in most brain regions, except for the dentate gyrus of the hippocampus, the marmoset brain contains significant amounts of both [125I][Leu31,Pro34]PYY (Y1‐like) and [125I]PYY3–36 (Y2‐like) binding sites. Additionally, [125I][Leu31,Pro34]PYY/BIBP3226‐insensitive binding sites were not clearly detected in the vervet and human brains. On the other hand, Y5‐like binding sites were observed in few regions of the marmoset brain. Finally, [125I]hPP (Y4/Y5‐like) were very discretely distributed in the rat brain, being concentrated in the paraventricular nucleus of the hypothalamus and the interpeduncular nucleus. The marmoset brain is apparently not enriched with specific [125I]hPP sites. Taken together, these data show that significant species differences exist in the level of expression and distribution of various NPY receptor subtypes in the mammalian brain. J. Comp. Neurol. 402:372–384, 1998.

The Neuropeptide Y (NPY) Y1 Receptor Subtype Mediates NPY-induced Antidepressant-like Activity in the Mouse Forced Swimming Test

The present study was undertaken to investigate the possible antidepressant-like effects of neuropeptide Y (NPY) in the mouse forced swimming test, an animal model widely used for the screening of potential antidepressant drugs. In addition, experiments were performed, using agonists and selective antagonists, to assess the potential role of NPY Y1 and Y2 receptor subtypes in this model. Complementary studies were performed in an open field apparatus to rule out any changes in locomotor activity that might have interfered with the interpretation of data from the mouse forced swimming test. Intracerebroventricular injections (0.03 nmole-3 nmole) of NPY, [Leu31Pro34]PYY (Y1 agonist), NPY13-36 (Y2 agonist), BIBP3226, BIBO3304 (Y1 antagonists) and BIIE0246 (Y2 antagonist) were performed 30 min prior to testing in the mouse forced swimming test and open field. NPY administration significantly reduced immobility time in a dose dependent manner (p < .01 vs. control group), as did [Leu31Pro34]PYY (p < .01 vs. control group) and BIIE0246 (p < .05 vs. control group). In contrast, BIBO3304, BIBP3226 and NPY13-36 did not display any activity at the doses tested. However, pretreatment with BIBO3304 or BIBP3226 significantly blocked the anti-immobility effects of NPY. Data from the open field demonstrated that BIIE0246 increased horizontal ambulation at the dose found to be active in the forced swimming test. Taken together, our results demonstrate that NPY displays antidepressant-like activity in the mouse forced swimming test, and suggest that this activity is mediated by the NPY Y1 receptor subtype.

Autoradiographic distribution of [125I]Leu31,Pro34]PYY and [125I]PYY3–36 binding sites in the rat brain evaluated with two newly developed Y1 and Y2 receptor radioligands

The peptide YY derivatives [Leu31,Pro34]PYY and PYY3–36 are highly selective Y1 and Y2 agonists, devoid of activity on the Y3 receptor subtype [Dumont et al. (1994) Molec. Brain Res., 26:3220–3324]. These selective ligands were iodinated and used to evaluate the respective quantitative autoradiographic distribution of the Y1 and Y2 receptor subtypes in the rat brain, excluding a potential contamination from Y3 receptor. Specific [125I][Leu31,Pro34]PYY (Y1), and [125I]PYY3–36 (Y2) binding sites are detected in various brain regions, but each showed a differential distribution profile. Y1/[125I][Leu31,Pro34]PYY sites are especially concentrated in superficial layers of the cortex, the olfactory tubercle, islands of Calleja, tenia tecta, molecular layer of the dentate gyrus, several thalamic nuclei, and the posterior part of the medial mammaliary nucleus. These areas generally contained only low densities of Y2/[125I]PYY3–36 binding sites. In contrast, [125I]PYY3–36 binding is most abundant in multiple other regions including the lateral septum, piriform cortex, triangular septal nucleus, bed nucleus of the stria terminalis, oriens layer and stratum radiatum of the dorsal hippocampus, ventral tegmental area, substantia nigra, dorsal raphe nucleus, and the granular cell layer of the cerebellum. Few areas of the rat brain contained significant amounts of both [125I][Leu31,Pro34]‐PYY and [125I]PYY3–36 binding sites such as the anterior olfactory nuclei, oriens layer and stratum radiatum of the ventral hippocampus, nucleus tractus solitarius, area postrema, and inferior olive. Taken together, these results and the use of two selective radioligands demonstrate further the discrete, differential distribution of the Y1 and Y2 receptor subtypes in the rat brain.

Multiple receptors for neuropeptide Y in the hippocampus: putative roles in seizures and cognition

Neuropeptide Y (NPY) is widely distributed throughout the central nervous system (CNS) and is one of the most conserved peptides in evolution, suggesting an important role in the regulation of basic physiological functions, including learning and memory. In addition, experimental studies have suggested that NPY, together with its receptors, may have a direct implication in several pathological disorders, including epilepsy/seizure. NPY-like immunoreactivity and NPY receptors have been shown to be present throughout the brain, but is concentrated in the hippocampus. The hippocampal formation has been repeatedly implicated in the modulation of cognition, as well as the pathogenesis of seizure. This review will concentrate on the hippocampal distribution of NPY, its receptors and the putative role played by this peptide in seizure, together with the regulation of cognitive function associated with learning and memory.

A possible role of neuropeptide Y in depression and stress

Neuropeptide Y (NPY) mediates its physiological effects through at least four receptors known as Y(1), Y(2), Y(4), and Y(5). This peptide is one of the most abundant peptides in the central nervous system and is highly conserved throughout evolution. The most abundant receptors of the NPY family, the Y(1) and Y(2) receptors, are densely expressed in the cortex, hippocampus, and amygdala. These brain regions are particularly associated with mood disorders, stress responses, and memory processing. With this in mind, researchers suggested the involvement of NPY as well as the Y(1) and Y(2) receptors in affective disorders. Earlier studies showed that NPY and the Y(1) and Y(2) receptors mediate some aspects of depression-like disorders and stress responses in rodents. Recent research also suggests the involvement of the Y(4) and Y(5) receptors in emotion-related processes in rodents. In addition, human studies have consistently suggested a role for NPY in stress responses, whereas conflicting data have been obtained in relation to the role of NPY in depression-related illnesses. However, novel evidence from polymorphisms in the prepro-NPY gene has shed new light on the potential clinical relevance of NPY in depression. In this article, we review the literature from both animal and human studies regarding the contribution of NPY and its receptors in depression and stress.

Neuropeptide Y (NPY) Y2 receptors mediate behaviour in two animal models of anxiety: evidence from Y2 receptor knockout mice

The behavioural phenotype of mice lacking neuropeptide Y (NPY) Y(2)-type receptors was assessed in two well documented animal models of anxiety: namely, the elevated plus maze and the open field. NPY Y(2)-/- mice made more entries into, and spent significantly more time on, the open arms of the elevated plus maze when compared to their wild-type Y(2)+/+ controls (P<0.001). This effect was not due to non-specific changes in locomotor activity as the number of closed arm entries did not differ between groups. In addition, NPY Y(2)-/- mice displayed increased preference for the central area of the open field when compared to Y(2)+/+ animals (P<0.01), whereas total entries did not differ between groups. This study suggests that NPY Y(2) receptors may play an inhibitory role and supports the hypothesis that Y(2) receptors are involved in the regulation of anxiety-like behaviours by NPY.

Neuropeptide Y (NPY) and depression: From animal studies to the human condition

Neuropeptide Y (NPY) is widely distributed throughout the central nervous system (CNS) and is one of the most conserved peptides in evolution, suggesting an important role in the regulation of basic physiological functions. In addition, both pre-clinical and clinical evidence have suggested that NPY, together with its receptors, may have a direct implication in several psychiatric disorders, including depression and related illnesses. NPY-like immunoreactivity and NPY receptors are expressed throughout the brain, with varying concentrations being found throughout the limbic system. Such brain structures have been repeatedly implicated in the modulation of emotional processing, as well as in the pathogenesis of depressive disorders. This review will concentrate on the distribution of NPY, its receptors, and the putative role played by this peptide in depressive illness based on both pre-clinical and clinical evidence.

Pharmacological characterization of human NPFF1 and NPFF2 receptors expressed in CHO cells by using NPY Y1 receptor antagonists

Neuropeptide FF (NPFF) belongs to an opioid-modulatory system including two precursors (pro-NPFF(A) and pro-NPFF(B)) and two G-protein coupled receptors (NPFF(1) and NPFF(2)). The pharmacological and functional profiles of human NPFF(1) and NPFF(2) receptors expressed in Chinese hamster ovary (CHO) cells were compared by determining the affinity of several peptides derived from both NPFF precursors and by measuring their abilities to inhibit forskolin-induced cAMP accumulation. Each NPFF receptor recognizes peptides from both precursors with nanomolar affinities, however, with a slight preference of pro-NPFF(A) peptides for NPFF(2) receptors and of pro-NPFF(B) peptides for NPFF(1) receptors. BIBP3226 ((R)-N(2)-(diphenylacetyl)-N-[(4-hydroxyphenyl)-methyl]-argininamide) and BIBO3304 ((R)-N(2)-(diphenylacetyl)-N-[4-(aminocarbonylaminomethyl)-benzyl]-argininamide trifluoroacetate), two selective neuropeptide Y (NPY) Y(1) receptor antagonists, display relative high affinities for NPFF receptors and exhibit antagonist properties towards hNPFF(1) receptors. The structural determinants responsible for binding of these molecules to NPFF receptors were investigated and led to the synthesis of hNPFF(1) receptor antagonists with affinities from 40 to 80 nM. Our results demonstrate differences in pharmacological characteristics between NPFF(1) and NPFF(2) receptors and the feasibility of subtype-selective antagonists.