Efficacy of the MCHR1 Antagonist <i>N</i>-[3-(1-{[4-(3,4-Difluorophenoxy)phenyl]methyl}(4-piperidyl))-4-methylphenyl]-2-methylpropanamide (SNAP 94847) in Mouse Models of Anxiety and Depression following Acute and Chronic Administration Is Independent of Hippocampal Neurogenesis

David, D. J.; Klemenhagen, Kristen C.; Holick, Kerri A; Saxe, Michael; Mendez, Indira; Santarelli, Luca; Craig, Douglas A.; Zhong, Haiquan; Swanson, Chad J.; Hegde, Laxminarayan G.; Ping, Xiaoli; Dong, Dan; Marzabadi, Mohammad R.; Gerald, Christophe; Hen, René

doi:10.1124/jpet.106.109678

Cited by 122 publications

(96 citation statements)

References 39 publications

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“…A causal relationship between the regulation of neurogenesis and behavioral responses has been suggested by studies demonstrating that the effects of chronic antidepressant administration require increased neurogenesis (13,14), although the current findings are correlative. However, two recent studies found neurogenesis-independent effects of antidepressants (15,16), indicating that alternate mechanisms underlie the behavioral responses (5). Previous studies have demonstrated that IL-1␤ produces a rapid and presumably neurogenesisindependent effect on behavioral despair (36).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, antidepressant treatment increases hippocampal neurogenesis, blocks the antineurogenic effects of stress (11,12), and reduces or even reverses hippocampal atrophy (9, 11). Recent studies demonstrate that new hippocampal neurons are required for the actions of antidepressants in behavioral models of depression and anxiety (13, 14) with some exceptions (15,16).…”

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confidence: 99%

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IL-1β is an essential mediator of the antineurogenic and anhedonic effects of stress

Koo

Duman

2008

Proc. Natl. Acad. Sci. U.S.A.

775

564

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Stress decreases neurogenesis in the adult hippocampus, and blockade of this effect is required for the actions of antidepressants in behavioral models of depression. However, the mechanisms underlying these effects of stress have not been identified. Here, we demonstrate an essential role for the proinflammatory cytokine IL-1␤. Administration of IL-1␤ or acute stress suppressed hippocampal cell proliferation. Blockade of the IL-1␤ receptor, IL-1RI, by using either an inhibitor or IL-1RI null mice blocks the antineurogenic effect of stress and blocks the anhedonic behavior caused by chronic stress exposure. In vivo and in vitro studies demonstrate that hippocampal neural progenitor cells express IL-1RI and that activation of this receptor decreases cell proliferation via the nuclear factor-B signaling pathway. These findings demonstrate that IL-1␤ is a critical mediator of the antineurogenic and depressive-like behavior caused by acute and chronic stress.cytokine ͉ depression ͉ neurogenesis T he profound consequences of stress exposure, defined as disturbances of physiological homeostasis, include a detrimental impact on certain aspects of brain function (1, 2). In particular, uncontrollable stress is a major contributing factor for neuropsychiatric disorders such as major depression and posttraumatic stress disorders (3, 4). Alterations at the cellular level in the hippocampus have been linked to the pathophysiology of stress-related mood disorders (5-7). Many studies demonstrate that stressful experiences suppress hippocampal neurogenesis, which could contribute to the hippocampal atrophy observed in depressed patients (8-10). In contrast, antidepressant treatment increases hippocampal neurogenesis, blocks the antineurogenic effects of stress (11,12), and reduces or even reverses hippocampal atrophy (9, 11). Recent studies demonstrate that new hippocampal neurons are required for the actions of antidepressants in behavioral models of depression and anxiety (13, 14) with some exceptions (15,16).Despite this progress, the mechanisms underlying the antineurogenic and behavioral actions of stress remain ill defined. One possibility is that excessive proinflammatory cytokines, particularly IL-1␤, contribute to the actions of stress. Animal studies demonstrate that exposure to stress increases IL-1␤ in several brain areas, including the hippocampus (17-20), and central administration of IL-1␤ produces several stress-like effects, including activation of the hypothalamic-pituitary-adrenal (HPA) axis (17, 21), inhibition of hippocampal long-term potentiation (22), down-regulation of hippocampal brain-derived neurotrophic factor (23), and impaired hippocampal-dependent contextual fear conditioning (24). In contrast, blockade of the receptor, IL-1RI that mediates the actions of IL-1␤ (25) inhibits these stress-like effects (23, 24) and blocks the antiproliferative effects of INF-␣ in the hippocampus (26).Based on this evidence, the current study was undertaken to test the hypothesis that the antineurogenic and depressiv...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

IL-1β is an essential mediator of the antineurogenic and anhedonic effects of stress

Koo

Duman

2008

Proc. Natl. Acad. Sci. U.S.A.

775

564

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“…The inhibitory effect of TPI 1361-17 on cocaine self-administration, a dopamine-induced response, may seem contrary to the increased performance that another MCH1R antagonist, peptide 30 has in the forced swim test (19), a model where reduced dopamine levels correlate with increased depression-like state. However, it should be noted that the physiology of depression, more than that of cocaine addiction, involves the activities of neurotransmitter systems others than dopamine (48), and that, for unknown reasons, different MCH1R antagonists exert variable performance in antidepressant-like assays (49).…”

Section: Discussionmentioning

confidence: 99%

The melanin-concentrating hormone system modulates cocaine reward

Chung

Hopf

Nagasaki

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

130

140

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Drug addiction is mediated by complex neuronal processes that converge on the shell of the nucleus accumbens (NAcSh). The NAcSh receives inputs from the lateral hypothalamus (LH), where selfstimulation can be induced. Melanin-concentrating hormone (MCH) is produced mainly in the LH, and its receptor (MCH1R) is highly expressed in the NAcSh. We found that, in the NAcSh, MCH1R is coexpressed with dopamine receptors (D1R and D2R), and that MCH increases spike firing when both D1R and D2R are activated. Also, injecting MCH potentiates cocaine-induced hyperactivity in mice. Mice lacking MCH1R exhibit decreased cocaine-induced conditioned place preference, as well as cocaine sensitization. Using a specific MCH1R antagonist, we further show that acute blockade of the MCH system not only reduces cocaine self-administration, but also attenuates cue-and cocaine-induced reinstatement. Thus, the MCH system has an important modulatory role in cocaine reward and reinforcement by potentiating the dopaminergic system in the NAcSh, which may provide a new rationale for treating cocaine addiction.T he shell of the nucleus accumbens (NAcSh) is known to be an important center for reward and motivation. It is a major terminal area of the mesolimbic dopamingergic system, which projects from the ventral tegmental area (VTA) (1). The NAcSh neurons express both dopamine D1 and D2 receptors, which have opposite effects on cAMP-dependent signaling; however, motivated behaviors require concomitant D1 and D2 receptor signaling in the NAcSh (2). The NAcSh receives inputs from different brain areas, in particular, from the lateral hypothalamus (LH) (3). The importance of the LH in reward and motivation has been shown by Olds (4), who discovered that electrical activation of the LH induced an extraordinarily intense self-stimulation response in rats. However, the transmitter(s) responsible for this action have not been established definitively. We now know of 2 neuropeptides that are uniquely synthesized in the LH: the orexins/hypocretins (5), and melanin-concentrating hormone (MCH) (6-8). The orexin/ hypocretin neurons do not project prominently to the NAcSh, whereas the MCH neurons do (9). This data suggested to us that the MCH system may regulate the activities of the NAcSh neurons to influence reward.MCH is a cyclic, 19-amino acid peptide originally isolated from salmon pituitary as a melanophore-concentrating factor (10). It is also present in rats and humans (11,12), where it is viewed as important in regulating nutritional homeostasis (8, 13). In mammals, MCH is expressed predominantly centrally, and occurs only in 2 nuclei: the perikarya of the LH area (LHA), and the zona incerta (ZI). However, MCH fibers project in many areas throughout the CNS (6, 9), indicating that the MCH system may have a broad range of physiological roles. In rodents, MCH is known to interact with one G protein-coupled receptor, MCH1R (14-18). MCH1R is expressed in many brain regions (9), and the NAcSh has one of the highest MCH1R expression levels. Indeed, the ...

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“…Behavioral response to forced swimming was measured as described in David et al (2007). Mice were placed in clear glass buckets 20 cm deep, filled 2/3 of the way with 25 1C water, and videotaped from the side.…”

Section: Nsfmentioning

confidence: 99%

Developmental Effects of Serotonin 1A Autoreceptors on Anxiety and Social Behavior

Donaldson

Piel

Santos

et al. 2013

Neuropsychopharmacol

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The serotonin 1A receptor (5-HT1A) has a major role in modulating the effects of serotonin on mood and behavior. Previous studies have shown that knockout of 5-HT1A selectively in the raphe leads to higher levels of anxiety during adulthood. However, it remains unclear whether this phenotype is due to variation in receptor levels specifically during development or throughout life. To test the hypothesis that developmental sensitivity may underlie the effects of 5-HT1A on anxiety, we used an inducible transgenic system to selectively suppress 5-HT1A levels in serotonergic raphe neurons from post-natal days (P) 14 to P30, with a maximal reduction of 40% at P21 and return to regular levels by P30. This developmental decrease in receptor levels has long-lasting consequences, increasing anxiety and decreasing social investigation in adulthood. In addition, post-natal knockdown of autoreceptors leads to long-term increases in the excitability of serotonergic neurons, which may represent a mechanism underlying the effects of post-natal receptor variation on behavior later in life. Finally, we also examined the interplay between receptor variation and juvenile exposure to stress (applied from P14 to P21). Similar to receptor knockdown, juvenile exposure to stress led to increased anxiety phenotypes but did not exacerbate 5-HT1A knockdown-mediated anxiety levels. This work indicates that the effects of 5-HT1A autoreceptors on anxiety and social behaviors are developmentally mediated and suggests that natural variations in the expression of 5-HT1A may act during development to influence individual anxiety levels and contribute to susceptibility to anxiety disorders.

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Efficacy of the MCHR1 Antagonist N-[3-(1-{[4-(3,4-Difluorophenoxy)phenyl]methyl}(4-piperidyl))-4-methylphenyl]-2-methylpropanamide (SNAP 94847) in Mouse Models of Anxiety and Depression following Acute and Chronic Administration Is Independent of Hippocampal Neurogenesis

Cited by 122 publications

References 39 publications

IL-1β is an essential mediator of the antineurogenic and anhedonic effects of stress

IL-1β is an essential mediator of the antineurogenic and anhedonic effects of stress

The melanin-concentrating hormone system modulates cocaine reward

Developmental Effects of Serotonin 1A Autoreceptors on Anxiety and Social Behavior

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