The social defeat animal model of depression shows diminished levels of orexin in mesocortical regions of the dopamine system, and of dynorphin and orexin in the hypothalamus

Nocjar, Christine; Zhang, J.; Feng, Ping; Panksepp, Jaak

doi:10.1016/j.neuroscience.2012.05.033

Cited by 91 publications

(58 citation statements)

References 127 publications

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“…Differential expression of orexin and dynorphin by the same population of hypothalamic neurons may be a mechanism by which the excitability of DA neurons in the VTA can be regulated by external stimuli, as well as by experience or disease. As one example, orexin mRNA levels are decreased following a type of chronic social stress that results in a depressive-like phenotype in mice (48) and rats (49). This depressive-like phenotype could be due, at least in part, to reductions in orexin expression that render the actions of dynorphin unopposed.…”

Section: Discussionmentioning

confidence: 99%

Hypocretin (orexin) facilitates reward by attenuating the antireward effects of its cotransmitter dynorphin in ventral tegmental area

Muschamp

Hollander

Thompson

et al. 2014

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

211

213

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Hypocretin (orexin) and dynorphin are neuropeptides with opposing actions on motivated behavior. Orexin is implicated in states of arousal and reward, whereas dynorphin is implicated in depressive-like states. We show that, despite their opposing actions, these peptides are packaged in the same synaptic vesicles within the hypothalamus. Disruption of orexin function blunts the rewarding effects of lateral hypothalamic (LH) stimulation, eliminates cocaine-induced impulsivity, and reduces cocaine selfadministration. Concomitant disruption of dynorphin function reverses these behavioral changes. We also show that orexin and dynorphin have opposing actions on excitability of ventral tegmental area (VTA) dopamine neurons, a prominent target of orexin-containing neurons, and that intra-VTA orexin antagonism causes decreases in cocaine self-administration and LH self-stimulation that are reversed by dynorphin antagonism. Our findings identify a unique cellular process by which orexin can occlude the reward threshold-elevating effects of coreleased dynorphin and thereby act in a permissive fashion to facilitate reward.O rexin promotes arousal (1) and has been implicated in the rewarding effects of food (2, 3), sexual behavior (4), and drugs of abuse (5, 6). It is produced primarily within the hypothalamus (7), and acts at orexin 1 receptor (OX 1 R) and OX 2 R (also known as Hcrt-R1 and Hcrt-R2), which are expressed in many brain areas, including the ventral tegmental area (VTA) of the midbrain (8). Dynorphin, in contrast, is expressed widely, promotes depressive-like behaviors, and plays a key role in mediating the aversive effects of stress (9, 10). Activation of kappaopioid receptor (KORs), the receptors at which dynorphin acts (11), can attenuate the rewarding effects of drugs of abuse (12, 13) via actions that are mediated, at least in part, within midbrain dopamine (DA) systems (14, 15). Despite their seemingly opposing effects on motivation, there is evidence that these peptides may act in tandem; for example, both orexin and dynorphin are released during electrical stimulation of the hypothalamus (16). Like DA neurons, orexin and dynorphin neurons increase their activity in response to arousing stimuli like rewards and stressors (17). The functional effects of this pattern of neuropeptide coexpression on brain reward systems, and, in turn, on motivated behavior, are poorly understood because orexin and dynorphin are not traditionally studied together. Given their opposing effects on behavior and neuronal physiology when studied alone, it can be hypothesized that dominance in the effects of one peptide over the other could cause widely divergent behavioral phenotypes in reward sensitivity. For example, dominant orexin signaling may enhance reward sensitivity and reward seeking, whereas dominant dynorphin signaling may result in decreased reward sensitivity and anergia. Because these states have major relevance to psychiatric illnesses like addiction and depression, where reward processing is disordered, we sought ...

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Section: Discussionmentioning

confidence: 99%

Hypocretin (orexin) facilitates reward by attenuating the antireward effects of its cotransmitter dynorphin in ventral tegmental area

Muschamp

Hollander

Thompson

et al. 2014

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

211

213

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“…65 Decreased orexin neurotransmitter and dynorphin protein in the VTA, PFC and hypothalamus 74 were also found, as well as increased DA levels in the VTA and NAc. 37 They might also have alterations in neurotrophic factors molecules, such as BDNF metabolites in brain areas, including VTA, NAc, PFC, AMY and substantia nigra.…”

Section: 77mentioning

confidence: 94%

“…These depressive-like behaviors were accompanied by diminished levels of orexin in mesocortical regions of the DA reward system and of orexin and dynorphin in the hypothalamus. 74 VTA hypofunction associated with anhedonic behavior had already been reported, but after a more severe continuous SD exposure. 37 The hypothalamus sends an orexin projection to the VTA, which, when stimulated, produces effort and reward motivation behaviors.…”

mentioning

confidence: 87%

“…Reduced orexin and dynorphin VTA, mPFC and hypothalamus Nocjar et al 74 Decreased horizontal and vertical locomotion, increased inactivity in OF, decreased sucrose preference Decreased T3, T4 and CORT serum levels HPA-axis Olivares et al…”

mentioning

confidence: 99%

“…Nocjar et al 74 investigated a possible neural basis for anhedonia using exposure to an intermittent SD protocol. The animals showed a generalized depressive phenotype, as defined by decreased sucrose and sexual preference after 3 weeks of stress discontinuation and apathy-like behavior in the FST one month after stress discontinuation.…”

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confidence: 99%

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Social defeat protocol and relevant biomarkers, implications for stress response physiology, drug abuse, mood disorders and individual stress vulnerability: a systematic review of the last decade

Vasconcelos

Stein

Almeida

2015

Trends Psychiatry Psychother.

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Introduction: Social defeat (SD) in rats, which results from male intraspecific confrontations, is ethologically relevant and useful to understand stress effects on physiology and behavior.Methods: A systematic review of studies about biomarkers induced by the SD protocol and published from 2002 to 2013 was carried out in the electronic databases PubMed, Web of Knowledge and ScienceDirect. The search terms were: social defeat, rat, neurotrophins, neuroinflammatory markers, and transcriptional factors.Results: Classical and recently discovered biomarkers were found to be relevant in stress-induced states. Findings were summarized in accordance to the length of exposure to stress: single, repeated, intermittent and continuous SD. This review found that the brain-derived neurotrophic factor (BDNF) is a distinct marker of stress adaptation. Along with glucocorticoids and catecholamines, BDNF seems to be important in understanding stress physiology.Conclusion: The SD model provides a relevant tool to study stress response features, development of addictive behaviors, clinic depression and anxiety, as well as individual differences in vulnerability and resilience to stress.

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New directions for the treatment of depression: Targeting the photic regulation of arousal and mood (PRAM) pathway

2017

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Both preclinical and clinical studies demonstrate that depression is strongly associated with reduced light availability, which in turn contributes to decreased function of brain regions that control mood. Here, we review findings that support a critical pathway for the control of mood that depends upon ambient light. We put forward a novel hypothesis, functionally linking retina to locus coeruleus (LC) in depression, and discuss the role of norepinephrine in affective disease. Finally, we discuss how utilizing the chemogenetic tool Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to precisely control this retina–LC circuit may be used as a novel therapeutic to treat depression.

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The social defeat animal model of depression shows diminished levels of orexin in mesocortical regions of the dopamine system, and of dynorphin and orexin in the hypothalamus

Cited by 91 publications

References 127 publications

Hypocretin (orexin) facilitates reward by attenuating the antireward effects of its cotransmitter dynorphin in ventral tegmental area

Hypocretin (orexin) facilitates reward by attenuating the antireward effects of its cotransmitter dynorphin in ventral tegmental area

Social defeat protocol and relevant biomarkers, implications for stress response physiology, drug abuse, mood disorders and individual stress vulnerability: a systematic review of the last decade

New directions for the treatment of depression: Targeting the photic regulation of arousal and mood (PRAM) pathway

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