Role of the Brain's Reward Circuitry in Depression

Nestler, Eric J.

doi:10.1016/bs.irn.2015.07.003

Cited by 89 publications

(77 citation statements)

References 75 publications

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“…First, dopaminergic imbalance of the mesolimbic pathway is considered the hallmark of both addiction and PD-ICD. 51,52 Finally, serotoninergic pathways-historically considered an essential substrate for depression 53 -have recently been shown to underlie PD-ICD. 49,50 Second, the molecular mechanisms of addiction and PD-ICD-namely ΔFosBare also implied in depression.…”

Section: Discussionmentioning

confidence: 99%

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Depression as a Risk Factor for Impulse Control Disorders in Parkinson Disease

Marín‐Lahoz

Sampedro

Martínez‐Horta

et al. 2019

Annals of Neurology

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Objective: To longitudinally evaluate the role of depression in the development of impulse control disorders (ICDs) in Parkinson disease (PD) patients. Methods: Using data from the Parkinson's Progression Markers Initiative, we included PD patients without ICDs at baseline according to the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP). Patients were prospectively evaluated first quarterly and then biannually. Development of an ICD was defined as an increase in QUIP scores during follow-up. Using survival proportional hazard models, we studied the effect of baseline depression on ICD risk. We also evaluated this effect controlling for dopamine agonist use as a time-dependent variable and for other potential confounders. Results: Among 354 patients, 68 were depressed at baseline. The median follow-up was 4.08 years. Depression at baseline was associated with higher ICD risk (hazard ratio [HR] = 1.96, 95% confidence interval [CI] = 1.32-2.9, p < 0.001). This risk remained significant after controlling for dopamine agonist use (HR = 1.97, 95% CI = 1.33-2.9, p < 0.001), which was also independently linked to ICD development (HR = 1.87, 95% CI = 1.3-2.7, p < 0.001). Therefore, depressed patients faced an even higher ICD risk when receiving dopamine agonists. Controlling for multiple potential confounders did not alter these results. Interpretation: Depression predisposes to the development of ICDs in PD. This risk is magnified by dopamine agonists. Dopamine agonists should thus be used cautiously in depressed PD patients. ANN NEUROL 2019;86:762-769 View this article online at wileyonlinelibrary.com.

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Section: Discussionmentioning

confidence: 99%

“…49,50 Second, the molecular mechanisms of addiction and PD-ICD-namely ΔFosBare also implied in depression. 51,52 Finally, serotoninergic pathways-historically considered an essential substrate for depression 53 -have recently been shown to underlie PD-ICD. 24,54 Therefore, certain circumstances may predispose to both depression and ICDs.…”

Section: Discussionmentioning

confidence: 99%

Depression as a Risk Factor for Impulse Control Disorders in Parkinson Disease

Marín‐Lahoz

Sampedro

Martínez‐Horta

et al. 2019

Annals of Neurology

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“…13,14 A substantial body of work from both clinical and animal studies implicates a role for altered monoamine neurotransmission, particularly dopamine dysfunction at discrete mesocorticolimbic structures, in the pathophysiology of the cognitive and motivational symptoms of depression. [15][16][17][18][19] Significantly, these cognitive and motivational processes affected by depression, including attention, behavioural flexibility, decision-making and effort-related processes, are key to parenting. 20,21 In parallel, compelling evidence indicates that the mesocorticolimbic monoamine systems facilitate early aspects of mother-infant attachment, social memory, and motivation in rats and humans.…”

Section: Introductionmentioning

confidence: 99%

Depression‐related disturbances in rat maternal behaviour are associated with altered monoamine levels within mesocorticolimbic structures

Winokur

Lopes

Moparthi

et al. 2019

J Neuroendocrinology

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The ability of mothers to sensitively attune their maternal responses to the needs of their developing young is fundamental to a healthy mother‐young relationship. The biological mechanisms that govern how mothers adjust caregiving to the dynamic changes in the demands of the young remain an open question. In the present study, we examined whether changes in monoamine levels, within discrete mesocorticolimbic structures involved in cognitive and motivational processes key to parenting, modulate this flexibility in caregiving across the postpartum period. The present study used a Wistar‐Kyoto (WKY) animal model of depression and control Sprague‐Dawley (SD) rats, which differ dramatically in their cognitive, motivational, and parenting performance. Levels of the monoamine neurotransmitters, dopamine, noradrenaline and serotonin, as well as their major metabolites, were measured within the medial prefrontal cortex, striatum, nucleus accumbens and medial preoptic area of SD and WKY mothers at early (postpartum day [PPD]7‐8), late (PPD15‐16) and weaning (PPD25) postpartum stages using high‐performance liquid chromatography with electrochemical detection. Consistent with our prior work, we find that caregiving of SD mothers declined as the postpartum period progressed. Relative to nulliparous females, early postpartum mothers had lower intracellular concentrations of monoamines, as well as lower noradrenaline turnover, and an elevated serotonin turnover within most structures. Postpartum behavioural trajectories subsequently corresponded to a progressive increase in all three monoamine levels within multiple structures. Compared to SD mothers, WKY mothers were inconsistent and disorganised in caring for their offspring and exhibit profound deficits in maternal behaviour. Additionally, WKY mothers had generally lower levels of all three monoamines, as well as different patterns of change across the postpartum period, compared to SD mothers, suggesting dysfunctional central monoamine pathways in WKY mothers as they transition and experience motherhood. Taken together, the results of the present study suggest a role for monoamines at multiple mesocorticolimbic structures with repect to modulating caregiving behaviours attuned to the changing needs of the young.

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“…In this study, we identified sex-based disruption in the Glu–Gln cycle involving astrocytes targeting the PFC-NAc pathway (Nestler and Carlezon, 2006; Nestler, 2015), using an animal model of depression for males and females.…”

Section: Introductionmentioning

confidence: 99%

Disruption of the Glutamate–Glutamine Cycle Involving Astrocytes in an Animal Model of Depression for Males and Females

Rappeneau

Blaker

Petro

et al. 2016

Front. Behav. Neurosci.

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Background: Women are twice as likely as men to develop major depression. The brain mechanisms underlying this sex disparity are not clear. Disruption of the glutamate–glutamine cycle has been implicated in psychiatric disturbances. This study identifies sex-based impairments in the glutamate–glutamine cycle involving astrocytes using an animal model of depression.Methods: Male and female adult Long-Evans rats were exposed to chronic social defeat stress (CSDS) for 21 days, using a modified resident-intruder paradigm. Territorial aggression was used for males and maternal aggression was used for females to induce depressive-like deficits for intruders. The depressive-like phenotype was assessed with intake for saccharin solution, weight gain, estrous cycle, and corticosterone (CORT). Behaviors displayed by the intruders during daily encounters with residents were characterized. Rats with daily handling were used as controls for each sex. Ten days after the last encounter, both the intruders and controls were subjected to a no-net-flux in vivo microdialysis to assess glutamate accumulation and extracellular glutamine in the nucleus accumbens (NAc). The contralateral hemispheres were used for determining changes in astrocytic markers, including glial fibrillary acidic protein (GFAP) and glutamate transporter-1 (GLT-1).Results: Both male and female intruders reduced saccharin intake over the course of CSDS, compared to their pre-stress period and to their respective controls. Male intruders exhibited submissive/defensive behaviors to territorial aggression by receiving sideways threats and bites. These males showed reductions in striatal GLT-1 and spontaneous glutamine in the NAc, compared to controls. Female intruders exhibited isolated behaviors to maternal aggression, including immobility, rearing, and selfgrooming. Their non-reproductive days were extended. Also, they showed reductions in prefrontal and accumbal GFAP+ cells and prefrontal GLT-1, compared to controls. When 10 μM of glutamate was infused, these females showed a significant accumulation of glutamate compared to controls. Infusions of glutamate reduced extracellular glutamine for both male and female intruders compared to their respective controls.Conclusion: Twenty-one days of territorial or maternal aggression produced a depressive-like phenotype and impaired astrocytes in both male and female intruders. Disruption of the glutamate–glutamine cycle in the PFC-striatal network may be linked to depressive-like deficits more in females than in males.

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Role of the Brain's Reward Circuitry in Depression

Cited by 89 publications

References 75 publications

Depression as a Risk Factor for Impulse Control Disorders in Parkinson Disease

Depression as a Risk Factor for Impulse Control Disorders in Parkinson Disease

Depression‐related disturbances in rat maternal behaviour are associated with altered monoamine levels within mesocorticolimbic structures

Disruption of the Glutamate–Glutamine Cycle Involving Astrocytes in an Animal Model of Depression for Males and Females

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