Dopamine D2-Like Receptors and the Antidepressant Response

Gershon, Ari A.; Vishne, Tali; Grunhaus, Leon

doi:10.1016/j.biopsych.2006.05.031

Cited by 138 publications

(87 citation statements)

References 107 publications

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“…Although findings derived from experimental animal studies and functional neuroimaging are far from being consistent, recent reviews have raised the possibility that depression might be characterized by decreased sensitivity of dopaminergic receptors and decreased dopaminergic release within ventral striatal regions know to be critically implicated in incentive processing (D'Aquila et al, 2000;Dunlop and Nemeroff, 2007;Gershon et al, 2007). Of relevance to the present findings, in a recent pharmacological challenge study using the same probabilistic reward task, we found that a single dose of a dopamine D2 agonist (pramipexole) -hypothesized to activate presynaptic dopaminergic autoreceptors and thus reduce phasic dopaminergic bursts (e.g., Fuller et al, 1982;Tissari et al, 1983) -impaired the development of response bias and reduced the differentiation between rich and lean hit rates in healthy subjects .…”

Section: Discussionmentioning

confidence: 99%

Reduced hedonic capacity in major depressive disorder: Evidence from a probabilistic reward task

Pizzagalli

Iosifescu

Hallett

et al. 2008

Journal of Psychiatric Research

647

693

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Objective-Anhedonia, the lack of reactivity to pleasurable stimuli, is a cardinal feature of depression that has received renewed interest as a potential endophenotype of this debilitating disease. The goal of the present study was to test the hypothesis that individuals with major depression are characterized by blunted reward responsiveness, particularly when anhedonic symptoms are prominent.Methods-A probabilistic reward task rooted within signal-detection theory was utilized to objectively assess hedonic capacity in 23 unmedicated subjects meeting DSM-IV criteria for major depressive disorder (MDD) and 25 matched control subjects recruited from the community. Hedonic capacity was defined as reward responsiveness -i.e., the participants' propensity to modulate behavior as a function of reward.Results-Compared to controls, MDD subjects showed significantly reduced reward responsiveness. Trial-by-trial probability analyses revealed that MDD subjects, while responsive to delivery of single rewards, were impaired at integrating reinforcement history over time and expressing a response bias toward a more frequently rewarded cue in the absence of immediate reward. This selective impairment correlated with self-reported anhedonic symptoms, even after considering anxiety symptoms and general distress.Conclusions-These findings indicate that MDD is characterized by an impaired tendency to modulate behavior as a function of prior reinforcements, and provides initial clues about which aspects of hedonic processing might be dysfunctional in depression.

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Section: Discussionmentioning

confidence: 99%

Reduced hedonic capacity in major depressive disorder: Evidence from a probabilistic reward task

Pizzagalli

Iosifescu

Hallett

et al. 2008

Journal of Psychiatric Research

647

693

View full text Add to dashboard Cite

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“…s1R ligands exert potent neuromodulation on excitatory neurotransmitter systems, such as the glutamate and dopamine systems, which are both involved in behavioral despair (Belozertseva et al, 2007;Gershon et al, 2007). Selective s1R agonists cause antidepressant-like effects on rats in swim tests (Gudelsky, 1995;Urani et al, 2001), noting that DHEA and DHEAS are also potent s1R agonists (Urani et al, 2001).…”

Section: Introductionmentioning

confidence: 99%

DHEA Lessens Depressive-Like Behavior via GABA-ergic Modulation of the Mesolimbic System

Genud

Merenlender

Gispan-Herman

et al. 2008

Neuropsychopharmacol

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Alterations in the levels of dehydroepiandrosterone (DHEA) in the brain can allosterically modulate g-aminobutyric-acid-type-A (GABA A R), N-methyl-D-aspartate (NMDAR), and Sigma-1 (s1R) receptors. In humans, DHEA has antidepressive effects; however, the mechanism is unknown. We examined whether alterations in DHEA also occur in an animal model of depression, the Flinders-sensitiveline (FSL) rats, with the intention of determining the brain site of DHEA action and its antidepressant mechanism. We discovered that DHEA levels were lower in some brain regions involved with depression of FSL rats compared to Sprague-Dawley (SD) controls. Moreover, DHEA (1 mg/kg IP for 14 days)-treated FSL rats were more mobile in the forced swim test than FSL controls. In the NAc and VTA, significant changes were observed in the levels of the d-subunit of GABA A , but not of s1R mRNA, in FSL rats compared to SD rats. The d-subunit controls the sensitivity of the GABA A R to the neurosteroid. Indeed, treatment (14 days) of FSL rats with the GABA A agonist muscimol (0.5 mg/kg), together with DHEA (a negative modulator of GABA A ), reversed the effect of DHEA on immobility in the swim test. Perfusion of DHEA sulfate (DHEAS) (3 nM and 30 nM for 14 days) into the VTA and NAc of FSL rats improved their performance in the swim test for at least 3 weeks post-treatment. Our results imply that alterations in DHEA are involved in the pathophysiology of depression and that the antidepressant action of DHEA is mediated via GABA A Rs in the NAc and VTA.

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“…This latter finding was used to argue that there is reduced synaptic DA in depression, leading to postsynaptic supersensitivity including supersensitivity to psychostimulants. The interpretation of postsynaptic supersensitivity is likely to be an oversimplification of the pathological process in depression, because numerous studies demonstrate that enhancement of D2-like receptor sensitivity is an important action of antidepressant drug action (Gershon et al, 2007). Despite our lack of a thorough understanding of DA pathobiology in depression, both preclinical and clinical findings suggest that brain dopaminergic activity is reduced in depression.…”

Section: Introductionmentioning

confidence: 99%

Dopamine receptor gene expression in human amygdaloid nuclei: Elevated D4 receptor mRNA in major depression

Xiang

Szebeni

et al. 2008

Brain Research

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Previous findings from this laboratory demonstrating changes in dopamine (DA) transporter and D2 receptors in the amygdaloid complex of subjects with major depression indicate that disruption of dopamine neurotransmission to the amygdala may contribute to behavioral symptoms associated with depression. Quantitative real-time RT-PCR was used to investigate the regional distribution of gene expression of DA receptors in the human amygdala. In addition, relative levels of mRNA of DA receptors in the basal amygdaloid nucleus were measured postmortem in subjects with major depression and normal control subjects. All five subtypes of DA receptor mRNA were detected in all amygdaloid subnuclei, although D1, D2, and D4 receptor mRNAs were more abundant than D3 and D5 mRNAs by an order of magnitude. The highest level of D1 mRNA was found in the central nucleus, whereas D2 mRNA was the most abundant in the basal nucleus. Levels of D4 mRNA were highest in the basal and central nuclei. In the basal nucleus, amounts of D4, but not D1 or D2, mRNAs were significantly higher in subjects with major depression and depressed suicide victims, as compared to control subjects. These findings demonstrate that the D1, D2 and D4 receptors are the major subtypes of DA receptors in the human amygdala. Elevated DA receptor gene expression in depressive subjects further implicates altered dopaminergic transmission in the amygdala in depression.

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Dopamine D2-Like Receptors and the Antidepressant Response

Cited by 138 publications

References 107 publications

Reduced hedonic capacity in major depressive disorder: Evidence from a probabilistic reward task

Reduced hedonic capacity in major depressive disorder: Evidence from a probabilistic reward task

DHEA Lessens Depressive-Like Behavior via GABA-ergic Modulation of the Mesolimbic System

Dopamine receptor gene expression in human amygdaloid nuclei: Elevated D4 receptor mRNA in major depression

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