The dopamine hypothesis of bipolar affective disorder: the state of the art and implications for treatment

Ashok, Abhishekh Hulegar; Marques, Tiago Reis; Jauhar, Sameer; Nour, Matthew M.; Goodwin, Guy M.; Young, Allan H.; Howes, Oliver

doi:10.1038/mp.2017.16

Cited by 398 publications

(261 citation statements)

References 152 publications

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“…The antimanic actions of antidopaminergic drugs provide important evidence for a hyperdopaminergic state in mania (Ashok et al . ). Another important key function of dopamine outside the CNS is in regulation of renal electrolyte homeostasis.…”

Section: Introductionmentioning

confidence: 97%

“…Although the neurobiological mechanisms underlying the aetiology of BD are not understood completely, the dopamine hypothesis has been the leading key theory for manic episode. The antimanic actions of antidopaminergic drugs provide important evidence for a hyperdopaminergic state in mania (Ashok et al 2017). Another important key function of dopamine outside the CNS is in regulation of renal electrolyte homeostasis.…”

Section: Introductionmentioning

confidence: 99%

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Serum osmolarity in male patients with bipolar disorder manic episode

Kalelioğlu

Karamustafalıoğlu

Genç

et al. 2017

Experimental Physiology

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What is the central question of this study? The main goal of this study was, for the first time, to investigate the role of the serum osmolarity in bipolar disorder manic episode. What is the main finding and its importance? Our results demonstrate a diminished serum osmolarity in manic episode compared with healthy control subjects. This finding supports the hypothesis of a fluid and electrolyte imbalance during acute episodes. Decreased serum osmolarity might be a reflection of a relative haemodilution in mania. Imbalance of water and electrolyte homeostasis has been suggested to be associated with acute episodes of bipolar disorder. In this study, we aimed to investigate, for the first time, the serum osmolarity in bipolar disorder manic episode. A total of 68 bipolar inpatients in manic episode and 60 age- and sex-matched healthy control subjects were included in the study. Serum osmolarity was calculated from sodium (Na ), glucose and blood urea nitrogen (BUN) according to following formula: (2 × Na ) + (BUN/2.8) + (glucose/18). The significance level was accepted as P < 0.05. The serum osmolarity of manic patients was 295.34 ± 4.90 mosmol/l and that of the control group was 298.46 ± 5.33 mosmol/l. The serum osmolarity of the manic group was significantly lower than that of control subjects (P < 0.001). When we compared the components of serum osmolarity, a statistically significant difference was also observed between groups in terms of glucose (85.85 ± 12.25 mg/dl for manic, 92.95 ± 20.77 mg/dl for control subjects, P = 0.019) and Na (140.73 ± 2.06 mmol/l for manic, 142.06 ± 2.48 mmol/l for control subjects, P = 0.001). For BUN concentrations, there was no statistically significant difference between manic (25.50 ± 9.85 mg/dl) and control (26.61 ± 6.64 mg/dl) groups (P = 0.461). Our results demonstrate a diminished serum osmolarity in manic episode compared with healthy control subjects. This finding supports the hypothesis of a fluid and electrolyte imbalance during acute episodes. Decreased serum osmolarity might be a reflection of a relative haemodilution in mania. However, exploration of the role of fluid and electrolyte homeostasis and mechanisms of related hormones may contribute to a better understanding of the aetiology of bipolar disorder.

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Section: Introductionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

Serum osmolarity in male patients with bipolar disorder manic episode

Kalelioğlu

Karamustafalıoğlu

Genç

et al. 2017

Experimental Physiology

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“…Dopamine (DA) neurotransmission is required for motor control, learning, memory, motivation, and reward (Wise 2004;Iversen and Iversen 2007). DAergic dysregulation is evidenced in numerous neuropsychiatric disorders, including attentiondeficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), schizophrenia, bipolar disorder, addiction, and Parkinson's disease (PD) (Hyman, Malenka, and Nestler 2006;Sharma and Couture 2014;Ashok et al 2017;Howes et al 2017;Eissa et al 2018;Geibl, Henrich, and Oertel 2019). DA signaling is tightly controlled by the presynaptic dopamine transporter (DAT), which rapidly clears synaptically released DA.…”

Section: Introductionmentioning

confidence: 99%

Dopamine transporter trafficking and Rit2 GTPase: Mechanism of action and in vivo impact

Fagan

Kearney

Sweeney

et al. 2019

Preprint

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Following its evoked release, DA signaling is rapidly terminated by presynaptic reuptake, mediated by the cocaine-sensitive DAT. DAT surface availability is dynamically regulated by endocytic trafficking, and direct PKC activation acutely diminishes DAT surface expression by accelerating DAT internalization. Previous cell line studies demonstrated that PKC-stimulated DAT endocytosis requires both Ack1 inactivation, which releases a DAT-specific endocytic brake, and the neuronal GTPase, Rit2, which binds DAT. However, it is unknown whether Rit2 is required for PKC-stimulated DAT endocytosis in DAergic terminals, or whether there are region-and/or sexdependent differences in PKC-stimulated DAT trafficking. Moreover, the mechanisms by which Rit2 controls PKC-stimulated DAT endocytosis are unknown. Here, we directly examined these important questions. Ex vivo studies revealed that PKC activation acutely decreased DAT surface expression selectively in ventral, but not dorsal, striatum. AAV-mediated, conditional Rit2 knockdown in DAergic neurons impacted baseline DAT surface:intracellular distribution in DAergic terminals from female ventral, but not dorsal, striatum. Further, Rit2 was required for PKCstimulated DAT internalization in both male and female ventral striatum. FRET and surface pulldown studies in cell lines revealed that PKC activation drives DAT-Rit2 surface dissociation, and that the DAT N-terminus is required for both PKC-mediated DAT-Rit2 dissociation and DAT internalization. Finally, we found that Rit2 and Ack1 independently converge on DAT to facilitate PKC-stimulated DAT endocytosis. Together, our data provide greater insight into mechanisms that mediate PKC-regulated DAT internalization, and reveal unexpected region-specific differences in PKC-stimulated DAT trafficking in bona fide DAergic terminals. _______________________________________ DA neurotransmission is required for motor control, learning, memory, motivation, and reward (1,2). DAergic dysregulation is evidenced in numerous neuropsychiatric disorders, including ADHD, ASD, schizophrenia, bipolar disorder, addiction, and PD (3-8). DA signaling is tightly controlled by the presynaptic DAT, which rapidly clears synaptically released DA. DAT is also the primary target for addictive and therapeutic

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“…Clinically, the disorder is defined by the occurrence of at least one manic episode and often includes recurrent states of depressive, manic, mixed and euthymic episodes (Association, 2013). It is increasingly becoming evident that processing of motivation and reward are affected in all of these states (Ashok et al , 2017). This is supported by recent findings showing a transdiagnostic dopamine dysfunction spanning from bipolar disorder to schizophrenia (Jauhar et al , 2017).…”

Section: Introductionmentioning

confidence: 99%

Shared and dissociable features of apathy and reward system dysfunction in bipolar I disorder and schizophrenia

Kirschner

Cathomas

Manoliu

et al. 2019

Preprint

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BackgroundBipolar disorder I (BD-I) is defined by episodes of mania, depression, and euthymic states. These episodes are among other symptoms characterized by altered reward processing and negative symptoms (NS), in particular apathy. However, the neural correlates of these deficits are not well understood.MethodsWe first assessed the severity of negative symptoms in 25 euthymic BD-I patients compared to 25 healthy controls (HC) and 27 patients with schizophrenia (SZ). Then, we investigated ventral and dorsal striatal activation during reward anticipation in a Monetary Incentive Delayed Task and its association with NS.ResultsIn BD-I patients NS were clearly present and the severity of apathy was comparable to SZ patients. Apathy scores in the BD-I group but not in the SZ group correlated with sub-syndromal depression scores. At the neural level, we found significant ventral and dorsal striatal activation in BD-I patients and no group differences with HC or SZ patients. In contrast to patients with SZ, apathy did not correlate with striatal activation during reward anticipation. Explorative whole brain analyses revealed reduced extra-striatal activation in BD-I patients compared to HC and an association between reduced activation of the inferior frontal gyrus and apathy.ConclusionThis study found that in BD-I patients apathy is present to an extent comparable to schizophrenia, but is more strongly related to sub-syndromal depressive symptoms. The findings support the view of different pathophysiological mechanisms underlying apathy in the two disorders and suggest that extra-striatal dysfunction may contribute to impaired reward processing and apathy in BD-I.

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The dopamine hypothesis of bipolar affective disorder: the state of the art and implications for treatment

Cited by 398 publications

References 152 publications

Serum osmolarity in male patients with bipolar disorder manic episode

Serum osmolarity in male patients with bipolar disorder manic episode

Dopamine transporter trafficking and Rit2 GTPase: Mechanism of action and in vivo impact

Shared and dissociable features of apathy and reward system dysfunction in bipolar I disorder and schizophrenia

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