Mania: a Rational Neurobiology
Abstract
A cohesive picture has emerged over the last decade regarding the pathophysiology and treatment of bipolar disorder, a serious mental disorder that cycles between mania and depression. Mania is associated with overactive PKC intracellular signaling, and recent genome-wide association studies of bipolar disorder have implicated an enzyme that reduces the activation of PKC. Overactive PKC signaling in the prefrontal cortex may explain many of the symptoms of mania. Functional imaging studies have shown reduced activity in the right prefrontal cortex during the manic state. Dysfunction of the right prefrontal cortex is known to lead to a disinhibited profile, including poor impulse control, risk-taking, distractibility, poor sustained attention and delusions, which resemble the symptoms of mania. Structural imaging studies have further shown a loss of prefrontal volume in untreated patients with bipolar disorder. This loss of function and gray matter in the prefrontal cortex may arise from abnormal signaling cascades, notably PKC signaling. Studies in animals have shown that elevated PKC activity markedly and rapidly impairs the functioning of the prefrontal cortex, providing a link to the the loss of prefrontal regulation of thought and emotion during the manic state. Sustained elevation in PKC signaling may also lead to loss of gray matter in the prefrontal cortex, which can be protected by PKC inhibitors. Importantly, the current mainstays in the treatment of mania, lithium (…
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Medications for these disorders indirectly inhibit the PKC signalling pathway, for example lithium suppresses phosphatidylinositol signalling, and atypical antipsychotic medications block α1-adrenergic and 5-HT2 receptors coupled to Gq signalling.
“Importantly, medications for these disorders indirectly inhibit the PKC signalling pathway (for example, lithium suppresses phosphatidylinositol signalling), and the atypical antipsychotic medications block α1-adrenergic and serotonin (5-hydroxytryptamine, 5-HT) type 2 (5-HT2) receptors, which are coupled to Gq signalling139,140.”
From Stress signalling pathways that impair prefrontal cortex structure and function (2009) · cites this paper as [140]
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Paul, J., & Rajan, R. (2021) · Asian Journal of Pharmaceutical and Clinical Research · doi:10.22159/ajpcr.2022.v15i1.43731
- Authors
- Arnsten, A., & Manji, H.
- Affiliations
- Yale University (US)
- National Institutes of Health (US)
- Venue
- Future Neurology
- Publisher
- Informa UK Limited
- Published
- 2008-02-27
- Volume
- 3
- Issue
- 2
- Pages
- 125-131
- ISSN
- 1479-6708 (ISSN-L)
- 1748-6971
- OpenAlex
- W2142041309
- Cited by
- 14
- References
- 66
- Citations by year
- 2021: 1 · 2015: 1 · 2014: 1 · 2012: 1
- FWCI
- 2.34
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Future Neurology (publishedVersion)
- Topics
- Health Sciences › Medicine › Psychiatry and Mental health › Bipolar Disorder and Treatment
- Health Sciences › Medicine › Psychiatry and Mental health › Schizophrenia research and treatment
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Keywords
- mania, bipolar disorder, protein kinase C signaling, prefrontal cortex, gray matter loss, PKC inhibitors, lithium, valproic acid, tamoxifen, impulse control
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