Alexander Neumeister

Traumatic events and extreme stress exposure can elicit a variety of psychiatric syndromes.¹ However, relatively little is known regarding the human neurobiological mechanisms that underlie adaptive or pathologic responses to traumatic stress.^2,3 A subset of individuals exposed to trauma¹ develop posttraumatic stress disorder (PTSD), a disabling clinical syndrome characterized by recurrent intrusive memories of a traumatic event, repeated avoidance of reminders of the trauma, and high levels of arousal and anxiety.⁴ The neurobiological mechanisms through which specific features of stress, including the number, severity, and duration of stress exposure or the developmental timing of traumatization, modulate PTSD risk and severity are unknown.^5-9 Consequently, treatment options for these often chronically symptomatic patients remain limited.^10,11

Bipolar disorder (BPD) is a major medical and social burden, but little is known about the specific pathophysiology of BPD. The key biogenic amines in the aminergic system include serotonin (5-HT), norepinephrine (NE), dopamine (DA), and acetylcholine (ACh). By analyzing these neurotransmitters, this chapter highlights three hypotheses in the pathophysiology of BPD: the biogenic amine hypothesis, the cholinergic–aminergic balance hypothesis, and the permissive hypothesis. Evidence from select studies of cerebrospinal fluid, postmortem subjects, neuroimaging, genetic factors, and pharmacological agents will be used to reconcile these hypotheses. Possible explanations for discrepancies in these hypotheses are given, and directions for future studies are suggested.

Rationale Although serotonin (5-HT) dysregulation is implicated in the pathophysiology of major depressive disorder (MDD), the role of specific receptor subtypes remains to be elucidated. Emerging preclinical research suggests an important role for the 5-HT_1B receptor in behavioral regulation and depressive phenotypes. In particular, 5-HT_1B heteroreceptors located within the striatum have been shown to play an essential role in antidepressant action. Objectives The objective of this study was to determine 5-HT_1B receptor binding potential (BP _ND) in the region of the ventral striatum/ventral pallidum (VS/VP) in individuals with MDD and healthy control participants. Methods Ten participants with MDD (30.8 ± 9.5 years, five men/five women) in a current major depressive episode (MDE) and ten healthy control participants (30.7 ± 10.5 years, five men/five women) underwent positron emission tomography (PET) scanning with the selective 5-HT_1B receptor radioligand [¹¹C]P943. Results Within the VS/VP region of interest, [¹¹C]P943 BP _ND was significantly reduced in the MDD group compared with the healthy control group (1.37 ± 0.13 and 1.68 ± 0.16, respectively; 18.7% between-group difference; p < 0.001). Conclusions Consistent with preclinical and postmortem data, our findings suggest abnormally reduced function of VS/VP 5-HT_1B receptors in humans with MDD. Abnormal 5-HT_1B heteroreceptor function may contribute to dysfunctional reward signaling within the striatum, including the nucleus accumbens, via interaction with dopamine, γ-amino-butyric acid, or glutamate systems. Our findings suggest reduced 5-HT_1B receptor signaling in the VS/VP in MDD and contribute to the therapeutic rationale for testing 5-HT_1B agonists as a novel class of antidepressants.