Abstract
Major depressive disorder (MDD) is the leading cause of disability worldwide. The serotonin hypothesis may be the model of MDD pathophysiology with the most support. The majority of antidepressants enhance synaptic serotonin levels quickly, while it usually takes weeks to discern MDD treatment effect. It has been hypothesized that the time lag between serotonin increase and reduction of MDD symptoms is due to downregulation of inhibitory receptors such as the serotonin 1B receptor (5-HT1BR). The research on 5-HT1BR has previously been hampered by a lack of selective ligands for the receptor. The last extensive review of 5-HT1BR in the pathophysiology of depression was published 2009, and based mainly on findings from animal studies. Since then, selective radioligands for in vivo quantification of brain 5-HT1BR binding with positron emission tomography has been developed, providing new knowledge on the role of 5-HT1BR in MDD and its treatment. The main focus of this review is the role of 5-HT1BR in relation to MDD and its treatment, although studies of 5-HT1BR in obsessive-compulsive disorder, alcohol dependence, and cocaine dependence are also reviewed. The evidence outlined range from animal models of disease, effects of 5-HT1B receptor agonists and antagonists, case-control studies of 5-HT1B receptor binding postmortem and in vivo, with positron emission tomography, to clinical studies of 5-HT1B receptor effects of established treatments for MDD. Low 5-HT1BR binding in limbic regions has been found in MDD patients. When 5-HT1BR ligands are administered to animals, 5-HT1BR agonists most consistently display antidepressant-like properties, though it is not yet clear how 5-HT1BR is best approached for optimal MDD treatment.
Highlights
Major depression is a significant contributor to the global burden of disease, and likely the leading cause of disability in the industrialized world (Whiteford et al 2013)
The main body of the literature on 5-HT1B receptors in relation to depression consists of research in animals, data from human studies on 5-HT1B receptor in major depressive disorder (MDD) are slowly accumulating
The evidence summarized above supports a role of the 5-HT1B receptor as an interesting target for antidepressant treatment
Summary
Major depression is a significant contributor to the global burden of disease, and likely the leading cause of disability in the industrialized world (Whiteford et al 2013). 5-HT1B receptor binding in the p11 knockout mice is reduced, but not depleted (Svenningsson et al 2006) This more moderate reduction in 5-HT1B receptor levels would be in line with human case-control studies, in which globally low brain binding and mRNA expression has been found in patients with major depressive disorder (MDD) (Tiger et al 2016) and suicide subjects (Anisman et al 2008), respectively. Despite the methodological differences and the small number of cases and controls, previous postmortem and in vivo studies consistently support a trend of low levels of cerebral 5-HT1B receptor related measures in unmedicated MDD subjects (Anisman et al 2008; Murrough et al 2011b; Tiger et al 2016). Low 5-HT1B receptor binding and expression in ACC and hippocampus, key regions of the neurocircuitry of MDD (Mayberg 1997) has been reported
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