Regulation of Corticolimbic Reactivity via the 5-HT 1A Autoreceptor in the Pathophysiology and Treatment of Depression

Abstract

According to the National Institute of Mental Health, major depressive disorder (MDD) is among the leading causes of mortality and disability in the USA. In a given year, nearly 7% of Americans experience at least one clinically significant episode of MDD, manifested by a combination of symptoms that interfere with the ability to work, study, sleep, eat and enjoy once pleasurable activities. While an MDD episode may occur only once, they are typically recurring and result in lifetime disability. Although there are a number of widely applied pharmacological and psychological approaches to the treatment of MDD, the efficacy of these is poor, with less than 50% of individuals experiencing a therapeutic response [1]. Combination therapies may lead to higher rates of therapeutic response for a few individuals, but many others will experience severe side effects leading to treatment discontinuation [2]. In light of the immense personal and public health burden of MDD, the existing poor efficacy of available treatments has precipitated dedicated research efforts to better understand the pathophysiology of MDD with the aim of identifying predictive markers of disease liability and generating more effective intervention. Although the neurobiological mechanisms through which disturbances in emotional behavior, mood and temperament emerge and contribute to the development of MDD are not wholly understood, a myriad of converging evidence inextricably links these phenomena with functioning of the central serotonin (5-HT) system and its inter-related subsystems. Multiple mechanisms contribute to the regulation of 5-HT neurotransmission and variability in these regulatory mechanisms is associated with individual differences in temperament and risk for MDD. Key among these is the 5-HT type 1A (5-HT1A) somatodendritic autoreceptor, which is expressed on a population of serotonergic neurons projecting from the brainstem raphe nuclei to cortical and limbic target regions. The 5-HT1A autoreceptor mediates negative-feedback regulation of 5-HT neurons through G-protein coupled signaling cascades, resulting in diminished neuronal activity and subsequent 5-HT release at postsynaptic targets. These postsynaptic targets include the amygdala and prefrontal cortex, key nodes of a corticolimbic circuitry supporting emotional reactivity and control. In the context of emotional behavior, the subcortical amygdala mediates rapid physiological and behavioral arousal in response to salient, biological stimuli (e.g., threat-related facial expressions, such as anger and fear). In addition to regulating the activity of numerous hypothalamic and brainstem autonomic centers, the amygdala can stimulate the activity of the ventromedial and orbitofrontal cortices [3]. These prefrontal regions are critical for the integration of amygdala-mediated arousal in the service of complex, adaptive behavioral responses to environmental challenges [4,5]. The subsequent stimulation of dorsomedial, ventrolateral and dorsolateral prefrontal regions, resulting from such engagement of the ventromedial and orbitofrontal cortices, then precipitates top-down inhibition of the amygdala [6–8]. The coordinated activity within this distributed corticolimbic circuitry largely governs emotional arousal and regulation, and dysfunction of circuit components are pathological markers of MDD [9,10].