In vivo assessment of serotonergic signaling pathways underlying the corticolimbic response to threat in humans

A corticolimbic circuit including the amygdala and medial prefrontal cortex (mPFC) affects sensitivity to threat, related aspects of personality and risk for psychopathology. Serotonin (5‐HT) is a potent neuromodulator of this circuit, however, 5‐HT receptors mediating these effects and genetic sources of variability in 5‐HT receptor availability are not understood. We determined the association between 5‐HT1A and 5‐HT2A binding and the response to threat within this corticolimbic circuit using a multimodal neuroimaging strategy in humans in vivo. Corticolimbic circuit function was assessed with a threat‐related faces matching paradigm using functional magnetic resonance imaging (fMRI). Regional 5‐HT1A and 5‐HT2A binding was assessed with [11C]WAY100635 and [18F]altanserin PET, respectively. We evaluated the association between receptor binding and common polymorphisms (rs6295, rs6311 and 5‐HTTLPR) in 5‐HT related genes.In Study 1 we found that 5‐HT1A binding within the dorsal raphe nucleus was inversely associated with threat‐related amygdala reactivity. This is consistent with 5‐HT1A autoreceptors negatively regulating 5‐HT release, which within the amygdalapotentiates its response to threat. In Study 2 we found that mPFC 5‐HT2A binding was inversely associated with threat‐related amygdala reactivity and positively associated with amygdala habituation and amygdala‐mPFC functional connectivity. In Study 3 we found that mPFC 5‐HT1A binding significantly moderated the inverse association between mPFC 5‐HT2A binding and amygdala reactivity.These findings are consistent with the co‐localization of 5‐HT1A and 5‐HT2A on glutamatergic neurons within mPFC indicating the 5‐HT2A receptor is localized to facilitate regulation of the amygdala and the 5‐HT1A receptor is localized to moderate its effects within mPFC. In Study 4 we found that 5‐HTTLPR genotype predicted 5‐HT1A and 5‐HT2A binding in brain regions within this circuit such that the S and LG alleles were associated with reduced 5‐HT1A and 5‐HT2A binding.These findings provide novel insight into mechanisms that mediate the effects of 5‐HT signaling on the response to threat of a key corticolimbic circuit in humans. Our findings indicate that 5‐HT1A and 5‐HT2A receptors contribute significantly to threat‐related corticolimbic circuit function in humans. Furthermore, the 5‐HTTLPR may contribute to individual variability in neural and behavioral sensitivity to threat by biasing 5‐HT1A and 5‐HT2A availability

The Key Role of the Amygdala in Stress

Several data highlighted that stress exposure is strongly associated with several psychiatric disorders. The amygdala, an area of the brain that contributes to emotional processing, has a pivotal role in psychiatric disorders and it has been demonstrated to be highly responsive to stressful events. Here we will review evidences indicating how the amygdala changes its functionality following exposure to stress and how this contributes to the onset of anxiety disorders

The role of serotonergic system at the interface of aggression and suicide

Alterations in serotonin (5-HT) neurochemistry have been implicated in the aetiology of all major neuropsychiatric disorders, ranging from schizophrenia to mood and anxiety-spectrum disorders. This review will focus on the mulifaceted implications of 5-HT-ergic dysfunctions in the pathophysiology of aggressive and suicidal behaviours. After a brief overview of the anatomical distribution of the 5-HT-ergic system in the key brain areas that govern aggression and suicidal behaviours, the implication of 5-HT markers (5-HT receptors, transporter as well as synthetic and metabolic enzymes) in these conditions is discussed. In this regard, particular emphasis is placed on the integration of pharmacological and genetic evidence from animal studies with the findings of human experimental and genetic association studies. Traditional views postulated an inverse relationship between 5-HT and aggression and suicidal behaviours; however, ample evidence has shown that this perspective may be overly simplistic, and that such pathological manifestations may reflect alterations in 5-HT homeostasis due to the interaction of genetic, environmental and gender-related factors, particularly during early critical developmental stages. The development of animal models that may capture the complexity of such interactions promises to afford a powerful tool to elucidate the pathophysiology of impulsive aggression and suicidability, and find new effective therapies for these conditions

Brain serotonergic circuitries

Brain serotonergic circuitries interact with other neurotransmitter systems on a multitude of different molecular levels. In humans, as in other mammalian species, serotonin (5-HT) plays a modulatory role in almost every physiological function. Furthermore, serotonergic dysfunction is thought to be implicated in several psychiatric and neurodegenerative disorders. We describe the neuroanatomy and neurochemistry of brain serotonergic circuitries. The contribution of emergent in vivo imaging methods to the regional localization of binding site receptors and certain aspects of their functional connectivity in correlation to behavior is also discussed. 5-HT cell bodies, mainly localized in the raphe nuclei, send axons to almost every brain region. It is argued that the specificity of the local chemocommunication between 5-HT and other neuronal elements mainly depends on mechanisms regulating the extracellular concentration of 5-HT, the diversity of high-affinity membrane receptors, and their specific transduction modalities

Targeting neurotransmitter receptors for central nervous system therapeutics : from molecular signalling to behavioural pharmacology

EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Age- and sex-specific effects of amphetamines on cognition and serotonin in the orbitofrontal cortex

Use of amphetamines is a global health problem associated with significant social and financial burdens. Worldwide, amphetamines are second only to marijuana and opiates, respectively, for most abused illicit drug and highest prevalence of addiction. Epidemiological data reveal that adolescent and female drug users are at higher risk to develop addiction and have worse treatment outcomes than adults or males. Drug-induced cognitive deficits and neuroadaptations, in combination with different patterns of drug-seeking, represent possible mechanisms by which heightened vulnerability to addiction may be conferred in adolescents and females. Using a rodent model, this hypothesis was tested with two specific aims: (1) by assessing the impact of exposure to amphetamines on cognitive flexibility and 5-HT2C receptor structure and function (Experiments 1, 3, 4) and (2) by examining age and sex differences in intravenous methamphetamine self-administration (Experiment 2). In Experiment 1, male and female Sprague-Dawley rats were treated with amphetamine (3 mg/kg i.p.) during adolescence or young adulthood and tested in a Pavlovian outcome devaluation task at the same age in adulthood. Subsequently, the impact of systemic 5-HT2C receptor antagonism on devaluation was tested in a separate group of amphetamine-treated rats. In Experiment 2, male and female Sprague-Dawley rats were trained to self-administer methamphetamine at 3 doses (0.02, 0.05, 0.08 mg/kg/inf) during adolescence or adulthood and, subsequently, tested for motivation to work for four doses of methamphetamine using a progressive ratio schedule of reinforcement. Rats that acquired methamphetamine self-administration at the highest dose were used in Experiments 3 and 4. In Experiment 3, rats with a history of self-administration were tested for cognitive flexibility in an operant strategy shifting task. Subsequently, in Experiment 4, immunohistochemical analysis of the brains examined colocalization of 5-HT2C receptors with parvalbumin-immunoreactive interneurons in the orbitofrontal cortex. These studies revealed complex interactions of age and sex on drug-induced changes and heightened drug-seeking in adult rats. Taken together and in the context of broader literature, this work supports the assertion that pervasive, and sometimes subtle, drug-induced changes in cognition and neurobiology along with different patterns of drug-seeking may be mechanisms of heightened vulnerability in adolescent and female users

Cognitive Control as a 5-HT1A-Based Domain That Is Disrupted in Major Depressive Disorder

Heterogeneity within Major Depressive Disorder (MDD) has hampered identification of biological markers (e.g., intermediate phenotypes, IPs) that might increase risk for the disorder or reflect closer links to the genes underlying the disease process. The newer characterizations of dimensions of MDD within Research Domain Criteria (RDoC) domains may align well with the goal of defining IPs. We compare a sample of 25 individuals with MDD compared to 29 age and education matched controls in multimodal assessment. The multimodal RDoC assessment included the primary IP biomarker, positron emission tomography (PET) with a selective radiotracer for 5-HT1A [(11C)WAY-100635], as well as event-related functional MRI with a Go/No-go task targeting the Cognitive Control network, neuropsychological assessment of affective perception, negative memory bias and Cognitive Control domains. There was also an exploratory genetic analysis with the serotonin transporter (5-HTTLPR) and monamine oxidase A (MAO-A) genes. In regression analyses, lower 5-HT1A binding potential (BP) in the MDD group was related to diminished engagement of the Cognitive Control network, slowed resolution of interfering cognitive stimuli, one element of Cognitive Control. In contrast, higher/normative levels of 5-HT1A BP in MDD (only) was related to a substantial memory bias toward negative information, but intact resolution of interfering cognitive stimuli and greater engagement of Cognitive Control circuitry. The serotonin transporter risk allele was associated with lower 1a BP and the corresponding imaging and cognitive IPs in MDD. Lowered 5HT 1a BP was present in half of the MDD group relative to the control group. Lowered 5HT 1a BP may represent a subtype including decreased engagement of Cognitive Control network and impaired resolution of interfering cognitive stimuli. Future investigations might link lowered 1a BP to neurobiological pathways and markers, as well as probing subtype-specific treatment targets

Serotonin and Threat: from Gene to Behaviour

Anxiety and fear are emotions provoked by threatening situations and shape adaptive behaviours, but excessive and uncontrollable anxiety and fear form core symptoms of anxiety disorders. High trait anxiety, an individual’s disposition to feel anxious, is associated with greater risk of developing depression and anxiety disorders. This raises the question: why are some more vulnerable to experiencing negative emotions associated with threat than others? As serotonin has been implicated as a key neuromodulator of emotion, the thesis addresses this question by adopting a multi-systems approach to investigate the link between serotonin and both threat-driven behaviour and trait anxiety with the common marmoset as a model. Firstly, factors underlying threat-related behaviour modelled with an exploratory factor analysis revealed a relationship between a predominantly avoidant fear coping style and an increased propensity for anxiety, establishing a link between specific fear-driven behavioural patterns and anxiety. After characterising anxiety and fear-driven behaviours, mRNA quantification of brain regions implicated in anxiety revealed serotonergic gene expressions corresponding to anxiety and fear-driven behaviours. Most notably, amygdala serotonin transporter expression was positively associated with anxious behaviour and was differentiated by the serotonin transporter polymorphism. Based on this association, the hypothesis that increased amygdala serotonin transporter expression may contribute to the high trait anxious phenotype was tested. Consistent with this hypothesis, blockade of amygdala serotonin transporters via local infusions of a selective serotonin reuptake inhibitor (SSRI), citalopram reduced key characteristics of the high trait anxious phenotype: high state anxiety, and both the behavioural and physiological expression of conditioned fear. Anatomically, high anxious animals showed reduced basolateral amygdala (BLA) volume in adulthood. Moreover, BLA volume in adulthood was differentiated by the serotonin transporter polymorphism. During development, high anxious animals showed a delayed BLA growth trajectory. These findings demonstrate morphological changes in the BLA across different developmental timepoints predictive of high anxiety in adulthood. Taken together, findings here provide evidence of amygdala serotonin’s role in trait anxious expression, and propose behavioural, genetic, molecular and anatomical factors that may contribute to an individual’s vulnerability to anxiety.Work here was supported by an MRC Programme grant (ACR: MR/M023990/1) and performed within the Behavioural and Clinical Neuroscience Institute, University of Cambridge, funded jointly by the Wellcome Trust and MRC. SKLQ was supported by a scholarship by the Malaysian Public Service Department