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Anxious temperament (AT) in human and non-human primates is a trait-like phenotype evident early in life that is characterized by increased behavioural and physiological reactivity to mildly threatening stimuli. Studies in children demonstrate that AT is an important risk factor for the later development of anxiety disorders, depression and comorbid substance abuse. Despite its importance as an early predictor of psychopathology, little is known about the factors that predispose vulnerable children to develop AT and the brain systems that underlie its expression. To characterize the neural circuitry associated with AT and the extent to which the function of this circuit is heritable, we studied a large sample of rhesus monkeys phenotyped for AT. Using 238 young monkeys from a multigenerational single-family pedigree, we simultaneously assessed brain metabolic activity and AT while monkeys were exposed to the relevant ethological condition that elicits the phenotype. High-resolution (18)F-labelled deoxyglucose positron-emission tomography (FDG-PET) was selected as the imaging modality because it provides semi-quantitative indices of absolute glucose metabolic rate, allows for simultaneous measurement of behaviour and brain activity, and has a time course suited for assessing temperament-associated sustained brain responses. Here we demonstrate that the central nucleus region of the amygdala and the anterior hippocampus are key components of the neural circuit predictive of AT. We also show significant heritability of the AT phenotype by using quantitative genetic analysis. Additionally, using voxelwise analyses, we reveal significant heritability of metabolic activity in AT-associated hippocampal regions. However, activity in the amygdala region predictive of AT is not significantly heritable. Furthermore, the heritabilities of the hippocampal and amygdala regions significantly differ from each other. Even though these structures are closely linked, the results suggest differential influences of genes and environment on how these brain regions mediate AT and the ongoing risk of developing anxiety and depression.
The authors examined the hypothesis that rhesus monkeys with extreme right frontal electroencephalographic activity would have higher cortisol levels and would be more fearful compared with monkeys with extreme left frontal activity. The authors first showed that individual differences in asymmetric frontal electrical activity are a stable characteristic. Next, the authors demonstrated that relative right asymmetric frontal activity and cortisol levels are correlated in animals 1 year of age. Additionally, extreme right frontal animals had elevated cortisol concentrations and more intense defensive responses. At 3 years of age, extreme right frontal animals continued to have elevated cortisol concentrations. These findings demonstrate important relations among extreme asymmetric frontal electrical activity, cortisol levels, and trait-like fear-related behaviors in young rhesus monkeys.
Children with anxious temperament (AT) are particularly sensitive to new social experiences and have increased risk for developing anxiety and depression. The young rhesus monkey is optimal for studying the origin of human AT because it shares with humans the genetic, neural, and phenotypic underpinnings of complex social and emotional functioning. In vivo imaging in young monkeys demonstrated that central nucleus of the amygdala (Ce) metabolism is relatively stable across development and predicts AT. Transcriptome-wide gene expression, which reflects combined genetic and environmental influences, was assessed within the Ce. Results support a maladaptive neurodevelopmental hypothesis linking decreased amygdala neuroplasticity to early-life dispositional anxiety. For example, high AT individuals had decreased mRNA expression of neurotrophic tyrosine kinase, receptor, type 3 (NTRK3). Moreover, variation in Ce NTRK3 expression was inversely correlated with Ce metabolism and other AT-substrates. These data suggest that altered amygdala neuroplasticity may play a role the early dispositional risk to develop anxiety and depression.
BACKGROUND: Asymmetric patterns of frontal brain activity and brain corticotropin-releasing hormone (CRH) systems have both been separately implicated in the processing of normal and abnormal emotional responses. Previous studies in rhesus monkeys demonstrated that individuals with extreme right frontal asymmetric brain electrical activity have high levels of trait-like fearful behavior and increased plasma cortisol concentrations. METHODS: In this study we assessed cerebrospinal fluid (CSF) CRH concentrations in monkeys with extreme left and extreme right frontal brain electrical activity. CSF was repeatedly collected at 4, 8, 14, 40, and 52 months of age. RESULTS: Monkeys with extreme right frontal brain activity had increased CSF CRH concentrations at all ages measured. In addition, individual differences in CSF CRH concentrations were stable from 4 to 52 months of age. CONCLUSIONS: These findings suggest that, in primates, the fearful endophenotype is characterized by increased fearful behavior, a specific pattern of frontal electrical activity, increased pituitary-adrenal activity, and increased activity of brain CRH systems. Data from other preclinical studies suggests that the increased brain CRH activity may underlie the behavioral and physiological characteristics of fearful endophenotype.
The corticotrophin-releasing hormone (CRH) system integrates the stress response and is associated with stress-related psychopathology. Previous reports have identified interactions between childhood trauma and sequence variation in the CRH receptor 1 gene (CRHR1) that increase risk for affective disorders. However, the underlying mechanisms that connect variation in CRHR1 to psychopathology are unknown. To explore potential mechanisms, we used a validated rhesus macaque model to investigate association between genetic variation in CRHR1, anxious temperament (AT) and brain metabolic activity. In young rhesus monkeys, AT is analogous to the childhood risk phenotype that predicts the development of human anxiety and depressive disorders. Regional brain metabolism was assessed with (18)F-labeled fluoro-2-deoxyglucose (FDG) positron emission tomography in 236 young, normally reared macaques that were also characterized for AT. We show that single nucleotide polymorphisms (SNPs) affecting exon 6 of CRHR1 influence both AT and metabolic activity in the anterior hippocampus and amygdala, components of the neural circuit underlying AT. We also find evidence for association between SNPs in CRHR1 and metabolism in the intraparietal sulcus and precuneus. These translational data suggest that genetic variation in CRHR1 affects the risk for affective disorders by influencing the function of the neural circuit underlying AT and that differences in gene expression or the protein sequence involving exon 6 may be important. These results suggest that variation in CRHR1 may influence brain function before any childhood adversity and may be a diathesis for the interaction between CRHR1 genotypes and childhood trauma reported to affect human psychopathology.
PET imaging of the neuroreceptor systems in the brain has earned a prominent role in studying normal development, neuropsychiatric illness and developing targeted drugs. The dopaminergic system is of particular interest due to its role in the development of cognitive function and mood as well as its suspected involvement in neuropsychiatric illness. Nonhuman primate animal models provide a valuable resource for relating neurochemical changes to behavior. To facilitate comparison within and between primate models, we report in vivo D2/D3 binding in a large cohort of adolescent rhesus monkeys. METHODS: In this work, the in vivo D2/D3 dopamine receptor availability was measured in a cohort of 33 rhesus monkeys in the adolescent stage of development (3.2-5.3 years). Both striatal and extrastriatal D2/D3 binding were measured using [F-18]fallypride with a high resolution small animal PET scanner. The distribution volume ratio (DVR) was measured for all subjects and group comparisons of D2/D3 binding among the cohort were made based on age and sex. Because two sequential studies were acquired from a single [F-18]fallypride batch, the effect of competing (unlabeled) ligand mass was also investigated. RESULTS: Among this cohort, the rank order of regional D2/D3 receptor binding did not vary from previous studies with adult rhesus monkeys, with: putamen>caudate>ventral striatum>amygdala approximately substantia nigra>medial dorsal thalamus>lateral temporal cortex approximately frontal cortex. The DVR coefficient of variation ranged from 14%-26%, with the greatest variance seen in the head of the caudate. There were significant sex differences in [F-18]fallypride kinetics in the pituitary gland, but this was not observed for regions within the blood-brain barrier. Furthermore, no regions in the brain showed significant sex or age related differences in DVR within this small age range. Based on a wide range of injected fallypride mass across the cohort, significant competition effects could only be detected in the substantia nigra, thalamus, and frontal cortex, and were not evident above intersubject variability in all other regions. CONCLUSION: These data represent the first report of large cohort in vivo D2/D3 dopamine whole brain binding in the adolescent brain and will serve as a valuable comparison for understanding dopamine changes during this critical time of development and provide a framework for creating a dopaminergic biochemical atlas for the rhesus monkey.
Neuroanatomists posit that the central nucleus of the amygdala (Ce) and bed nucleus of the stria terminalis (BST) comprise two major nodes of a macrostructural forebrain entity termed the extended amygdala. The extended amygdala is thought to play a critical role in adaptive motivational behavior and is implicated in the pathophysiology of maladaptive fear and anxiety. Resting functional connectivity of the Ce was examined in 107 young anesthetized rhesus monkeys and 105 young humans using standard resting-state functional magnetic resonance imaging (fMRI) methods to assess temporal correlations across the brain. The data expand the neuroanatomical concept of the extended amygdala by finding, in both species, highly significant functional coupling between the Ce and the BST. These results support the use of in vivo functional imaging methods in nonhuman and human primates to probe the functional anatomy of major brain networks such as the extended amygdala.
Freezing is an adaptive defensive behavior that is expressed in response to an imminent threat. In prior studies with rhesus monkeys, stable individual differences in animals' propensities to freeze have been demonstrated. To understand the factors associated with these individual differences, freezing behavior was examined in infant rhesus monkeys and their mothers, in conjunction with levels of the stress-related hormone cortisol. In both mothers and infants, basal cortisol levels were positively correlated with freezing duration. Additionally, the number of offspring a mother had was negatively correlated with her infant's cortisol level. These findings suggest a link between basal cortisol levels and an animal's propensity to freeze, as well as a mechanism by which maternal experience may affect infants' cortisol levels.
A growing body of literature has documented the differential role of the frontal regions of the two cerebral hemispheres in certain positive and negative affective processes. This corpus of evidence has led to the hypothesis of a possible differential effect of diazepam on asymmetry of frontal activation. To examine this question, nine infant rhesus monkeys were tested on two occasions during which brain electrical activity was recorded from left and right frontal and parietal scalp regions. During one session, recordings were obtained under a baseline restraint condition and then after an injection of diazepam (1 mg/kg). In the other session, following the same baseline restraint condition, a vehicle injection was given. In response to diazepam, the animals showed an asymmetrical decrease in power in the 4-8 Hz frequency band, which was most pronounced in the left frontal region. No change in electroencephalogram (EEG) activity was observed in response to vehicle. Asymmetry in parietal EEG activity was also unchanged by diazepam. Diazepam also produced overall reductions in power across different frequency bands in both frontal and parietal regions. Good test-retest stability of EEG measures of activation asymmetry was also found between the two testing sessions separated by three months. The possible proximal cause of the asymmetrical change in frontal brain electrical activity in response to diazepam, as well as the implications of these findings for understanding the mechanism of action of benzodiazepines are discussed.
Based on previous findings in humans and rhesus monkeys suggesting that diazepam has asymmetrical effects on frontal lobe activity and other literature supporting a role for the benzodiazepine system in the mediation of individual differences in anxiety and fearfulness, the relation between asymmetrical changes in scalp-recorded regional brain activity in response to diazepam and the temperamental dimension of behavioral inhibition indexed by freezing time in 9 rhesus monkeys was examined. Animals showed greater relative left-sided frontal activation in response to diazepam compared with the preceding baseline. The magnitude of this shift was strongly correlated with an aggregate measure of freezing time (r = .82). The implications of these findings for understanding the role of regional differences in the benzodiazepine system in mediating individual differences in fearfulness are discussed.
Children with an anxious temperament (AT) are at risk for developing psychiatric disorders along the internalizing spectrum, including anxiety and depression. Like these disorders, AT is a multidimensional phenotype and children with extreme anxiety show varying mixtures of physiological, behavioral, and other symptoms. Using a well-validated juvenile monkey model of AT, we addressed the degree to which this phenotypic heterogeneity reflects fundamental differences or similarities in the underlying neurobiology. The rhesus macaque is optimal for studying AT because children and young monkeys express the anxious phenotype in similar ways and have similar neurobiology. Fluorodeoxyglucose (FDG)-positron emission tomography (FDG-PET) in 238 freely behaving monkeys identified brain regions where metabolism predicted variation in three dimensions of the AT phenotype: hypothalamic-pituitary-adrenal (HPA) activity, freezing behavior, and expressive vocalizations. We distinguished brain regions that predicted all three dimensions of the phenotype from those that selectively predicted a single dimension. Elevated activity in the central nucleus of the amygdala and the anterior hippocampus was consistently found across individuals with different presentations of AT. In contrast, elevated activity in the lateral anterior hippocampus was selective to individuals with high levels of HPA activity, and decreased activity in the motor cortex (M1) was selective to those with high levels of freezing behavior. Furthermore, activity in these phenotype-selective regions mediated relations between amygdala metabolism and different expressions of anxiety. These findings provide a framework for understanding the mechanisms that lead to heterogeneity in the clinical presentation of internalizing disorders and set the stage for developing improved interventions.
Aversive Pavlovian conditioning is an important tool used to investigate neurobiological mechanisms underlying the acquisition and expression of fear. Most studies have used nonprimate species employing electrical shock as the unconditioned stimulus (US). Although important advances have been made in understanding the neural substrates of conditioned fear, the extent to which these findings apply to primates is unclear. Research in primates has not progressed because of the lack of a conditioning paradigm that does not use shock. Therefore, we developed a method that uses a US consisting of a loud noise coupled with a stream of compressed air aimed at the face to aversively condition heart rate response in rhesus monkeys. With this US, rhesus monkeys rapidly acquire a conditioned bradycardia. The availability of an easy, reliable, and efficient method of aversive conditioning that does not require electrical shock, will facilitate studies investigating neurobiological mechanisms underlying the acquisition and expression of fear in primates.
In children, behavioral inhibition (BI) in response to potential threat predicts the development of anxiety and affective disorders, and primate lesion studies suggest involvement of the orbitofrontal cortex (OFC) in mediating BI. Lesion studies are essential for establishing causality in brain-behavior relationships, but should be interpreted cautiously because the impact of a discrete lesion on a complex neural circuit extends beyond the lesion location. Complementary functional imaging methods assessing how lesions influence other parts of the circuit can aid in precisely understanding how lesions affect behavior. Using this combination of approaches in monkeys, we found that OFC lesions concomitantly alter BI and metabolism in the bed nucleus of stria terminalis (BNST) region and that individual differences in BNST activity predict BI. Thus it appears that an important function of the OFC in response to threat is to modulate the BNST, which may more directly influence the expression of BI.
Temperamentally anxious individuals can be identified in childhood and are at risk to develop anxiety and depressive disorders. In addition, these individuals tend to have extreme asymmetric right prefrontal brain activity. Although common and clinically important, little is known about the pathophysiology of anxious temperament. Regardless, indirect evidence from rodent studies and difficult to interpret primate studies is used to support the hypothesis that the amygdala plays a central role. In previous studies using rhesus monkeys, we characterized an anxious temperament endophenotype that is associated with excessive anxiety and fear-related responses and increased electrical activity in right frontal brain regions. To examine the role of the amygdala in mediating this endophenotype and other fearful responses, we prepared monkeys with selective fiber sparing ibotenic acid lesions of the amygdala. Unconditioned trait-like anxiety-fear responses remained intact in monkeys with >95% bilateral amygdala destruction. In addition, the lesions did not affect EEG frontal asymmetry. However, acute unconditioned fear responses, such as those elicited by exposure to a snake and to an unfamiliar threatening conspecific were blunted in monkeys with >70% lesions. These findings demonstrate that the primate amygdala is involved in mediating some acute unconditioned fear responses but challenge the notion that the amygdala is the key structure underlying the dispositional behavioral and physiological characteristics of anxious temperament.
Numerous studies demonstrate that the rhesus monkey is an excellent species with which to investigate mechanisms underlying human emotion and psychopathology. To examine the role of the central nucleus of the amygdala (CeA) in mediating the behavioral and physiological responses associated with fear and anxiety, we used rhesus monkeys to assess the effects of excitotoxic lesions of the CeA. Behavioral and physiological responses of nine monkeys with bilateral CeA destruction (ranging from 46 to 98%) were compared with five animals with asymmetric lesions (42-86.5% destruction on the most affected side) and with 16 unoperated controls. Results suggest that similar to rodent species, the primate CeA plays a role in mediating fear- and anxiety-related behavioral and endocrine responses. Compared with controls and the asymmetric-lesion group, bilaterally lesioned monkeys displayed significantly less fear-related behavior when exposed to a snake and less freezing behavior when confronted by a human intruder. In addition, bilaterally lesioned monkeys had decreased levels of CSF corticotrophin-releasing factor (CRF), and both lesioned groups had decreased plasma ACTH concentrations. In contrast to these findings, patterns of asymmetric frontal brain electrical activity, as assessed by regional scalp EEG, did not significantly differ between control and lesioned monkeys. These findings suggest that in primates, the CeA is involved in mediating fear- and anxiety-related behavioral and pituitary-adrenal responses as well as in modulating brain CRF activity.
BACKGROUND: Excessive behavioral inhibition during childhood marks anxious temperament and is a risk factor for the development of anxiety and affective disorders. Studies in nonhuman primates can provide important information related to the expression of this risk factor, since threat-induced freezing in rhesus monkeys is a trait-like characteristic analogous to human behavioral inhibition. The orbitofrontal cortex (OFC) and amygdala are part of a circuit involved in the processing of emotions and associated physiological responses. Earlier work demonstrated involvement of the primate central nucleus of the amygdala (CeA) in mediating anxious temperament. This study assessed the role of the primate OFC in mediating anxious temperament and its involvement in fear responses. METHODS: Twelve adolescent rhesus monkeys were studied (six lesion and six control monkeys). Lesions were targeted at regions of the OFC that are most interconnected with the amygdala. Behavior and physiological parameters were assessed before and after the lesions. RESULTS: The OFC lesions significantly decreased threat-induced freezing and marginally decreased fearful responses to a snake. The lesions also resulted in a leftward shift in frontal brain electrical activity consistent with a reduction in anxiety. The lesions did not significantly decrease hypothalamic-pituitary-adrenal (HPA) activity or cerebrospinal fluid (CSF) concentrations of corticotrophin-releasing factor (CRF). CONCLUSIONS: These findings demonstrate a role for the OFC in mediating anxious temperament and fear-related responses in adolescent primates. Because of the similarities between rhesus monkey threat-induced freezing and childhood behavioral inhibition, these findings are relevant to understanding mechanisms underlying anxious temperament in humans.
The serotonin transporter (5-HTT) plays a critical role in regulating serotonergic neurotransmission and is implicated in the pathophysiology of anxiety and affective disorders. Positron emission tomography scans using [(11)C]DASB [(11)C]-3-amino-4-(2-dimethylaminomethylphenylsulfanyl)-benzonitrile] to measure 5-HTT availability (an index of receptor density and binding) were performed in 34 rhesus monkeys in which the relationship between regional brain glucose metabolism and anxious temperament was previously established. 5-HTT availability in the amygdalohippocampal area and bed nucleus of the stria terminalis correlated positively with individual differences in a behavioral and neuroendocrine composite of anxious temperament. 5-HTT availability also correlated positively with stress-induced metabolic activity within these regions. Collectively, these findings suggest that serotonergic modulation of neuronal excitability in the neural circuitry associated with anxiety mediates the developmental risk for affect-related psychopathology.
The length polymorphism of the serotonin (5-HT) transporter gene promoter region has been implicated in altered 5-HT function and, in turn, neuropsychiatric illnesses, such as anxiety and depression. The nonhuman primate has been used as a model to study anxiety-related mechanisms in humans based upon similarities in behavior and the presence of a similar 5-HT transporter gene polymorphism. Stressful and threatening contexts in the nonhuman primate model have revealed 5-HT transporter genotype dependent differences in regional glucose metabolism. Using the rhesus monkey, we examined the extent to which serotonin transporter genotype is associated with 5-HT transporter binding in brain regions implicated in emotion-related pathology. METHODS: Genotype data and high resolution PET scans were acquired in 29 rhesus (Macaca mulatta) monkeys. [C-11]DASB dynamic PET scans were acquired for 90 min in the anesthetized animals and images of distribution volume ratio (DVR) were created to serve as a metric of 5-HT transporter binding for group comparison based on a reference region method of analysis. Regional and voxelwise statistical analysis were performed with corrections for anatomical differences in gray matter probability, sex, age and radioligand mass. RESULTS: There were no significant differences when comparing l/l homozygotes with s-carriers in the regions of the brain implicated in anxiety and mood related illnesses (amygdala, striatum, thalamus, raphe nuclei, temporal and prefrontal cortex). There was a significant sex difference in 5-HT transporter binding in all regions with females having 18%-28% higher DVR than males. CONCLUSIONS: Because these findings are consistent with similar genotype findings in humans, this further strengthens the use of the rhesus model for studying anxiety-related neuropathologies.
A variant allele in the promoter region of the serotonin transporter gene, SLC6A4, the s allele, is associated with increased vulnerability to develop anxiety-related traits and depression. Furthermore, functional magnetic resonance imaging (fMRI) studies reveal that s carriers have increased amygdala reactivity in response to aversive stimuli, which is thought to be an intermediate phenotype mediating the influences of the s allele on emotionality. We used high-resolution microPET [18F]fluoro-2-deoxy-D-glucose (FDG) scanning to assess regional brain metabolic activity in rhesus monkeys to further explore s allele-related intermediate phenotypes. Rhesus monkeys provide an excellent model to understand mechanisms underlying human anxiety, and FDG microPET allows for the assessment of brain activity associated with naturalistic environments outside the scanner. During FDG uptake, monkeys were exposed to different ethologically relevant stressful situations (relocation and threat) as well as to the less stressful familiar environment of their home cage. The s carriers displayed increased orbitofrontal cortex activity in response to both relocation and threat. However, during relocation they displayed increased amygdala reactivity and in response to threat they displayed increased reactivity of the bed nucleus of the stria terminalis. No increase in the activity of any of these regions occurred when the animals were administered FDG in their home cages. These findings demonstrate context-dependent intermediate phenotypes in s carriers that provide a framework for understanding the mechanisms underlying the vulnerabilities of s-allele carriers exposed to different types of stressors.
BACKGROUND: Hypothalamic-pituitary-adrenal (HPA) system activation is adaptive in response to stress, and HPA dysregulation occurs in stress-related psychopathology. It is important to understand the mechanisms that modulate HPA output, yet few studies have addressed the neural circuitry associated with HPA regulation in primates and humans. Using high-resolution F-18-fluorodeoxyglucose positron emission tomography (FDG-PET) in rhesus monkeys, we assessed the relation between individual differences in brain activity and HPA function across multiple contexts that varied in stressfulness. METHODS: Using a logical AND conjunctions analysis, we assessed cortisol and brain metabolic activity with FDG-PET in 35 adolescent rhesus monkeys exposed to two threat and two home-cage conditions. To test the robustness of our findings, we used similar methods in an archival data set. In this data set, brain metabolic activity and cortisol were assessed in 17 adolescent male rhesus monkeys that were exposed to three stress-related contexts. RESULTS: Results from the two studies revealed that subgenual prefrontal cortex (PFC) metabolism (Brodmann's area 25/24) consistently predicted individual differences in plasma cortisol concentrations regardless of the context in which brain activity and cortisol were assessed. CONCLUSIONS: These findings suggest that activation in subgenual PFC may be related to HPA output across a variety of contexts (including familiar settings and novel or threatening situations). Individuals prone to elevated subgenual PFC activity across multiple contexts may be individuals who consistently show heightened cortisol and may be at risk for stress-related HPA dysregulation.
[F-18]Mefway was developed to provide an F-18 labeled positron emission tomography (PET) neuroligand with high affinity for the serotonin 5-HT(1A) receptor to improve the in vivo assessment of the 5-HT(1A) system. The goal of this work was to compare the in vivo kinetics of [F-18]mefway, [F-18]MPPF, and [C-11]WAY100635 in the rhesus monkey. METHODS: Each of four monkeys were given bolus injections of [F-18]mefway, [C-11]WAY100635, and [F-18]MPPF and scans were acquired with a microPET P4 scanner. Arterial blood was sampled to assay parent compound throughout the time course of the PET experiment. Time activity curves were extracted in the high 5-HT(1A) binding areas of the anterior cingulate cortex (ACG), mesial temporal cortex, raphe nuclei, and insula cortex. Time activity curves were also extracted in the cerebellum, which was used as a reference region. The in vivo kinetics of the radiotracers were compared based on the nondisplaceable distribution volume (V(ND) ) and binding potential (BP(ND) ). RESULTS: At 30 min, the fraction of radioactivity in the plasma due to parent compound was 19%, 28%, and 29% and cleared from the arterial plasma at rates of 0.0031, 0.0078, and 0.0069 (min⁻¹) ([F-18]mefway, [F-18]MPPF, [C-11]WAY100635). The BP(ND) in the brain regions were mesial temporal cortex: 7.4 ± 0.6, 3.1 ± 0.4, 7.0 ± 1.2, ACG: 7.2 ± 1.2, 2.1 ± 0.2, 7.9 ± 1.2; raphe nuclei: 3.7 ± 0.6, 1.3 ± 0.3, 3.3 ± 0.7; and insula cortex: 4.2 ± 0.6, 1.2 ± 0.1, 4.7 ± 1.0 for [F-18]mefway, [F-18]MPPF, and [C-11]WAY100635 respectively. CONCLUSIONS: In the rhesus monkey, [F-18]mefway has similar in vivo kinetics to [C-11]WAY100635 and yields greater than 2-fold higher BP(ND) than [F-18]MPPF. These properties make [F-18]mefway a promising radiotracer for 5-HT(1A) assay, providing higher counting statistics and a greater dynamic range in BP(ND).