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A Functional Subset of Serotonergic Neurons in the Rat Ventrolateral Periaqueductal Gray Implicated in the Inhibition of Sympathoexcitation and Panic
Abstract
The ability of serotonin (5-HT) to facilitate or attenuate autonomic, endocrine, and behavioral responses to stressful stimuli has received much attention. The effects of 5-HT on physiologic and behavioral responses to stressful stimuli seem to depend on the brain region where it is released and the effector system it acts upon. This and the distinct morphology and topographic organization of subpopulations of serotonergic neurons have led to the hypothesis that subpopulations of serotonergic neurons are functionally distinct. Serotonin's role as a modulator of the "fight-or-flight" response is mediated in part by 5-HT release in the dorsolateral periaqueductal gray (DLPAG) and in the rostral ventrolateral medulla (RVLM), an area that contains sympathoexcitatory C1 adrenergic (A) neurons. The release of 5-HT in either region inhibits stress-induced sympathetic activity in part via actions on 5-HT(1A) receptors. In addition, 5-HT release in the DLPAG inhibits fight-or-flight or "Go" behaviors. The origin of endogenous 5-HT in the DLPAG and RVLM seems to be a subpopulation of serotonergic neurons within the ventrolateral PAG, a region implicated in "freezing" or "No Go" behaviors. These serotonergic neurons are located in the lateral "wings" of the dorsal raphe nucleus (DRN) a region also referred to as the ventrolateral DRN. The existence of a functional subpopulation of serotonergic neurons capable of inhibiting sympathoexcitation and fight-or-flight behavioral responses may be clinically relevant for explaining in part the efficacy of serotonergic drugs in the treatment of hypertension and panic attacks in panic disorder patients.
... These DR subdivisions were chosen to replicate previous findings, in that the DRI is activated by acute M. vaccae challenge, whereas the DRC is not (Lowry et al., 2007); both the DRI and DRVL/ VLPAG (but not the DRC) are activated by lipopolysaccharide (LPS) (Hollis et al., 2006), and, therefore, the DRVL/VLPAG was chosen for comparison to these previous findings. The DRVL and adjacent VLPAG contain a distinct cluster of multipolar serotonergic neurons (Johnson et al., 2004), together defined as the "lateral wings" of the DR (Steinbusch 1981(Steinbusch , 1984. As serotonergic neurons in the DRVL and VLPAG appear to be functionally related (Johnson et al. 2004), cells in these structures were counted as a single population, using the designation DRVL/VLPAG. ...
... The DRVL and adjacent VLPAG contain a distinct cluster of multipolar serotonergic neurons (Johnson et al., 2004), together defined as the "lateral wings" of the DR (Steinbusch 1981(Steinbusch , 1984. As serotonergic neurons in the DRVL and VLPAG appear to be functionally related (Johnson et al. 2004), cells in these structures were counted as a single population, using the designation DRVL/VLPAG. Cells were counted in both the left and the right DRVL/VLPAG and the cell counts were summed to give a total number of cells in the DRVL/VLPAG. ...
... This delayed response appears to be dependent on ongoing inflammation as it is sensitive to the synthetic immunosuppressive glucocorticoid, dexamethasone, as well as inhibitors of eicosanoid synthesis (Zhang et al. 2003;Ochalski et al. 1993). Furthermore, this delayed hypothermia response to (Johnson et al. 2004) and were counted as a single population); ir, immunoreactive; mlf, medial longitudinal fasciculus; M.v., M. vaccae; Tph, tryptophan hydroxylase; Veh, borate-buffered saline vehicle. Rostrocaudal coordinates are indicated in mm with reference to bregma. ...
Peripheral immune activation can have profound physiologic and behavioral effects. One mechanism through which immune activation may affect physiology and behavior is through actions on brainstem neuromodulatory systems, such as serotonergic systems. To test this hypothesis, in Experiment 1, adult male BALB/c mice were implanted with telemetric recording devices and then immunized with Mycobacterium vaccae NCTC 11659 (0.1 mg, s.c.; Days − 28, − 14; N = 36). On Day 1, mice received an acute challenge with M. vaccae (0.1 mg, s.c.) or borate-buffered saline vehicle. Core body temperature and locomotor activity recordings were conducted during a 36 h period beginning 24 h prior to challenge; 12 h following acute challenge, mice were either tested in a 6-min forced swim test, or served as home cage controls (n = 9 per group). In Experiment 2, the protocol was repeated, but with the aim of assessing c-Fos expression in brainstem serotonergic neurons, assessed 90 min following exposure to forced swim (N = 32; n = 8 per group). In Experiment 1, acute M. vaccae challenge in M. vaccae-immunized mice, relative to vehicle-challenged controls, decreased locomotor activity and core body temperature measured 3 h following challenge, as measured by continuous telemetric recordings, and decreased immobility in the forced swim test measured 12 h following challenge. In Experiment 2, acute M. vaccae challenge in M. vaccae-immunized mice decreased home cage locomotion, in alignment with findings in Experiment 1, as measured by video-based behavioral analysis, and, among mice exposed to the forced swim test, increased c-Fos expression in subsets of serotonergic neurons within the dorsal raphe nucleus (DR) measured 13.5 h following challenge. Together, these data are consistent with the hypothesis that acute peripheral immune activation with a heat-killed preparation of M. vaccae transiently induces mild hypothermia in association with suppression of locomotor activity, activates subsets of serotonergic neurons in the DR, and induces antidepressant-like behavioral responses.
... GABA tonically inhibits defensive behaviour in the amygdala, hypothalamus and the PAG, an effect opposed by excitatory amino acids [41]. Serotonin release in the dlPAG and in the rostral ventrolateral medulla inhibits active fight-or-flight behaviours [73]. Interestingly, there are indications that endogenous serotonin in these regions originates not only from the dorsal raphe nucleus but also from the vlPAG, suggesting an additional mechanism by which vlPAG activity can inhibit dlPAG-driven fight-or-flight reactions [73]. ...
... Serotonin release in the dlPAG and in the rostral ventrolateral medulla inhibits active fight-or-flight behaviours [73]. Interestingly, there are indications that endogenous serotonin in these regions originates not only from the dorsal raphe nucleus but also from the vlPAG, suggesting an additional mechanism by which vlPAG activity can inhibit dlPAG-driven fight-or-flight reactions [73]. ...
... However, given the limited spatial resolution of BOLD-fMRI, there is need for more high-resolution imaging of the PAG to enable partialization of the PAG and investigate the role of human vlPAG and dlPAG in freezing and fight-or-flight, respectively [92]. In addition, this defensive fear network is part of a larger network encompassing ventromedial and ventrolateral PFC as well as ACC implicated in regulation of emotional behaviour and salience processing [73,93,94]. In two studies, we found that the perigenual ACC is particularly involved when people shift from freezing to active fight [81]. ...
Upon increasing levels of threat, animals activate qualitatively different defensive modes, including freezing and active fight-or-flight reactions. Whereas freezing is a form of behavioural inhibition accompanied by parasympathetically dominated heart rate deceleration, fight-or-flight reactions are associated with sympathetically driven heart rate acceleration. Despite the potential relevance of freezing for human stress-coping, its phenomenology and neurobiological underpinnings remain largely unexplored in humans. Studies in rodents have shown that freezing depends on amygdala projections to the brainstem (periaqueductal grey). Recent neuroimaging studies in humans have indicated that similar brain regions may be involved in human freezing. In addition, flexibly shifting between freezing and active defensive modes is critical for adequate stress-coping and relies on fronto-amygdala connections. This review paper presents a model detailing these neural mechanisms involved in freezing and the shift to fight-or-flight action. Freezing is not a passive state but rather a parasympathetic brake on the motor system, relevant to perception and action preparation. Study of these defensive responses in humans may advance insights into human stress-related psychopathologies characterized by rigidity in behavioural stress reactions. The paper therefore concludes with a research agenda to stimulate translational animal–human research in this emerging field of human defensive stress responses.
This article is part of the themed issue ‘Movement suppression: brain mechanisms for stopping and stillness’.
... Given the relevance of DR serotonergic neurons in the regulation of panic, anxiety, and central CO 2 chemosensitivity, we quantified TPH-like immunoreactivity within two subdivisions of the raphe nucleus: the DRVL/VLPAG division where 5-HT neurons are implicated in the inhibition of panic-associated responses (Johnson et al., 2004), and the DRD division that is reported to facilitate anxiety-related responses (Hale et al., 2012). Figure panels 4a-c show representative photomicrographs of TPH-2-positive neurons and the rostro-caudal extent of quantified neurons within these areas. ...
... Serotonin neurons in the raphe are CO 2 -chemosensors (Severson et al., 2003). Furthermore, serotonergic neurons in the DRVL/VLPAG provide inhibitory input to the dorsal PAG to modulate panicassociated responses (Johnson et al., 2004). Interestingly, association of polymorphisms within the TPH-2 gene and CO 2 responses is observed, further supporting a role of the serotonergic system in the effects of CO 2 (Abe et al., 2012). ...
... No differences were observed in the DR subdivision known to modulate anxiogenic behaviors. In support of a functional distinction between these nuclei, homeostatic, panicogenic stimuli such as CO 2 and lactate infusion recruit neurons within the DRVL/VLPAG while inescapable stress, anxiogenic drugs, and avoidance tasks on the elevated T-maze, considered as a test for generalized anxiety (not panic), activate serotonergic neurons within the DRD (Johnson et al., 2004;Lowry et al., 2008;Spiacci et al., 2012). ...
Inhalation of carbon dioxide (CO2) is frequently employed as a biological challenge to evoke intense fear and anxiety. In individuals with panic disorder, CO2 reliably evokes panic attacks. Sensitivity to CO2 is highly heterogeneous among individuals, and although a genetic component is implicated, underlying mechanisms are not clear. Preclinical models that can simulate differential responsivity to CO2 are therefore relevant. In the current study we investigated CO2-evoked behavioral responses in four different rat strains: Sprague-Dawley (SD), Wistar (W), Long Evans (LE) and Wistar-Kyoto, (WK) rats. We also assessed tryptophan hydroxylase 2 (TPH-2)-positive serotonergic neurons in anxiety/panic regulatory subdivisions of the dorsal raphe nucleus (DR), as well as dopamine β hydroxylase (DβH)-positive noradrenergic neurons in the locus coeruleus, implicated in central CO2-chemosensitivity. Behavioral responsivity to CO2 inhalation varied between strains. CO2-evoked immobility was significantly higher in LE and WK rats as compared with W and SD cohorts. Differences were also observed in CO2-evoked rearing and grooming behaviors. Exposure to CO2 did not produce conditioned behavioral responses upon re-exposure to CO2 context in any strain. Reduced TPH-2 positive cell counts were observed specifically in the panic-regulatory dorsal raphe ventrolateral (DRVL)-ventrolateral periaqueductal grey (VLPAG) subdivision in CO2-sensitive strains. Conversely, DβH positive cell counts within the LC were significantly higher in CO2-sensitive strains. Collectively, our data provide evidence for strain dependent, differential CO2-sensitivity and potential differences in monoaminergic systems regulating panic and anxiety. Comparative studies between CO2-vulnerable and resistant strains may facilitate the mechanistic understanding of differential CO2-sensitivity in the development of panic and anxiety disorders.
... The most important of these features is that fear conditioning (even contextual fear conditioning) is under immediate control of the level of threat in the environment [85][86][87][88][89] so that, for example, the degree of freezing to context is proportional to shock intensity and number of trials [90,91]. The principal argument underlying the proposal that contextual fear conditioning is a model of anxiety is that freezing to context is a response to ''diffuse'' signals of threat, as opposed to the discrete signals which are thought to mediate anxiety [92]; moreover, contextual fear conditioning hinders the evocation of fear responses from the dorsal periaqueductal gray area [93], and freezing to context is reduced by benzodiazepines, 5-HT 1A receptor agonists, selective serotonin reuptake inhibitors, and monoamine oxidase inhibitors [94][95][96]; while the first three groups of drugs are effective in the clinical management of generalized anxiety disorder, MAO inhibitors are not (Table 1.1), somewhat weakening the argument. ...
... Importantly, the presence of the short allele of the 5-HTTLPR polymorphism has been associated with anxiety symptoms in adult humans [91], and there are evidences of associations between this polymorphism and certain physiological and behavioral endophenotypes of anxiety. Carriers of the short allele exhibit increased startle responses to unexpected loud sounds [93], risk aversion [94][95][96][97], amygdala activity to fearful faces and to novel neutral stimuli [98][99][100], and functional coupling between amygdala and ventromedial prefrontal cortex when viewing positive or negative emotionally charged images [101,102]. ...
... 3.1 and 3.2). Nonetheless, the microinjection of serotonin in the BLA facilitates inhibitory avoidance in the elevated T-maze, without effects on escape responses [94], and the destruction of serotonergic fibers in the BLA with the neurotoxin 5,7-dihydroxytryptamine (5,7-DHT) releases punished behavior in the Vogel test, but spares anxiety-like behavior in the elevated plus-maze [95]. Since, the activation of 5-HT 2C receptors in the BLA also produces an anxiogenic effect [94,[96][97][98][99], and the blockade of these receptors is anxiolytic (but not panicolytic) in the elevated T-maze [94], it is possible that the serotonergic tone on BLA 5-HT 2C Rs is predominant on the control of anxietylike behavior by this structure. ...
While anxiogenic stimuli activate neurons in the raphe and lead to serotonin release in limbic forebrain targets, panicogenic stimuli do not necessarily do so. For example, escape performance in an elevated T-maze does not increase c-Fos-like immunoreactivity in the raphe. Nonetheless, the observation of a panicolytic role of serotonin in the PAG and an anxiogenic role in the amygdala and hippocampus suggests that the raphe is not a homogeneous structure. In fact, the dorsal raphe can be divided at least into six subregions based on cytoarchitecture and distribution of serotonergic neurons. These comprise the rostral (DRr), dorsal (DRD), ventral (DRV), lateral wing (lwDR), caudal (DRC), and interfascicular (DRI) portions (Fig. 5.1). Among those, the rostral, ventral, and interfascicular subregions play little role in the control of defense responses, and discussion of their functions can be found elsewhere. Here, we will discuss evidence for a role of the DRD, lwDR and DRC in anxiety and fear.
... Further, surgical and pharmacological manipulations of the DR result in altered anxiety states [10][11][12]. There is also evidence that serotonergic neurons in the DRVL/VLPAG provide inhibitory input to the dorsal periaqueductal gray (DPAG) to attenuate panic-like responses to mild to moderate stressors [13,14]. Therefore, developmental disruption of subpopulations of ''anxiogenic'' or ''panic-inhibiting'' serotonergic neurons and the associated connectivity may profoundly impact stress-related anxiety-and panic-like responses. ...
... The DRD and DRVL/VLPAG have been implicated in responses to stress-, anxiety-and panic-related stimuli, suggesting that these subregions of the DR may be especially sensitive to stress-or anxiogenic challenges [7]. In particular, the DRD has been associated with anxiety-promoting responses while the DRVL/VLPAG is related to inhibiting paniclike responses [14,45]. In support of this functional assignment, inescapable stress, anxiogenic drugs, fear-potentiated startle, and the avoidance task in the elevated T-maze activate serotonergic DRD neurons [46][47][48][49], and panicogenic stimuli such as hypercapnia or sodium lactate infusions activate DRVL/VLPAG serotonergic neurons that are associated with inhibition of paniclike behavior [13,50]. ...
... Increased activation of the DRD in nonstress Fgf8-deficient mice compared to WT non-stress mice is consistent with their anxiety-like phenotype. Similarly, blunted activation of DRVL/VLPAG neurons in response to stress is consistent with a failure to activate the panic-and anxietysuppressing serotonergic system, a circuit normally recruited in response to moderate stressors [14]. Together these data suggest that disruptions in DRD and DRVL/VLPAG neuronal activation may contribute to increased vulnerability to panic-and anxietylike behaviors in Fgf8-deficient mice. ...
Functionally heterogeneous populations of serotonergic neurons, located within the dorsal raphe nucleus (DR), play a role in stress-related behaviors and neuropsychiatric illnesses such as anxiety and depression. Abnormal development of these neurons may permanently alter their structure and connections, making the organism more susceptible to anxiety-related disorders. A factor that critically regulates the development of serotonergic neurons is fibroblast growth factor 8 (Fgf8). In this study, we used acute restraint stress followed by behavioral testing to examine whether Fgf8 signaling during development is important for establishing functional stress- and anxiety-related DR neurocircuits in adulthood. Wild-type and heterozygous male mice globally hypomorphic for Fgf8 were exposed to acute restraint stress and then tested for anxiety-like behavior on the elevated plus-maze. Further, we measured c-Fos immunostaining as a marker of serotonergic neuronal activation and tissue 5-hydroxyindoleacetic acid concentrations as a marker of serotonin functional output. Results showed that Fgf8 hypomorphs exhibited 1) an exaggerated response of DR anxiety-promoting circuits and 2) a blunted response of a DR panic-inhibiting circuit to stress, effects that together were associated with increased baseline anxiety-like behavior. Overall, our results provide a neural substrate upon which Fgf8 deficiency could affect stress response and support the hypothesis that developmental disruptions of serotonergic neurons affect their postnatal functional integrity.
... Serotonergic innervation to the PFA mainly originates from the dorsal (DR) and median (MR) raphe nuclei [29,30]. However, a distinct cluster of serotonergic neurons located within the lateral wings of the DR (lwDR) is hypothesized to functionally reduce panic responses [31][32][33]. ...
... This suffocation-associated stressor (5 min infusion of normoxic 20% CO 2 ) elicits core symptoms of a panic attack in humans (e.g., catastrophic fear accompanied by cardiovascular and thermoregulatory responses) [61] and has predictive validity since fluoxetine and alprazolam, two clinically relevant panicolytic drugs utilized to treat patients with recurrent panic attacks, attenuate panic-related behavioral [62] and physiological responses [14,63] elicited by 20% CO 2 inhalation in rodents. Collectively, these data support the hypothesis that PFA-projecting serotonergic fibers originating from the lwDR/MR inhibit innate panic behaviors and anxiety avoidance [32,33]. ...
The serotonin (5-HT) system is heavily implicated in the regulation of anxiety and trauma-related disorders such as panic disorder and post-traumatic stress disorder, respectively. However, the neural mechanisms of how serotonergic neurotransmission regulates innate panic and fear brain networks are poorly understood. Our earlier studies have identified that orexin (OX)/glutamate neurons within the perifornical hypothalamic area (PFA) play a critical role in adaptive and pathological panic and fear. While site-specific and electrophysiological studies have shown that intracranial injection and bath application of 5-HT inhibits PFA neurons via 5-HT1a receptors, they largely ignore circuit-specific neurotransmission and its physiological properties that occur in vivo. Here, we investigate the role of raphe nuclei 5-HT inputs into the PFA in panic and fear behaviors. We initially confirmed that photostimulation of glutamatergic neurons in the PFA of rats produces robust cardioexcitation and flight/aversive behaviors resembling panic-like responses. Using the retrograde tracer cholera toxin B, we determined that the PFA receives discrete innervation of serotonergic neurons clustered in the lateral wings of the dorsal (lwDRN) and in the median (MRN) raphe nuclei. Selective lesions of these serotonergic projections with saporin toxin resulted in similar panic-like responses during the suffocation-related CO2 challenge and increased freezing to fear-conditioning paradigm. Conversely, selective stimulation of serotonergic fibers in the PFA attenuated both flight/escape behaviors and cardioexcitation responses elicited by the CO2 challenge and induced conditioned place preference. The data here support the hypothesis that PFA projecting 5-HT neurons in the lwDRN/MRN represents a panic/fear-off circuit and may also play a role in reward behavior.
... It has been proposed that it is due to the interaction of the PAG with other nuclei and the activation or inhibition of serotonin receptors inside and outside PAG. That is, "the effects of 5-HT on behavioral responses depend on the region of the brain where it is released and the effector system on which it acts" (Johnson et al. 2004) (See Fig. 1). ...
... This is not decisive since the endogenous release of 5-HT in the dPAG is due to a subpopulation of serotonergic neurons within the vlPAG-vlDRN circuit capable of inhibiting fightor-flight behavioral responses (See Fig. 1). This is clinically relevant for the pharmacological treatment of panic disorders (Johnson et al. 2004). ...
Serotonin 5-hydroxytryptamine (5-HT) is a key neurotransmitter for the modulation and/or regulation of numerous physiological processes and psychiatric disorders (e.g., behaviors related to anxiety, pain, aggressiveness, etc.). The periaqueductal gray matter (PAG) is considered an integrating center for active and passive defensive behaviors, and electrical stimulation of this area has been shown to evoke behavioral responses of panic, fight-flight, freezing, among others. The serotonergic activity in PAG is influenced by the activation of other brain areas such as the medial hypothalamus, paraventricular nucleus of the hypothalamus, amygdala, dorsal raphe nucleus, and ventrolateral orbital cortex. In addition, activation of other receptors within PAG (i.e., CB1, Oxytocin, µ-opioid receptor (MOR), and γ-aminobutyric acid (GABAA)) promotes serotonin release. Therefore, this review aims to document evidence suggesting that the PAG-evoked behavioral responses of anxiety, panic, fear, analgesia, and aggression are influenced by the activation of 5-HT1A and 5-HT2A/C receptors and their participation in the treatment of various mental disorders.
... Serotonergic neurons in the ventrolateral part of the DR (DRVL) and in the adjacent ventrolateral part of the periaqueductal gray (VLPAG) appear to form part of an anti-panic-like system (Johnson et al., 2004(Johnson et al., , 2008. Consistent with this hypothesis, serotonergic neurons in the DRVL ( Fig. 1; red shading) receive strong input from brain regions associated with control of autonomic nervous system function and send output to the dorsolateral periaqueductal gray and rostroventrolateral medulla, brainstem regions important for central autonomic control. ...
... Consistent with these findings, DRVL/VLPAG serotonergic neurons are part of a sympathomotor command system, controlling both somatic motor and sympathetic function (Kerman et al., 2006). Serotonergic signaling arising from the DRVL/VLPAG serotonergic neurons is thought to inhibit panic like responses through projections to the dorsal periaqueductal gray, where serotonin inhibits elicited panic via actions on 5-HT 1A and 5-HT 2A receptors (Pobbe & Zangrossi, 2005;de Oliveira et al., 2011;Pobbe et al., 2011) and through projections to the ventrolateral medulla, where serotonin inhibits sympathetic outflow (Davies et al., 2007; for review, see Johnson et al., 2004). In support of this model, we have found in a rat model of panic disorder involving i.v. ...
Previous studies have demonstrated that depressed patients have dysfunction of thermoregulatory cooling, while antidepressants of diverse pharmacological profiles induce sweating as a clinical side effect, suggesting that the pathophysiology of depression as well as antidepressant drug action may involve interactions with thermoregulatory pathways. To test this hypothesis, we investigated interactions between acute whole body warming and treatment with the selective serotonin reuptake inhibitor, citalopram, on body temperature, measured using chronically implanted telemetric recording devices, and antidepressant‐like behavior in the forced swim test in rats. Using a subthreshold dose of citalopram, we found that citalopram, by itself, induced hyperthermia that was comparable to that induced by exposure to increased ambient temperature (37 degrees C) for 85 min. Neither citalopram by itself, nor exposure to increased ambient temperature induced antidepressant‐like effects in the forced swim test. However, when rats were both treated with citalopram and exposed to elevated ambient temperature, rats experienced an exaggerated hyperthermia that was highly correlated with antidepressant‐like behavioral responses. These data provide a rationale for novel therapeutic strategies for the treatment of affective disorders, including development of novel antidepressant drugs.
... Our imaging protocol localized effects to different PAG columns, which are associated with distinct patterns of behavioral and autonomic responses (Carrive and Morgan, 2012). In particular, the ventrolateral PAG is associated with sympathetic inhibition (Johnson et al., 2004), whereas the dorsal PAG is associated with sympathetic activation (Dean et al., 2016). Thus, we investigated whether activity during cognitive demand engaged particular subregions of the PAG. ...
... The similarities in PAG activation observed across human imaging studies (i.e., the present results and vlPAG activation observed in Satpute et al., 2013) could reflect a shared mechanism involved in coordinating autonomic outcomes associated with passive coping. Ventrolateral PAG activity could be involved in inhibiting sympathetic outflow (Bago and Dean, 2001;Johnson et al., 2004;Hermans et al., 2013), which could lead to subjective changes in arousal, with complex effects on cognitive performance depending on the need for attentional orienting (proparasympathetic) versus metabolic activation (prosympathetic). A related functional role of vlPAG during working memory is to marshal cognitive resources, that is, to suppress competing motivations (Gear et al., 1999;Sprenger et al., 2012;Geuter et al., 2016) to engender "task focus." ...
Recent theoretical advances have motivated the hypothesis that the periaqueductal gray (PAG) participates in behaviors that involve changes in the autonomic control of visceromotor activity, including during cognitively demanding tasks. We used ultra-high-field (7 tesla) fMRI to measure human brain activity at 1.1 mm resolution while participants completed a working memory task. Consistent with prior work, participants were less accurate and responded more slowly with increasing memory load-signs of increasing task difficulty. Whole-brain fMRI analysis revealed increased activity in multiple cortical areas with increasing working memory load, including frontal and parietal cortex, dorsal cingulate, supplementary motor area, and anterior insula. Several dopamine-rich midbrain nuclei, such as the substantia nigra and ventral tegmental area, also exhibited load-dependent increases in activation. To investigate PAG involvement during cognitive engagement, we developed an automated method for segmenting and spatially normalizing the PAG. Analyses using cross-validated linear support vector machines showed that the PAG discriminated high versus low working memory load conditions with 95% accuracy in individual subjects based on activity increases in lateral and ventrolateral PAG. Effect sizes in the PAG were comparable in magnitude to those in many of the cortical areas. These findings suggest that cognitive control is not only associated with cortical activity in the frontal and parietal lobes, but also with increased activity in the subcortical PAG and other midbrain regions involved in the regulation of autonomic nervous system function.SIGNIFICANCE STATEMENT Functional neuroimaging in humans has shown that cognitive control engages multiple corticostriatal networks and brainstem nuclei, but theoretical advances suggest that the periaqueductal gray (PAG) should also be engaged during cognitively demanding tasks. Recent advances in ultra-high-field fMRI provided an opportunity to obtain the first evidence that increased activation of intermediate and rostral portions of lateral and ventrolateral PAG columns in humans is modulated by cognitive load. These findings suggest that cognitive control is not solely mediated by activity in the cortex, but that midbrain structures important for autonomic regulation also play a crucial role in higher-order cognition.
... One consequence of BLA priming is the activation of serotonergic neurons within the dorsal raphe nucleus and median raphe nucleus, suggesting that the BLA stimulates serotonin release from these regions (Spiga et al. 2006). Additionally, intra-BLA Ucn1 priming increases tph2 mRNA expression within the DRVL, a region of the dorsal raphe nucleus associated with inhibition of panic-like escape behaviors (Spiacci et al. 2016;Donner et al. 2012a;Johnson et al. 2004). As noted earlier, the BLA is in a central position to influence areas of the brain involved with anxiety-related physiological and behavioral responses such as the CeA (Tye et al. 2011), vHPC (Felix-Ortiz et al. 2013, mPFC (Felix-Ortiz et al. 2016), and BNST, and that a "primed" and hyperactive BLA could be a mechanism for the development of stress-induced anxiety states. ...
... Loss of local GABA synthesis within the DMH over the course of days increases anxiety-like behavior and sympathetic output, which, in turn, makes rats vulnerable to panic-like physiological responses to intravenous infusions of sodium lactate (Shekhar et al. 1996;Johnson and Shekhar 2006), a substance demonstrated to elicit panic symptoms in patients with panic disorder in a laboratory setting (Goetz et al. 1996). Evidence for a functional change in neural systems that normally inhibit panic-like behaviors, such as serotonergic neurons in the dorsal raphe nucleus ventrolateral part (DRVL) (Johnson et al. 2004), was provided by an attenuation of the activation of serotonergic neurons within the DRVL (Johnson et al. 2008a) in response to intravenous sodium lactate after intra-DMH L -AG (Johnson et al. 2008a). Additionally, areas such as the CeL, CeM, and BNSTL were shown to have increases in c-Fos expression, a neuronal marker of activation (Sagar et al. 1988), after intra-DMH L -AG and subsequent intravenous sodium lactate challenge, which confirms a role for the DMH in control of neural systems regulating anxiety-and fear-related responses (Johnson et al. 2008b). ...
Anxiety disorders and trauma- and stressor-related disorders, such as posttraumatic stress disorder (PTSD), are common and are associated with significant economic and social burdens. Although trauma and stressor exposure are recognized as a risk factors for development of anxiety disorders and trauma or stressor exposure is recognized as essential for diagnosis of PTSD, the mechanisms through which trauma and stressor exposure lead to these disorders are not well characterized. An improved understanding of the mechanisms through which trauma or stressor exposure leads to development and persistence of anxiety disorders or PTSD may result in novel therapeutic approaches for the treatment of these disorders. Here, we review the current state-of-the-art theories, with respect to mechanisms through which stressor exposure leads to acute or chronic exaggeration of avoidance or anxiety-like defensive behavioral responses and fear, endophenotypes in both anxiety disorders and trauma- and stressor-related psychiatric disorders. In this chapter, we will explore physiological responses and neural circuits involved in the development of acute and chronic exaggeration of anxiety-like defensive behavioral responses and fear states, focusing on the role of the hypothalamic-pituitary-adrenal (HPA) axis and glucocorticoid hormones.
... Animals exposed to ethanol during adolescence were, as adults, more anxious and drank more than the animals not previously exposed to ethanol (Pandey et al., 2015). Furthermore, the PAG receives a significant serotonergic innervation from the DRN involved in fight-or-flight behavioral responses (Johnson et al., 2004). Li and colleagues (2013) reported that acute ethanol produced a robust enhancement of glutamatergic synaptic transmission in the PAG. ...
... Genes for serotonin signaling were also found to be largely decreased in the DRN of adolescent alcohol-drinking P rats (McClintick et al., 2015). Release of serotonin in the dorsal lateral PAG inhibits stressinduced sympathetic activity via the Htr1a receptor (Johnson et al., 2004), which was found to be decreased À1.5-fold in these binge-drinking animals. Adra1a, an alpha adrenergic receptor subunit gene, also had decreased expression. ...
Background:
Binge drinking of alcohol during adolescence is a serious public health concern with long-term consequences, including increased pain, fear, and anxiety. The periaqueductal gray (PAG) is involved in processing pain, fear, and anxiety. The effects of adolescent binge drinking on gene expression in this region have yet to be studied.
Methods:
Male adolescent alcohol-preferring (P) rats were exposed to repeated binge drinking (three 1-hour sessions/d during the dark/cycle, 5 days/wk for 3 weeks starting at 28 days of age; ethanol intakes of 2.5 to 3 g/kg/session). We used RNA sequencing to assess the effects of ethanol intake on gene expression.
Results:
Ethanol significantly altered the expression of 1,670 of the 12,123 detected genes: 877 (53%) decreased. In the glutamate system, 23 genes were found to be altered, including reduction in 7 of 10 genes for metabotropic and NMDA receptors. Subunit changes in the NMDA receptor may make it less sensitive to ethanol. Changes in GABAA genes would most likely increase the ability of the PAG to produce tonic inhibition. Five serotonin receptor genes, 6 acetylcholine receptor genes, and 4 glycine receptor genes showed decreased expression in the alcohol-drinking rats. Opioid genes (e.g., Oprk1, Oprm1) and genes for neuropeptides linked to anxiety and panic behaviors (e.g., Npy1r) had mostly decreased expression. Genes for 27 potassium, 10 sodium, and 5 calcium ion channels were found to be differentially expressed. Nine genes in the cholesterol synthesis pathway had decreased expression, including Hmgcr, encoding the rate-limiting enzyme. Genes involved in the production of myelin also had decreased expression.
Conclusions:
The results demonstrate that binge alcohol drinking during adolescence produces developmental changes in the expression of key genes within the PAG; many of these changes point to increased susceptibility to pain, fear, and anxiety, which could contribute to excessive drinking to relieve these negative effects.
... Caudally, these neurons are found not in a ventrolateral position, but in a dorsolateral position just below the plane of the ventral border of the cerebral aqueduct [17]. Throughout the rostrocaudal extent of the DRVL, many of the serotonergic neurons in this cluster are located not in the DR but in the adjacent ventrolateral periaqueductal gray (VLPAG) [42,106]. The DRVL/VLPAG is dominated by a group of very large, multipolar serotonergic neurons [27]. ...
... Stimulation of the VLPAG region elicits opioid-mediated analgesia and a passive emotional coping strategy including behavioral quiescence, hypotension, bradycardia, and hyporeactivity to environmental stimuli [90]. An argument can be made that serotonergic neurons within the DRVL/VLPAG region participate in these responses, particularly inhibition of stress-induced autonomic and behavioral responses [106]. Recently, we have found that in an animal model of anxiety and susceptibility to panic-like cardiovascular responses following sodium lactate infusions, serotonergic neurons were activated in rats that "did not" panic, but were not activated in rats that responded to sodium lactate infusions with panic-like tachycardia and hypertension [272]. ...
The role of serotonergic systems in regulation of behavioral arousal and sleep-wake cycles is complex and may depend on both the receptor subtype and brain region involved. Increasing evidence points toward the existence of multiple topographically organized subpopulations of serotonergic neurons that receive unique afferent connections, give rise to unique patterns of projections to forebrain systems, and have unique functional properties. A better understanding of the properties of these subpopulations of serotonergic neurons may aid in the understanding of the role of serotonergic systems in regulation of behavioral arousal, sleep-wake cycles and other physiological and behavioral responses attributed to serotonin. In this chapter, we outline evidence for multiple serotonergic systems within the midbrain and pontine raphe complex that can be defined based on cytoarchitectonic and hodological properties. In addition, we describe how these topographically organized groups of serotonergic neurons correspond to the six major ascending serotonergic tracts innervating the forebrain.
... We and others have made significant advances in testing this hypothesis, and have found evidence supporting each of the three systems originally hypothesized by Deakin and Graeff. We and others have found evidence for the following systems: (1) Panic inhibition system, a serotonergic system in the ventrolateral part of the dorsal raphe nucleus (DRVL)/ventrolateral periaqueductal gray (VLPAG), projecting to the DPAG, that (a) is activated by panicogenic agents, including sodium lactate and hypercapnia (elevated atmospheric CO 2 ; Johnson et al., 2005), (b) selectively responds with increased tph2 mRNA expression following amygdala priming (Donner et al., 2012), a model of vulnerability to sodium lactate-induced panic attacks (Johnson et al., 2013;Sajdyk et al., 1999), and (c) is selectively dysregulated in an animal model of vulnerability to lactate-induced panic-like responses (Johnson et al., 2004(Johnson et al., , 2007. (2) Conflict anxiety facilitation system, a serotonergic system in the midline dorsal and caudal parts of the dorsal raphe nucleus (DRD/DRC), projecting to the basolateral nucleus of the amygdala (BLA; Abrams et al., 2005), that is activated by anxiogenic drugs (Abrams et al., 2005), anxiety-related neuropeptides (Staub et al., 2005(Staub et al., , 2006, and anxiety-provoking stimuli (Spannuth et al., 2011); this system is sensitized following inescapable shock in a model of learned helplessness (Rozeske et al., 2011). ...
... In order to better delineate the role of the PAG-evoked responses to anoxia and hypercapnia, an elegant study by Schenberg and colleagues (2012) investigated the effects of administration of either CO 2 , or KCN, or a combination of both on spontaneous or DPAGstimulated behavior in animals with or without prior electrolytic lesion of the DPAG. Slow infusions of low doses of KCN alone evoked spontaneous defensive behaviors and potentiated DPAGstimulated flight behaviors (e.g., galloping), and the effects of KCN were blocked by prior DPAG lesion; conversely, CO 2 alone increased behavioral arousal and attenuated DPAG-stimulated behaviors, possibly due to activation of neurons in the VLPAG and adjacent DRVL (Teppema et al., 1997) that are known to inhibit DPAG output (see Section 3 in this review and also; Johnson et al., 2004;Pobbe and Zangrossi, 2005;Schimitel et al., 2012;Stezhka and Lovick, 1994). Moreover, CO 2 given in combination with KCN did not block KCN-evoked behaviors, which would be predicted given the antagonistic effects of CO 2 or KCN alone, but rather paradoxically, CO 2 facilitates KCN-evoked behaviors (Schimitel et al., 2012). ...
The Deakin/Graeff hypothesis proposes that different subpopulations of serotonergic neurons through topographically organized projections to forebrain and brainstem structures modulate the response to acute and chronic stressors, and that dysfunction of these neurons increases vulnerability to affective and anxiety disorders, including Panic Disorder. We outline evidence supporting the existence of a serotonergic system originally discussed by Deakin/Graeff that is implicated in the inhibition of panic-like behavioral and physiological responses. Evidence supporting this panic inhibition system comes from the following observations: 1) serotonergic neurons located in the ‘ventrolateral dorsal raphe nucleus (DRVL) as well as the ventrolateral periaqueductal gray (VLPAG) inhibit dorsal periaqueductal gray-elicited panic-like responses; 2) chronic, but not acute, antidepressant treatment potentiates serotonin's panicolytic effect; 3) contextual fear activates a central nucleus of the amygdala-DRVL/VLPAG circuit implicated in mediating freezing and inhibiting panic-like escape behaviors; 4) DRVL/VLPAG serotonergic neurons are central chemoreceptors and modulate the behavioral and cardiorespiratory response to panicogenic agents such as sodium lactate and CO2. Implications of the panic inhibition system are discussed.
... (Deakin & Graeff, 1991;Graeff et al., 1996). Das panikinhibierende System, das sich im ventrolateralen Teil der DR (DRVL) sowie im ventrolateralen PAG (VLPAG) befindet und zum DPAG projiziert, wird durch panikinduzierende Substanzen wie CO2 und Natriumlactat aktiviert (Johnson et al., 2008;Johnson et al., 2005) und es konnte gezeigt werden, dass die Aktivität dieses antipanischen System in Tiermodellen für Panikverhalten abgeschwächt ist (Johnson et al., 2004;Johnson et al., 2007) (Porrino & Goldman-Rakic, 1982). Die unterschiedlichen Systeme können auch miteinander interagieren: das angstfördernde System kann das panikinhibierende System über einen Ce → DRVL/VLPAG-Schaltkreis aktivieren, wodurch das Angst-Netzwerk die Aktivität des Panik-Netzwerks hemmen kann. ...
Angsterkrankungen gehören zu den am weitesten verbreiteten psychischen Erkrankungen und stellen eine beträchtliche soziale und wirtschaftliche Herausforderung für unsere Gesellschaft dar. Aversive frühe Erfahrungen sind ein bekannter Risikofaktor für die Entwicklung verschiedener psychischer Erkrankungen, insbesondere Angststörungen. Während der frühen Entwicklung findet die Programmierung der Hypothalamus-Hypophysen-Nebennierenrinden- (HHN)-Achse, die die Ausschüttung des Stresshormons Cortisol in Menschen bzw. Corticosteron in Mäusen steuert, statt. Wenn Individuen in dieser kritischen Phase Stress ausgesetzt sind, wird die regelrechte Ausbildung der HHN-Achse gestört, was zu dysregulierten Verhaltensantworten auf Stressreize im späteren Leben führen kann. Das Serotonin (5-HT)-System als eines der ausgedehntesten Neurotransmittersysteme ist an der Vermittlung der Effekte von früher Stressexposition auf angstähnliche Verhaltensweisen beteiligt. Das Ziel dieser Studie ist es, die Interaktion zwischen genetischer Prädisposition und negativen Einflüssen in frühen Entwicklungsstadien auf die Ausbildung von Angstverhalten im Erwachsenenalter näher zu beleuchten. In dieser Studie wurden Tryptophanhydroxylase 2 (Tph2)-defiziente weibliche Mäuse als Modell für ein lebenslanges konstitutives 5-HT Synthesedefizit im zentralen Nervensystem verwendet. Nachkommen dieser Mauslinie wurden im frühen Lebensalter Maternaler Separation (MS), d.h. einem mütterlichen Trennungsparadigma, unterzogen und im Erwachsenenalter im „Open field“ (OF) oder in der „Dark-light box“ (DLB) getestet. Im Anschluss an die Verhaltensexperimente wurde die neuronale Aktivierung immunhistochemisch durch Darstellung des frühzeitig auftretenden Genprodukts c-Fos bestimmt. In der DLB zeigten homozygot Tph2-defiziente Mäuse eine verringerte motorische Aktivität im hellen Kompartiment, und dieser Effekt konnte durch MS normalisiert werden. Zusätzlich verstärkte MS bei diesem Genotyp das Auftreten von fluchtartigen Sprüngen. Im OF hat MS fluchtartige Verhaltensweisen in homo- und heterozygoten Tph2-defizienten Mäusen befördert. Beide Verhaltenstests führten zu spezifischen neuronalen Aktivierungsmustern, die mithilfe von c-Fos- Immunhistochemie ausgewertet wurden. Die Durchführung des DLB-Tests führte in Abhängigkeit vom Vorhandensein von Tph2 zur Aktivierung des paraventrikulären Kerns des Hypothalamus (PVN) und der basolateralen Amygdala (BL), wohingegen die Exposition gegenüber dem OF-Test zu einer Aktivierung der lateralen Amygdala (La) in Tieren, die einem mütterlichen Trennungsparadigma unterzogen wurden, sowie einer Aktivierung des ventrolateralen (VLPAG) und dorsolateralen (DLPAG) periaquäduktalen Höhlengraus in Abhängigkeit von Tph2 und MS führte. Zusammenfassend weisen die Ergebnisse dieser Studie darauf hin, dass MS aktive Verhaltensantworten auf aversive Reize in Abhängigkeit vom Vorhandensein von 5-HT im Gehirn fördert. Diese Effekte könnten durch die spezifische Aktivierung von mit Angstverhalten in Zusammenhang stehenden Gehirnregionen während der Verhaltensexperimente vermittelt werden.
... Noradrenaline secreted in nerve synapses affects the sympathetic nerv-ous system, causing an increase in the concentration of catecholamines in the blood serum. As a consequence, retention of water and sodium by the kidneys, reduction of renal blood flow, endothelial dysfunction, vasospasm, atherosclerosis, increased vascular stiffness, and increased heart rate and blood pressure are observed [22][23][24][25][26][27]. Autonomic dysfunction in patients with panic disorder is characterised not only by increased activity of the sympathetic nervous system, but also by decreased activity of the parasympathetic nervous system. ...
About 1/4 of the world's adult population suffers from hypertension. Due to the high prevalence of the disease, its impact on mortality and socio-economic costs, it is important to search for modifiable causes of its development. This review analyses studies in order to answer the question: Is there a higher prevalence of panic disorder in adults (≥18 years of age) with hypertension, than in normotensive group? There have been found 10 cross-sectional studies describing correlation between hypertension and panic disorder. Odds ratio for this two clinical entities ranged from OR = 3.31 (2.99-3.67) to OR = 1.19 (0.87-1.62). Moreover, frequency of coincidence of those two clinical entities was found between 4.2% and 18.75%. In the prospective studies there have been found a positive association between panic disorder and subsequent life-long development of hypertension OR= 1.7 (1.4-2.0). On the other hand, association between hypertension and subsequent development of panic disorder in the 12-months observation was OR = 3.23 (1.51-6.93), but in 3 years of observation it was insignificant OR = 1.12 (0.80-1.57). Based on the literaturereview, dueto the differences in methodology and the small number of prospective studies, it can only be suggested to clinicians that in some cases they should search for panic disorder in patients with hypertension, especially paroxysmal one.
... DRN is supposed to be composed of five subnuclei that differ anatomically and functionally [32,33]. Past studies have reported that dorsalmedial, ventromeidal and caudal DRN are closely related to anxiety-like behavior, while the lateral wings are more strongly associated with panic and fear [34][35][36][37][38]. In this study, we found that ErbB4-positive 5-HT neurons are primarily located within the dorsal and ventral regions of the DRN. ...
There is a close relationship between serotonergic (5-HT) activity and anxiety. ErbB4, a receptor tyrosine kinase, is expressed in 5-HT neurons. However, whether ErbB4 regulates 5-HT neuronal function and anxiety-related behaviors is unclear. Here, using transgenic and viral approaches, we show that mice with ErbB4 deficiency in 5-HT neurons exhibit heightened anxiety-like behavior and impaired fear extinction, possibly due to an increased excitability of 5-HT neurons in the dorsal raphe nucleus (DRN). Notably, the chemogenetic inhibition of 5-HT neurons in the DRN of ErbB4 mutant mice rescues anxiety-like behaviors. Altogether, our results unravel a previously unknown role of ErbB4 signaling in the regulation of DRN 5-HT neuronal function and anxiety-like behaviors, providing novel insights into the treatment of anxiety disorders.
... Distinctively, the dorsal part of the DR (DRD; also referred to as the dorsomedial DR) and caudal part of the DR (DRC) innervate forebrain structures that are involved in emotional control and anxiety [26,30,[32][33][34][35][36][37][38]. Additionally, the ventrolateral part of the DR (DRVL)/ ventrolateral periaqueductal gray (VLPAG) give rise to axons that travel to the dorsal periaqueductal gray [39,40], a projection that has been implicated in anti-panic functions of 5-HT [41,42,12,24,31,43]. The frontal cortex-projecting interfascicular part of the DR (DRI) and the MnR may be involved in promoting tolerance and adaption to chronic stress [18,[44][45][46][47][48], but see [49]. ...
Previous studies have highlighted interactions between serotonergic systems and adverse early life experience as important gene x environment determinants of risk of stress-related psychiatric disorders. Evidence suggests that mice deficient in Tph2, the rate-limiting enzyme for brain serotonin synthesis, display disruptions in behavioral phenotypes relevant to stress-related psychiatric disorders. The aim of this study was to determine how maternal separation in wild-type, heterozygous, and Tph2 knockout mice affects mRNA expression of serotonin-related genes. Serotonergic genes studied included Tph2, the high-affinity, low-capacity, sodium-dependent serotonin transporter (Slc6a4), the serotonin type 1a receptor (Htr1a), and the corticosterone-sensitive, low-affinity, high-capacity sodium-independent serotonin transporter, organic cation transporter 3 (Slc22a3). Furthermore, we studied corticotropin-releasing hormone receptors 1 (Crhr1) and 2 (Crhr2), which play important roles in controlling serotonergic neuronal activity. For this study, offspring of Tph2 heterozygous dams were exposed to daily maternal separation for the first two weeks of life. Adult, male wild-type, heterozygous, and homozygous offspring were subsequently used for molecular analysis. Maternal separation differentially altered serotonergic gene expression in a genotype- and topographically-specific manner. For example, maternal separation increased Slc6a4 mRNA expression in the dorsal part of the dorsal raphe nucleus in Tph2 heterozygous mice, but not in wild-type or knockout mice. Overall, these data are consistent with the hypothesis that gene x environment interactions, including serotonergic genes and adverse early life experience, play an important role in vulnerability to stress-related psychiatric disorders.
... Coordination of this active response is achieved, in part, through upregulating the sympathetic nervous system to produce an elevated state of sympathoexcitation in the body (Lovick, 1991;Löw et al., 2015;Wendt et al., 2017). As noted above, sympathoexcitation is measured by increased heart rate, blood pressure, body temperature, and galvanic skin responseall products of sympathetic expression that are measured reliably in humans during a threatening or fear-provoking context (Dean, 2011;Johnson, Lightman, & Lowry, 2004;Lang, 2014). ...
Post‐traumatic stress disorder (PTSD), a diagnosis that may follow the experience of trauma, has multiple symptomatic phenotypes. Generally, individuals with PTSD display symptoms of hyperarousal and of hyperemotionality in the presence of fearful stimuli. A subset of individuals with PTSD; however, elicit dissociative symptomatology (i.e., depersonalization, derealization) in the wake of a perceived threat. This pattern of response characterizes the dissociative subtype of the disorder, which is often associated with emotional numbing and hypoarousal. Both symptomatic phenotypes exhibit attentional threat biases, where threat stimuli are processed preferentially leading to a hypervigilant state that is thought to promote defensive behaviors during threat processing. Accordingly, PTSD and its dissociative subtype are thought to differ in their proclivity to elicit active (i.e., fight, flight) versus passive (i.e., tonic immobility, emotional shutdown) defensive responses, which are characterized by the increased and the decreased expression of the sympathetic nervous system, respectively. Moreover, active and passive defenses are accompanied by primarily endocannabinoid‐ and opioid‐mediated analgesics, respectively. Through critical review of the literature, we apply the defense cascade model to better understand the pathological presentation of defensive responses in PTSD with a focus on the functioning of lower‐level midbrain and extended brainstem systems.
... Une stimulation de la partie dorsale de la SGPA conduit à une tachycardie, tandis que la stimulation de la vl-SGPA provoque une bradycardie (Linnman et al., 2011). La SGPA aurait donc un rôle cardiaque et vasculaire important en modulant l'activité du système sympathique (Johnson et al., 2004;Green et al., 2006aGreen et al., , 2006bDampney et al., 2013). (Bandler et Carrive, 1988;Bandler et al., 1991;Depaulis et al., 1992). ...
Le paracétamol est sujet à controverse depuis sa découverte. Que ce soit son mécanisme d’action, ses effets indésirables ou son efficacité, de nombreuses études ont été réalisées et parfois se contredisent. Parfois critiqué pour son efficacité limitée, il n’a pourtant rien à envier aux autres antalgiques : il soulage les douleurs faibles à modérées sans effets indésirables aux doses thérapeutiques. Cela en fait un médicament de premier recours chez la femme enceinte, le nourrisson et l’enfant. D’après un rapport de l’ANSM, sur les 30 substances actives les plus vendues en France en 2013 (montant total 1,15 milliard de boîtes), le paracétamol domine très largement (plus de 500 millions de boîtes). C'est l’antalgique et l’antipyrétique le plus consommé au monde. La pharmacopée des antalgiques est vieillissante, l’évolution de l’arsenal thérapeutique depuis 50 ans est limitée. Ce constat amène à réévaluer les stratégies de recherche. Maintenant, notre intérêt serait de comprendre les mécanismes et les cibles de ces antalgiques afin de développer des analogues plus affins tout en limitant leurs effets indésirables. Basée cette stratégie, le paracétamol est un parfait candidat. En effet, son mécanisme d’action n’est pas parfaitement connu mais son efficacité n’est plus à prouver. L’objectif de ces travaux est d’élucider le mystère qui entoure son mécanisme d’action et de découvrir ses cibles. Les dernières études redéfinissent le paracétamol comme un précurseur métabolique à l’origine d’un dérivé lipidique actif, nommé AM404. Ce dernier serait synthétisé dans certaines régions cérébrales exprimant l’enzyme FAAH capable de catalyser cette réaction. Le mécanisme alors mis en jeu montre que le paracétamol, via l’AM404, activerait les récepteurs TRPV1 centraux et indirectement les récepteurs CB1 pour renforcer un mécanisme central d’atténuation de la douleur via les voies descendantes sérotoninergiques. Cependant, le noyau cérébral concerné et le mécanisme cellulaire mis en jeu demeurent inconnus. Des données comportementales associées à une étude d’imagerie fonctionnelle ont levé le voile sur plusieurs régions cérébrales potentiellement impliquées dans l’action du paracétamol, notamment la substance grise périaqueducale. Cette dernière a suscité notre intérêt, car ce noyau exprime à la fois la triade FAAH/TRPV1/CB1, mais aussi est un carrefour des voies descendantes sérotoninergiques. Une activation dans la substance grise périaqueducale des récepteurs TRPV1 et CB1 est à même de produire un effet antinociceptif dépendant de ces contrôles descendants. Ces travaux de thèse ont conduit à conforter que l’action antalgique du paracétamol implique un mécanisme supra-spinal dépendant de l’enzyme FAAH en condition pathologique. Plus précisément, nous avons étudié le rôle de la triade FAAH/TRPV1/CB1 au niveau de la SGPA. Nous avons découvert que le paracétamol interagissait avec une voie de signalisation cellulaire mGLUR5-PLC-DAGL responsable de la production de l’endocannabinoïde 2-AG. Ce mécanisme pourrait à la fois expliquer l’étroite collaboration existant entre les récepteurs TRPV1 et CB1 dans l’effet antalgique du paracétamol et le renforcement des voies descendantes sérotoninergiques. Le paracétamol est donc un promédicament dont l’action cérébrale recruterait un ensemble de systèmes complexes pour médier son effet antalgique. Ce mécanisme séduisant ouvre la piste à de nouveaux antalgiques toujours plus efficaces avec des effets indésirables moindres, à l’image du paracétamol.
... Representative images of c-Fos immunostaining are shown in Figure 2. In the sections of DRN, c-Fos immunoreactivity in rats that performed acute treadmill running was qualitatively higher in the ventrolateral region of the DRN (DRVL) compared to the dorsal or ventral regions of the DRN (The sub-region of the DRN is marked with the dotted line in Figure 2). The ventrolateral region of the DRN, which contains a distinct cluster of serotonergic neurons, are believed to play anti-aversive roles in stress-related functional properties (Lowry et al., 2000;Johnson et al., 2004). In the pre-training group, acute treadmill running at low speed increased c-Fos expression in the DRN, whereas high-speed treadmill running only slightly increased c-Fos expression in the DRN. ...
Increasing clinical evidence suggests that regular physical exercise can prevent or reduce the incidence of stress-related psychiatric disorders including depressive symptoms. Antidepressant effect of regular exercise may be implicated in monoaminergic transmission including serotonergic transmission, activation of the hypothalamic-pituitary-adrenal (HPA) axis, and hippocampal neurogenesis, but few general concepts regarding the optimal exercise regimen for stimulating neural mechanisms involved in antidepressant properties have been developed. Here, we examined how 4 weeks of treadmill running at different intensities (0, 15, 25 m/min, 60 min/day, 5 times/week) alters neuronal activity in the dorsal raphe nucleus (DRN), which is the major source of serotonin (5-HT) neurons in the central nervous system, and the hypothalamic paraventricular nucleus (PVN), in which corticotropin-releasing factor (CRF) neurons initiate the activation of the HPA axis, during one session of acute treadmill running at different speeds (0, 15, 25 m/min, 30 min) in male Wistar rats, using c-Fos immunohistochemistry. We also examined neurogenesis in the hippocampus using immunohistochemistry for doublecortin (DCX) and assessed depressive-like behavior using the forced swim test after regular exercise for 4 weeks. In the pre-training period, acute treadmill running at low speed, but not at high speed, increased c-Fos positive nuclei in the DRN compared with the sedentary control. The number of c-Fos positive nuclei in the PVN during acute treadmill running was increased in a running speed-dependent manner. Regular exercise for 4 weeks, regardless of the training intensity, induced an enhancement of c-Fos expression in the DRN during not only low-speed but also high-speed acute running, and generally reduced c-Fos expression in the PVN during acute running compared with pre-training. Furthermore, regular treadmill running for 4 weeks enhanced DCX immunoreactivity in the hippocampal dentate gyrus (DG), and resulted in decreased depressive-like behavior, regardless of the training intensity. These results suggest that long-term repeated exercise, regardless of the training intensity, improves depressive-like behavior through adaptive changes in the sensitivity of DRN and PVN neurons to acute exercise, and hippocampal neurogenesis.
... Esler has demonstrated excess catecholamine spill-over in hypertension (Esler et al. 2001) and autonomic dysfunction is now understood to be a core aetiology of what was previously termed ''essential'' hypertension. PDA and hypertension may share a failure of control of sympathetic activation, perhaps through compromise of those centres which control the C1-adrenergic cell group in the rostral-ventrolateral medulla, which include the raphe pallidum and ventrolateral periaqueductal grey, the latter under the influence of the pre-frontal cortex (Johnson et al. 2004; Davies et al. 2007). ...
{\bf Objective:}$ Biomarkers are defined as anatomical, biochemical or physiological traits that are specific to certain disorders or syndromes. The objective of this paper is to summarise the current knowledge of biomarkers for anxiety disorders, obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD). ${\bf Methods:}$ Findings in biomarker research were reviewed by a task force of international experts in the field, consisting of members of the World Federation of Societies for Biological Psychiatry Task Force on Biological Markers and of the European College of Neuropsychopharmacology Anxiety Disorders Research Network. ${\bf Results:}$ The present article (Part II) summarises findings on potential biomarkers in neurochemistry (neurotransmitters such as serotonin, norepinephrine, dopamine or GABA, neuropeptides such as cholecystokinin, neurokinins, atrial natriuretic peptide, or oxytocin, the HPA axis, neurotrophic factors such as NGF and BDNF, immunology and CO$_2$ hypersensitivity), neurophysiology (EEG, heart rate variability) and neurocognition. The accompanying paper (Part I) focuses on neuroimaging and genetics. ${\bf Conclusions:}$ Although at present, none of the putative biomarkers is sufficient and specific as a diagnostic tool, an abundance of high quality research has accumulated that should improve our understanding of the neurobiological causes of anxiety disorders, OCD and PTSD.
... More recent studies report that of the ascending 5-HT neurons (132)(133)(134), 16% are GABAergic and project to the medial prefrontal cortex (135), as also suggested by electrophysiological studies (136). These GAD + 5-HT neurons have distinct electrophysiological characteristics and may, interestingly, be involved in stress-related responses and disorders (130,(137)(138)(139). Shikanai et al. (130) have shown that lateral, but not medial, 5-HT/ GAD67 neurons are particularly sensitive to innocuous stressors. ...
Significance
The pathophysiology of depression remains unclear, but accumulated evidence implicates disturbances in monoaminergic transmission in the brain. Several studies suggest that members of the diverse family of neuropeptides may also be involved. In the rat, the neuropeptide galanin is coexpressed with noradrenaline and serotonin, and modulates the signaling of these neurotransmitters. Here, we explored a possible role of galanin and its receptors in a rat model of depression based on chronic mild stress using quantitative real-time PCR combined with viral-mediated delivery of galanin receptor 1 (Galr1) siRNA. Our results indicate involvement of the GALR1 receptor subtype in the ventral periaqueductal gray in depression-like behavior, possibly representing a novel target for antidepressant therapy.
... It is involved in the emotional regulation (e.g., in circuitries underlying fear, depression and anxiety), but also in autonomic control and pain (Behbehani, 1995;Satpute et al., 2013). Its ventrolateral subdivision (VLPAG), where the NPSR1 mRNA-expressing neurons are especially abundant, is critical for the expression of passive coping responses to nonimmediate "distal" danger (Johnson et al., 2004), but neurons in the vlPAG contribute to the regulation of REM sleep as well (Luppi et al., 2012). The NPSR1 mRNA-expression in the PAG is detected also in rodents (Xu et al., 2007;Clark et al., 2011). ...
Neuropeptide S (NPS) is a regulatory peptide with potent pharmacological effects. In rodents, NPS is expressed in a few pontine cell clusters. Its receptor (NPSR1) is, however, widely distributed in the brain. The anxiolytic and arousal-promoting effects of NPS make the NPS–NPSR1 system an interesting potential drug target in mood-related disorders. However, so far possible disease-related mechanisms involving NPS have only been studied in rodents. To validate the relevance of these animal studies for i.a. drug development, we have explored the distribution of NPS-expressing neurons in the human pons using in situ hybridization and stereological methods and we compared the distribution of NPS mRNA expressing neurons in the human and rat brain. The calculation revealed a total number of 22,317 ± 2411 NPS mRNA-positive neurons in human, bilaterally. The majority of cells (84%) were located in the parabrachial area in human: in the extension of the medial and lateral parabrachial nuclei, in the Kölliker-Fuse nucleus and around the adjacent lateral lemniscus. In human, in sharp contrast to the rodents, only very few NPS-positive cells (5%) were found close to the locus coeruleus. In addition, we identified a smaller cell cluster (11% of all NPS cells) in the pontine central gray matter both in human and rat, which has not been described previously even in rodents. We also examined the distribution of NPSR1 mRNA-expressing neurons in the human pons. These cells were mainly located in the rostral laterodorsal tegmental nucleus, the cuneiform nucleus, the microcellular tegmental nucleus region and in the periaqueductal gray. Our results show that both NPS and NPSR1 in the human pons are preferentially localized in regions of importance for integration of visceral autonomic information and emotional behavior. The reported interspecies differences must, however, be considered when looking for targets for new pharmacotherapeutical interventions.
... It is involved in the emotional regulation (e.g., in circuitries underlying fear, depression and anxiety), but also in autonomic control and pain (Behbehani, 1995;Satpute et al., 2013). Its ventrolateral subdivision (VLPAG), where the NPSR1 mRNA-expressing neurons are especially abundant, is critical for the expression of passive coping responses to nonimmediate "distal" danger (Johnson et al., 2004), but neurons in the vlPAG contribute to the regulation of REM sleep as well (Luppi et al., 2012). The NPSR1 mRNA-expression in the PAG is detected also in rodents (Xu et al., 2007;Clark et al., 2011). ...
Neuropeptide S (NPS) is a regulatory peptide with potent pharmacological effects. In rodents, NPS is expressed in a few pontine cell clusters. Its receptor (NPSR1) is, however, widely distributed in the brain. The anxiolytic and arousal-promoting effects of NPS make the NPS-NPSR1 system an interesting potential drug target in mood-related disorders. However, so far possible disease-related mechanisms involving NPS have only been studied in rodents. To validate the relevance of these animal studies for i.a. drug development, we have explored the distribution of NPS-expressing neurons in the human pons using in situ hybridization and stereological methods and we compared the distribution of NPS mRNA expressing neurons in the human and rat brain. The calculation revealed a total number of 22,317 ± 2411 NPS mRNA-positive neurons in human, bilaterally. The majority of cells (84%) were located in the parabrachial area in human: in the extension of the medial and lateral parabrachial nuclei, in the Kölliker-Fuse nucleus and around the adjacent lateral lemniscus. In human, in sharp contrast to the rodents, only very few NPS-positive cells (5%) were found close to the locus coeruleus. In addition, we identified a smaller cell cluster (11% of all NPS cells) in the pontine central gray matter both in human and rat, which has not been described previously even in rodents. We also examined the distribution of NPSR1 mRNA-expressing neurons in the human pons. These cells were mainly located in the rostral laterodorsal tegmental nucleus, the cuneiform nucleus, the microcellular tegmental nucleus region and in the periaqueductal gray. Our results show that both NPS and NPSR1 in the human pons are preferentially localized in regions of importance for integration of visceral autonomic information and emotional behavior. The reported interspecies differences must, however, be considered when looking for targets for new pharmacotherapeutical interventions.
... As to the pathophysiology of PD, the evidenced interaction between 5-HT and opioids in the DPAG for the regulation of proximal defense allows for the reconciliation between two prominent hypotheses that try to explain why PD patients are more vulnerable to panic attacks, namely the aforementioned lack of an opioid buffering system [26], and that of faulty 5-HT inhibition of brain stem regions that are responsible for the expression of the behavioral and neurovegetative symptoms of the panic attack. The most pertinent results concerning 5-HT were reported by Johnson et al. [88,89] using rats chronically infused with the GABA synthesis inhibitor l-allylglycine through a minipump placed inside the dorsomedial hypothalamus, what makes the animals responsive to lactate, like PD patients. Controls were infused with the inactive enantiomer, d-allylglycine. ...
The dorsal periaqueductal gray (DPAG) has long been implicated in the pathophysiology of anxiety, particularly in panic disorder (PD). Evidence obtained with animal models indicates that different neurotransmitters/neuromodulators in this midbrain area are involved in the regulation of anxiety- (e.g. inhibitory avoidance) and panic- (e.g. escape) associated defensive behaviors. Earlier findings showed that activation of serotonin (5-HT) 1A and 2A receptors in the DPAG inhibits escape expression, a panicolytic-like effect. Recently gathered evidence shows that different classes of antipanic drugs, such as the selective serotonin reuptake inhibitor antidepressant fluoxetine or the benzodiazepine alprazolam, enhance the inhibitory action of 5-HT upon these receptors. They also show that opioidergic mechanisms, through the activation of µ-receptors, contribute to this process. As with 5-HT, activation of GABAA or GABAB receptors, or cannabinoid type 1receptors as well as the tropomyosin-related kinase B receptors by brain-derived neurotrophic factor in the DPAG also inhibits escape expression. There is evidence that chronic antidepressant treatment, besides facilitating 5-HT/opioid neurotransmission, also increases brain-derived neurotrophic factor levels in this area with an impact on its panicolytic effect. On the other hand, facilitation of corticotrophin releasing factor- or cholecystokinin-mediated neurotransmission in the DPAG, via CRF1 and CCK2 receptors, respectively, causes panicogenic-like effects with implications for the pathogenesis of PD. A better understanding of the neurochemical control of defense in the DPAG may foster the development of new strategies for pharmacological treatment of PD.
... Interestingly, intra-PAG injections of FG-7142 result in strong panicogenic effects (Bueno et al., 2005), suggesting the site or sites of action of FG-7142 after treatment via different routes are critical to the behavioral outcomes. Serotonergic neurons in the DRVL/VLPAG region, through projections to the dorsal PAG and rostroventrolateral medulla, form part of an anti-panic-like serotonin system (Johnson et al., 2004), and one possibility is that peripheral administration of FG-7142, as in the present study, may be interacting simultaneously with anxiety-facilitating and anti-paniclike serotonin systems. ...
Anxiety is a complex and adaptive emotional state controlled by a distributed and interconnected network of brain regions, and disruption of these networks is thought to give rise to the behavioural symptoms associated with anxiety disorders in humans. The dorsal raphe nucleus (DR), which contains the majority of forebrain-projecting serotonergic neurons, is implicated in the control of anxiety states and anxiety-related behaviour via neuromodulatory effects on these networks. Relaxin-3 is the native neuropeptide ligand for the Gi/o-protein-coupled receptor, RXFP3, and is primarily expressed in the nucleus incertus (NI), a tegmental region immediately caudal to the DR. RXFP3 activation has been shown to modulate anxiety-related behaviour in rodents, and RXFP3 mRNA is expressed in the DR. In this study, we examined the response of relaxin-3-containing neurons in the NI and serotonergic neurons in the DR following pharmacologically-induced anxiety and exposure to an aversive environment. We administered the anxiogenic drug FG-7142 or vehicle to adult male Wistar rats and, 30 min later, exposed them to either the elevated plus-maze or home cage control conditions. Immunohistochemical detection of c-Fos was used to determine activation of serotonergic neurons in the DR and relaxin-3 neurons in the NI, measured 2 h following drug injection. Analysis revealed that FG-7142 administration and exposure to the elevated plus-maze are both associated with an increase in c-Fos expression in relaxin-3-containing neurons in the NI and in serotonergic neurons in dorsal and ventrolateral regions of the DR. These data are consistent with the hypothesis that relaxin-3 systems in the NI and serotonin systems in the DR interact to form part of a network involved in the control of anxiety-related behaviour.
Copyright © 2015. Published by Elsevier Ltd.
... ***p<0.001 the novel context (Homberg 2012) similar to the OF. Furthermore Tph2 −/− mice showed increased shock reactivity independent of CMS, which indicates that 5-HT is implicated in the suppression of flight responses (Johnson et al. 2004; Spannuth et al. 2011; Gutknecht et al. 2012), as thermal and tactile pain sensitivity was not changed in Tph2 −/− mice. Increased cue fear learning in male and female Tph2 −/− mice is in line with findings in other models of 5-HT deficiency (Dai et al. 2008; Kiyasova et al. 2011 ) and argue for specific effects of 5-HT neuron subgroups, which balance CMSevoked changes in limbic brain areas involved in cued conditioning (Mongeau et al. 1997; Sullivan et al. 2004; Pape and Pare 2010; Hale et al. 2012). ...
While brain serotonin (5-HT) function is implicated in gene-by-environment interaction (GxE) impacting the vulnerability-resilience continuum in neuropsychiatric disorders, it remains elusive how the interplay of altered 5-HT synthesis and environmental stressors is linked to failure in emotion regulation.
Here, we investigated the effect of constitutively impaired 5-HT synthesis on behavioral and neuroendocrine responses to unpredictable chronic mild stress (CMS) using a mouse model of brain 5-HT deficiency resulting from targeted inactivation of the tryptophan hydroxylase-2 (Tph2) gene.
Locomotor activity and anxiety- and depression-like behavior as well as conditioned fear responses were differentially affected by Tph2 genotype, sex, and CMS. Tph2 null mutants (Tph2(-/-)) displayed increased general metabolism, marginally reduced anxiety- and depression-like behavior but strikingly increased conditioned fear responses. Behavioral modifications were associated with sex-specific hypothalamic-pituitary-adrenocortical (HPA) system alterations as indicated by plasma corticosterone and fecal corticosterone metabolite concentrations. Tph2(-/-) males displayed increased impulsivity and high aggressiveness. Tph2(-/-) females displayed greater emotional reactivity to aversive conditions as reflected by changes in behaviors at baseline including increased freezing and decreased locomotion in novel environments. However, both Tph2(-/-) male and female mice were resilient to CMS-induced hyperlocomotion, while CMS intensified conditioned fear responses in a GxE-dependent manner.
Our results indicate that 5-HT mediates behavioral responses to environmental adversity by facilitating the encoding of stress effects leading to increased vulnerability for negative emotionality.
... Thus, on the basis of the currently used measures we cannot unambiguously resolve whether the reduced stress responsiveness reflects a beneficial ('anxiolytic-like') or a maladaptive state ('hypo-responsiveness'). Nonlinear measures (Meyer and Stiedl, 2003) may provide for an unambiguous interpretation of physiological versus pathological change, but cannot be applied with short ECG recordings as used here. The existence of functional subpopulations of serotonergic neurons acting at numerous sites of the CNS and the evidence for their tight control by stress hormones (Chaouloff, 1993;Johnson et al., 2004) suggest a complex interplay of central serotonergic activity with ANS and cardiac stress responsiveness. SSRI treatment may, thus, both influence supra-ordinate mechanisms (e.g., the central autonomic network) and/or affect hormone secretion patterns (Shores et al., 2001;Agelink et al., 2004). ...
BACKGROUND:
Central serotonergic pathways influence brain areas involved in vagal cardiovascular regulation and thereby influence sympathetic efferent activity. Selective serotonin reuptake inhibitors (SSRIs) affect multiple serotonergic pathways including central autonomic pathways. However, only few studies assessed SSRI-mediated effects on autonomic reactivity in healthy individuals using heart rate variability (HRV).
METHODS:
The present study assessed the influence of long-term treatment with escitalopram (ESC) on autonomic reactivity to an intravenous application of 50 µg cholecystokinin tetrapeptide (CCK-4) in 30 healthy young men using a double-blind, placebo (PLA)-controlled, randomized, within-subject cross-over design. Main outcome measures were time and frequency domain HRV parameters assessed at both baseline and immediately after CCK-4 application.
RESULTS:
Results showed substantial effects for the treatment × CCK-4 challenge interaction with respect to HR (p < .001; pη2 = .499), SDNN (p < .001; pη2 = 576), RMSSD (p = .015; pη2 = 194), NN50(%) (p = .008; pη2 = .224), LF(%) (p = .014; pη2 = .196) and moderate effects with respect to HF(%) (p = .099; pη2 = .094), with PLA subjects showing a higher increase in HR and SDNN and a higher decrease in RMSSD, NN50(%), LF(%) and HF (%) than in the ESC condition. Thus, ESC treatment significantly blunted the autonomic reactivity to CCK-4 challenge compared to PLA. Secondary analysis indicated no effect of 5-HTTLPR polymorphism on CCK-4-induced autonomic response. Conclusions: Our results support findings suggesting an effect of SSRI treatment on autonomic regulation and provide evidence that ESC treatment is associated with blunted autonomic reactivity in healthy men.
... The implications of these findings are twofold. At the conceptual level, it allows reconciliation between the opioid-deficiency hypothesis of panic vulnerability (Preter and Klein, 2008) with the proposal by Johnson et al. (2004Johnson et al. ( , 2008) that a deficient 5-HT inhibition in the dPAG would underpin the behavioral manifestations of the panic attack, while the same deficit in sympathomotor areas in the ventral medulla would allow for the neurovegetative symptoms of panic attack (for a discussion, see Graeff, 2012). At the clinical level, they may point to new therapeutic avenues for the treatment of panic patients that are refractory to the current antidepressant drugs. ...
... Future studies are needed to replicate this finding and further explore the role of autonomic stress reactivity as a potential biological mechanism conveying an elevated risk for the development of stress-related disorders in short allele carriers (Lang and McTeague, 2009). Nevertheless, the existence of functional subpopulations of serotonergic neurons acting at numerous sites of the CNS and the evidence for their tight control by stress hormones (Chaouloff, 1993;Johnson et al., 2004) suggest a complex interplay of central serotonergic activity with ANS and hypothalamic-pituitary-adrenal axis function towards maintenance of homeodynamics during stressful events and adaptation processes impacting on cardiac stress responsiveness. ...
Abnormal serotonin transporter (5-HTT) function and autonomic nervous system (ANS) dysregulation has been proposed in panic disorder. However, in contrast to hypothalamo-pituitary-adrenocortical (HPA) functioning, ANS reactivity during panic response has yet not been investigated in humans with respect to the 5-HTT genotype. The present study assessed the influence of challenging by cholecystokinin tetrapeptide (CCK-4) on heart rate variability (HRV) measures, to monitor autonomic reactivity and its relationship to 5-HTT-linked polymorphic region (5-HTTLPR) genotypes. We hypothesized substantial effects of the 5-HTTLPR genotype on autonomic reactivity. We studied 30 healthy young men, 15 of each with the long/long (l/l) or short/short (s/s) genotype for the 5-HTTLPR. All participants received an intravenous application of 50 μg CCK-4. HRV measures were assessed in both groups at baseline and immediately after CCK-4 application. Our results indicated lower parasympathetic activity in s/s carriers during baseline, time and frequency domain measures. CCK-4 application significantly enhanced the sympathetic tone in both groups, leading to diminished group differences. A significant treatment by genotype effect indicated reduced autonomic reactivity to CCK-4 challenge in the s/s compared to l/l carriers. Our findings show enhanced sympathetic and/or diminished cardiac vagal activity under basal conditions and blunted autonomic reactivity in s/s vs. l/l carriers. Our study provides novel data supporting claims that the s/s genotype represents a genetic vulnerability factor associated with inadequate hyporeactivity to stress and extends current knowledge on the impact of the central serotonergic activity on the sympathoadrenal pathway.
... Stimulation of the dorsolateral PAG evokes arousal, tachycardia, increased blood pressure and respiration, analgesia and increased motor activity as in a fight or flight response. In contrast, stimulation of neurons in the ventrolateral PAG causes an immobility as in freezing evoked by aversive stimuli (Johnson et al. 2004). ...
Acid sensing ion channels (ASICs) generate H(+) -gated Na(+) currents that contribute to neuronal function and animal behavior. Like ASIC1, ASIC2 subunits are expressed in the brain and multimerize with ASIC1 to influence acid-evoked currents and facilitate ASIC1 localization to dendritic spines. To better understand how ASIC2 contributes to brain function, we localized the protein and tested the behavioral consequences of ASIC2 gene disruption. For comparison, we also localized ASIC1 and studied ASIC1(-/-) mice. ASIC2 was prominently expressed in areas of high synaptic density, and with a few exceptions, ASIC1 and ASIC2 localization exhibited substantial overlap. Loss of ASIC1 or ASIC2 decreased freezing behavior in contextual and auditory cue fear conditioning assays, in response to predator odor, and in response to CO2 inhalation. In addition, loss of ASIC1 or ASIC2 increased activity in a forced swim assay. These data suggest that ASIC2, like ASIC1, plays a key role in determining the defensive response to aversive stimuli. They also raise the question of whether gene variations in both ASIC1 and ASIC2 might affect fear and panic in humans.
... We directly tested this by measuring the electrophysiological properties of the serotonergic raphe neurons in both the lateral wings (lwDR) and ventromedial (vmDR) aspect of the dorsal raphe in WT and KD animals as adults. We examined both of these subfields, because we previously found differences in their cell parameters (Crawford et al, 2010) and because they are known to have different projections, with the vmDR sending axons to forebrain structures such as the amygdala, medial prefrontal cortex, and caudate-putamen (Bang et al, 2012;Lowry et al, 2008;Michelsen et al, 2008), whereas the lwDR projects to sympathomimetic nuclei (Hale and Lowry, 2011;Johnson et al, 2004). We found that post-natal knockdown of receptors led to long-lasting changes in several of the membrane characteristics of the neurons, the sum of which resulted in increased cell excitability ( Figure 5). ...
The serotonin 1A receptor (5-HT1A) plays a major role in modulating the effects of serotonin on mood and behavior. Previous studies have shown that knockout of 5-HT1A selectively in the raphe leads to higher levels of anxiety during adulthood. However, it remains unclear whether this phenotype is due to variation in receptor levels specifically during development or throughout life. To test the hypothesis that developmental sensitivity may underlie the effects of 5-HT1A on anxiety, we used an inducible transgenic system to selectively suppress 5-HT1A levels in serotonergic raphe neurons from post-natal days 14-30, with a maximal reduction of 40% at post-natal day 21 and return of regular levels by post-natal day 30. This developmental decrease in receptor levels has long lasting consequences, increasing anxiety and decreasing social investigation in adulthood. In addition, postnatal knockdown of autoreceptors leads to long term increases in the excitability of serotonergic neurons, which may represent a mechanism underlying the effects of post-natal receptor variation on behavior later in life. Finally, we also examined the interplay between receptor variation and juvenile exposure to stress (applied from postnatal days 14 to 21). Similar to receptor knockdown, juvenile exposure to stress led to increased anxiety phenotypes, but did not exacerbate 5-HT1A knockdown-mediated anxiety levels. This work indicates that the effects of 5-HT1A autoreceptors on anxiety and social behaviors are developmentally mediated and suggests that natural variations in the expression of 5-HT1A may act during development to influence individual anxiety levels and contribute to susceptibility to anxiety disorders.Neuropsychopharmacology accepted article preview online, 2 August 2013. doi:10.1038/npp.2013.185.
Objective
Whereas numerous experimental and clinical studies suggest a complex involvement of serotonin in the regulation of anxiety, it remains to be clarified if the dominating impact of this transmitter is best described as anxiety-reducing or anxiety-promoting. The aim of this study was to assess the impact of serotonin depletion on acquisition, consolidation and expression of conditioned fear.
Methods
Male Sprague Dawley rats were exposed to foot shocks as unconditioned stimulus and assessed with respect to freezing behaviour when re-subjected to context. Serotonin depletion was achieved by administration of a serotonin synthesis inhibitor, para-chlorophenylalanine (PCPA) (300 mg/kg daily x 3), i) throughout the period from (and including) acquisition to (and including) expression, ii) during acquisition but not expression, iii) after acquisition only, and iv) during expression only.
Results
The time spent freezing was significantly reduced in animals that were serotonin-depleted during the entire period from (and including) acquisition to (and including) expression, as well as in those being serotonin-depleted during either acquisition only or expression only. In contrast, PCPA administrated immediately after acquisition, i.e. during memory consolidation, did not impact the expression of conditioned fear.
Conclusion
Intact serotonergic neurotransmission is important for both acquisition and expression of context-conditioned fear.
Integrated behavioral responses to emotionally salient stimuli require concomitant activation of descending neural circuits that integrate physiological, affective, and motor responses to stress. Our previous work interrogated descending circuits in the brainstem and spinal cord that project to motor and sympathetic targets. The hypothalamic paraventricular nucleus (PVN), a key node of this circuitry, integrates multiple motor and sympathetic responses activated by stress. The present study sought to determine whether descending projections from the PVN to targets in muscle and adrenal gland are differentially organized in rats with inborn differences in emotionality and stress responsivity. We utilized retrograde transsynaptic tract‐tracing with unique pseudorabies virus (PRV) recombinants that were injected into sympathectomized gastrocnemius muscle and adrenal gland in two rat models featuring inborn differences in emotional behavior. Our tract‐tracing results revealed a significant decrease in the number of PVN neurons with poly‐synaptic projections to the gastrocnemius in male Wistar Kyoto [WKY] rats (versus Sprague Dawley rats) and selectively‐bred Low Novelty Responder [bLR] rats (versus selectively‐bred High Novelty Responder [bHR] rats). These neuroanatomical differences mirrored behavioral observations showing that both WKY and bLR rats display marked inhibition of emotional motor responses in a variety of settings relative to their respective controls. Our findings suggest that, in male rodents, PVN poly‐synaptic projections to skeletal muscle may regulate emotional motor and coping responses to stress. More broadly, perturbations in PVN motor circuitry may play a role in mediating psychomotor disturbances observed in depression or anxiety‐related disorders.
Panic disorder draws its name from the Greek god Pan, god of flocks. Pan was known for suddenly frightening animals and humans ‘out of the blue’. The spontaneous ‘out of the blue’ character of panic attacks is the principal identifying characteristic of panic disorder and central to its recognition and diagnosis. We know the syndrome that we currently call panic disorder with and without agoraphobia has probably existed since the beginning of recorded history. Hippocrates presented cases of obvious phobic avoidance around 400 bc . One of the first modern descriptions was by Benedikt around 1870, describing individuals who developed sudden anxiety and dizziness in public places. Certainly, our current modern ideas of panic disorder evolved essentially simultaneously in the United States and Europe in the early to mid-1960s. Donald Klein in the United States described in 1964 the panic syndrome and reported that it was responsive to imipramine. Isaac Marks in the United Kingdom also described panic attacks and agoraphobic avoidance, and treating the syndrome effectively with behaviour therapy. Until the last several decades, panic disorder and agoraphobia were actually thought to be rare syndromes. It is now clear that individuals with these difficulties are anything but rare. In fact, panic disorder is one of the most common presenting problems in individuals seeking mental health treatment and the fifth most common problem seen in primary care settings. It was thought to be a mild problem, but we now know that it is associated with significant dysfunction. The disability in social, occupational, and family life is in fact comparable to major depression. Although there are differences in the understandings of panic disorder and its treatments across the world, this chapter will review the current understanding about panic disorder, its characteristics, diagnosis, aetiology, and treatments.
This article charts the history of deep brain stimulation (DBS) as applied to alleviate a number of neurological disorders, while in parallel mapping the electrophysiological circuits involved in generating and integrating neural signals driving the cardiorespiratory system during exercise. With the advent of improved neuroimaging techniques, neurosurgeons can place small electrodes into deep brain structures with a high degree accuracy to treat a number of neurological disorders, such as movement impairment associated with Parkinson’s disease and neuropathic pain. As well as stimulating discrete nuclei and monitoring autonomic outflow, local field potentials can also assess how the neurocircuitry responds to exercise. This technique has provided an opportunity to validate in humans putative circuits previously identified in animal models. The central autonomic network consists of multiple sites from the spinal cord to the cortex involved in autonomic control. Important areas exist at multiple evolutionary levels, which include the anterior cingulate cortex (telencephalon), hypothalamus (diencephalon), periaqueductal grey (midbrain), parabrachial nucleus and nucleus of the tractus solitaries (brainstem), and the intermediolateral column of the spinal cord. These areas receive afferent input from all over the body and provide a site for integration, resulting in a coordinated efferent autonomic (sympathetic and parasympathetic) response. In particular, emerging evidence from DBS studies have identified the basal ganglia as a major sub-cortical cognitive integrator of both higher center and peripheral afferent feedback. These circuits in the basal ganglia appear to be central in coupling movement to the cardiorespiratory motor program.
Heart occupies a special place in our life, and physiologically, it is central to the functions of the cardiovascular system. The heart has inherent ability to generate its own rhythm and modulate its functions. The neural centres in the medulla integrate the afferent information from cardiovascular system with the modulatory signals from the cortical and sub-cortical neural regions to control the rate, rhythm and contracility of the heart. The sympathetic and parasympathetic nerves innervate the heart and form a network of plexuses with the intrinsic cardiac nervous system. These sympathetic and parasympathetic drives are modulated to operate in antagonistic, synergistic and temporally sequenced mode in context-specific patterns. The overall neural organization ensures that the functioning of the heart is modulated to synchronize it with the overall scheme of homeostasis and to support the ongoing physical and emotional components of motivated behaviour.
According to rough estimates, at least one third of the population in developed countries suffers, to varying degrees, from certain forms of primary headache, the modern pharmacotherapy of which is not always effective and has a number of limitations. The non-pharmacological treatment of headache can be an alternative to the prescription of pharmacological agents and the only possible assistance option for patients developing drug-resistant cephalalgias. This review describes various methods of electrical neuromodulation that are used for the management of primary headaches. The authors provide information on current stages in implementation of implantable and non-invasive equipment into clinical practice, which makes possible electrical stimulations of peripheral nerves and of the sphenopalatine ganglion, as well as allows transcranial magnetic stimulation. Also the appearance and usage of portable electrical devices available on the world market are described, and mechanisms that can underlie anticephalgic action of neuromodulation therapy are discussed. Special attention is paid to the methods that are applied for electrostimulation of the vagus nerve and occipital nerves.
The high prevalence of anxiety disorders around the world leads to a high interest in the study of anxiety. At the moment, a lot of knowledge about the pathogenesis and therapy of anxiety disorders has been accumulated, which is well covered in modern domestic and world medical literature. It is known that many areas of the brain are involved in the modulation of anxiety, among which the amygdala is considered the key in the modulation of anxiety and fear. A large body of evidence supports the involvement of different neurotransmitter systems in the processes of anxiogenesis-anxiolysis (GABA, monoamines, glutamate, neuropeptides, neurosteroids). This article provides an analysis of methods of pharmacological impact on each of these systems, which serve to optimize the already known strategies of anxiolytic therapy.
Sudden unexpected death in epilepsy (SUDEP) is a devastating epilepsy complication. Seizure-induced respiratory arrest (S-IRA) occurs in many witnessed SUDEP patients and animal models as an initiating event leading to death. Thus, understanding the mechanisms underlying S-IRA will advance the development of preventive strategies against SUDEP. Serotonin (5-HT) is an important modulator for many vital functions, including respiration and arousal, and a deficiency of 5-HT signaling is strongly implicated in S-IRA in animal models, including the DBA/1 mouse. However, the brain structures that contribute to S-IRA remain elusive. We hypothesized that the dorsal raphe (DR), which sends 5-HT projections to the forebrain, is implicated in S-IRA. The present study used optogenetics in the DBA/1 mouse model of SUDEP to selectively activate 5-HT neurons in the DR. Photostimulation of DR 5-HT neurons significantly and reversibly reduced the incidence of S-IRA evoked by acoustic stimulation. Activation of 5-HT neurons in the DR suppressed tonic seizures in most DBA/1 mice without altering the seizure latency and duration of wild running and clonic seizures evoked by acoustic stimulation. This suppressant effect of photostimulation on S-IRA is independent of seizure models, as optogenetic stimulation of DR also reduced S-IRA induced by pentylenetetrazole, a proconvulsant widely used to model human generalized seizures. The S-IRA-suppressing effect of photostimulation was increased by 5-hydroxytryptophan, a chemical precursor for 5-HT synthesis, and was reversed by ondansetron, a specific 5-HT3 receptor antagonist, indicating that reduction of S-IRA by photostimulation of the DR is specifically mediated by enhanced 5-HT neurotransmission. Our findings suggest that deficits in 5-HT neurotransmission in the DR are implicated in S-IRA in DBA/1 mice, and that targeted intervention in the DR is potentially useful for prevention of SUDEP.
The dorsomedial hypothalamus (DMH) and the dorsal periaqueductal gray (DPAG) have been implicated in the genesis and regulation of panic-related defensive behaviors, such as escape. Previous results point to an interaction between serotonergic and opioidergic systems within the DPAG to inhibit escape, involving µ-opioid and 5-HT1A receptors (5-HT1AR). In the present study we explore this interaction in the DMH, using escape elicited by electrical stimulation of this area as a panic attack index. The obtained results show that intra-DMH administration of the non-selective opioid receptor antagonist naloxone (0.5 nmol) prevented the panicolytic-like effect of a local injection of serotonin (20 nmol). Pretreatment with the selective μ-opioid receptor (MOR) antagonist CTOP (1 nmol) blocked the panicolytic-like effect of the 5-HT1AR agonist 8-OHDPAT (8 nmol). Intra-DMH injection of the selective MOR agonist DAMGO (0.3 nmol) also inhibited escape behavior, and a previous injection of the 5-HT1AR antagonist WAY-100635 (0.37 nmol) counteracted this panicolytic-like effect. These results offer the first evidence that serotonergic and opioidergic systems work together within the DMH to inhibit panic-like behavior through an interaction between µ-opioid and 5-HT1A receptors, as previously described in the DPAG.
Panic patients experience recurrent panic attacks. Two main neurochemical hypotheses have been proposed to explain this vulnerability. The first suggests that panic patients have deficient serotonergic inhibition of neurons localized in the dorsal periaqueductal gray matter of the midbrain that organizes defensive reactions to cope with proximal threats as well as of sympathomotor control areas of the rostral ventrolateral medulla that generate neurovegetative symptoms of the panic attack. The second proposes that endogenous opioids buffer panic attacks in normal subjects, and their deficit results in heightened sensitivity to suffocation and separation anxiety in panic patients. Experimental results obtained in rat models of panic indicate that serotonin interacts synergistically with endogenous opioids in the dorsal periaqueductal gray through 5-HT1A and μ-opioid receptors to inhibit proximal defense and, supposedly, panic attacks. These findings allow reconciliation of the serotonergic and opioidergic hypotheses of panic pathophysiology. They also indicate that endogenous opioids are likely to participate in the panicolytic action of antidepressants and suggest that exogenous opioids may be useful for treating panic patients resistant to conventional pharmacotherapy.
Anxiety disorders are prevalent in human and veterinary medicine yet the underlying mechanism is poorly understood. Because serotonin (5-HT) neurons of the dorsal raphe (DR) are thought to play a prominent role, my goal was to understand the changes in DR 5-HT neurons that underlie anxiety and other stress-related disorders. Two DR subdivisions were studied in a series of experiments: the ventromedial DR (vmDR), a well characterized subfield with a high density of 5-HT neurons, and the lateral wing DR (lwDR), a largely uncharacterized subfield with a more sparse distribution of 5-HT neurons. Many stress paradigms activate 5-HT neurons of the lwDR more so than 5-HT neurons of the vmDR, suggesting a unique role for lwDR 5-HT cells in stress circuits. However, it is not known if lwDR 5-HT neurons possess physiological characteristics that contribute to their increased propensity to be activated by a stressor. I found that lwDR 5-HT neurons demonstrated increased intrinsic excitability, increased glutamatergic input, and similar GABAergic input when compared to vmDR 5-HT neurons. Using the chronic social defeat model of anxiety, the distinctions between lwDR and vmDR neurons were explored further. Social defeat induced anxious behavior and stress-associated pathological changes in the peripheral organs of intruder mice. For the first time, investigation into the neural mechanisms of social defeat has focused on 5-HT neuron physiology, revealing subregion-specific effects within the DR. Increased excitability was seen in the vmDR neurons of the most anxious mice. This was accompanied by a decrease in GABAergic input to vmDR 5-HT neurons potentially mediated by both presynaptic and postsynaptic changes. The lwDR 5-HT neurons demonstrated distinct stress-induced changes limited to the slower kinetics of postsynaptic GABAAR. The differential effect of social stress on inhibitory input to vmDR or lwDR neurons suggest that the 5-HT output in brain regions targeted by each subfield is differentially affected in anxiety disorders. Collectively these findings help fill the gap in our understanding of local DR circuitry, the heterogeneity of 5-HT neurons, and the distinct regulation of vmDR and lwDR neurons in the circuits that mediate stress and contribute to the pathophysiology of anxiety.
Objective: Biomarkers are defined as anatomical, biochemical or physiological traits that are specific to certain disorders or syndromes. The objective of this paper is to summarise the current knowledge of biomarkers for anxiety disorders, obsessive-compulsive disorder (OCD) and posttraumatic stress disorder (PTSD).
Methods: Findings in biomarker research were reviewed by a task force of international experts in the field, consisting of members of the World Federation of Societies for Biological Psychiatry Task Force on Biological Markers and of the European College of Neuropsychopharmacology Anxiety Disorders Research Network.
Results: The present article (Part II) summarises findings on potential biomarkers in neurochemistry (neurotransmitters such as serotonin, norepinephrine, dopamine or GABA, neuropeptides such as cholecystokinin, neurokinins, atrial natriuretic peptide, or oxytocin, the HPA axis, neurotrophic factors such as NGF and BDNF, immunology and CO2 hypersensitivity), neurophysiology (EEG, heart rate variability) and neurocognition. The accompanying paper (Part I) focuses on neuroimaging and genetics.
Conclusions: Although at present, none of the putative biomarkers is sufficient and specific as a diagnostic tool, an abundance of high quality research has accumulated that should improve our understanding of the neurobiological causes of anxiety disorders, OCD and PTSD.
Panic disorder (PD) patients are exquisitely and specifically sensitive to inhalations of 5–7 % carbon dioxide and infusions of 0.5 M sodium lactate. Another startling feature of clinical panic is the lack of increments of the ‘stress hormones’ corticotropin, cortisol and prolactin. PD is also more frequent in women and shows high comorbidity with childhood separation anxiety, late luteal period dysphoric disorder and depression. The hypothalamus-pituitary-adrenal axis is nevertheless activated in fear-like panics marked by palpitations, tremor and sweating, that are devoid of suffocation symptoms. These and other data suggest the existence of both respiratory and non-respiratory types of panic attacks. Increasing evidence suggests, on the other hand, that panics are mediated at midbrain’s dorsal periaqueductal grey matter (DPAG). Therefore, here we summarized data showing that: (1) the DPAG harbors a suffocation alarm system which is activated by low intravenous doses of potassium cyanide (KCN); (2) KCN evokes defensive behaviors that are facilitated by hypercapnia, blocked by lesions of DPAG and attenuated by clinically effective treatments with panicolytics; (3) DPAG stimulations do not change the stress hormones when escape is prevented by stimulating the rats in a small compartment; (4) DPAG-evoked panics responses are facilitated in neonatally-isolated adult rats, a model of childhood separation anxiety; (5) DPAG-evoked panic-like behaviors are facilitated in diestrus phase of rat ovulatory cycle. It is proposed a neural model of panic attacks in which the PAG is the fulcrum of threatening signals from both forebrain and hindbrain. This model emphasizes the role of PAG as a suffocation alarm system.
Despite the recognized importance of the dorsal raphe (DR) serotonergic (5-HT) nuclei in the pathophysiology of depression and anxiety, the molecular components/putative drug targets expressed by these neurons are poorly characterized. Utilizing the promoter of an ETS domain transcription factor that is a stable marker of 5-HT neurons (Pet-1) to drive 5-HT neuronal expression of YFP, we identified 5-HT neurons in live acute slices. We isolated RNA from single 5-HT neurons in the ventromedial and lateral wings of the DR and performed single-cell RNA-Seq analysis identifying >500 G-protein coupled receptors (GPCRs) including receptors for classical transmitters, lipid signals, and peptides as well as dozens of orphan-GPCRs. Using these data to inform our selection of receptors to assess, we found that oxytocin and lysophosphatidic acid 1 receptors are translated and active in costimulating, with the α1-adrenergic receptor, the firing of DR 5-HT neurons, while the effects of histamine are inhibitory and exerted at H3 histamine receptors. The inhibitory histamine response provides evidence for tonic in vivo histamine inhibition of 5-HT neurons. This study illustrates that unbiased single-cell transcriptomics coupled with functional analyses provides novel insights into how neurons and neuronal systems are regulated.-Spaethling, J. M., Piel, D., Dueck, H., Buckley, P. T., Morris, J. F., Fisher, S. A., Lee, J., Sul, J.-Y., Kim, J., Bartfai, T., Beck, S. G., Eberwine, J. H. Serotonergic neuron regulation informed by in vivo single-cell transcriptomics.
Adverse early life experience is thought to increase an individual’s susceptibility to mental health disorders, including anxiety and affective disorders, later in life. Our previous studies have shown that post-weaning social isolation of female rats during a critical period of development sensitizes an anxiety-related serotonergic dorsal raphe nucleus (DR) system in adulthood. Therefore, we investigated how post-weaning social isolation, in combination with a challenge with the anxiogenic drug, N-methyl-beta-carboline-3-carboxamide (FG-7142; a partial inverse agonist at the benzodiazepine allosteric site on the GABAA receptor), affects home cage behavior and serotonergic gene expression in the DR of female rats using in situ hybridization histochemistry. Juvenile female rats were reared in isolation or groups of three for a 3-week period from weaning (postnatal day (PD) 21 to mid-adolescence (PD42)), after which all rats were group-reared for an additional 16 days until adulthood. Among vehicle-treated rats, isolation-reared rats had decreased rodent tryptophan hydroxylase 2 (tph2) mRNA expression in ventral and ventrolateral subdivisions of the DR, a pattern observed previously in a rat model of panic disorder. Isolation-reared rats, but not group-reared rats, responded to FG-7142 with increased duration of vigilance and arousal behaviors. In addition, FG-7142 decreased tph2 expression, measured 4 h following treatment, in multiple subregions of the DR of group-reared rats but had no effect in isolation-reared rats. No treatment effects were observed on 5-HT1A receptor or serotonin transporter gene expression. These data suggest that adolescent social isolation alters tph2 expression in specific subregions of the DR and alters the effects of stress-related stimuli on behavior and serotonergic systems.
In vivo studies suggest that the stress-related neuropeptide corticotropin-releasing factor (CRF) modulates serotonergic neurotransmission. To investigate the underlying mechanisms for this interaction, the present study examined the effects of CRF in vitro on dorsal raphe neurons that displayed electrophysiological and pharmacological properties consistent with a serotonergic phenotype. In the presence of either 1 or 2 mm Ca(2+), perfusion of ovine CRF or rat/human CRF rapidly and reversibly increased firing rates of a subpopulation (19 of 70, 27%) of serotonergic neurons predominantly located in the ventral portion of the dorsal raphe nucleus. For a given responsive neuron, the excitatory effects of CRF were reproducible, and there was no tachyphylaxis. Excitatory effects were dose-dependent (over the range of 0.1-1.6 micrometer) and were completely absent after exposure to the competitive CRF receptor antagonists alpha-helical CRF(9-41) or rat/human [d-Phe(12), Nle(21, 38), alpha-Me-Leu(37)]-CRF(12-41). Both the proportion of responsive neurons and the magnitude of excitatory responses to CRF in the ventral portion of the caudal dorsal raphe nucleus were markedly potentiated in slices prepared from animals previously exposed to isolation and daily restraint stress for 5 d. Immunohistochemical staining of the recorded slices revealed close associations between CRF-immunoreactive varicose axons and tryptophan hydroxylase-immunoreactive neurons in the area of the recordings, providing anatomical evidence for potential direct actions of CRF on serotonergic neurons. The electrophysiological properties and the distribution of responsive neurons within the dorsal raphe nucleus are consistent with the hypothesis that endogenous CRF activates a topographically organized mesolimbocortical serotonergic system.
The ventrolateral cell column of the midbrain periaqueductal gray matter (vl-PAG) plays a major role in the attenuation of pain behaviour. It is established that this effect is exerted via modulation of neuronal activities in the rostral ventromedial medulla (RVM). Until recently it has been generally accepted that the vl-PAG exerts its modulatory effects upon RVM neurons through a direct monosynaptic pathway. However, recent data suggest that an additional indirect, di- or polysynaptic pathway may also exist. Using in vivo intracellular recordings we tested this hypothesis, by studying synaptic responses of somatosensory receptive RVM neurons evoked by electric stimulation of the vl-PAG in rats. RVM neurons were regarded as somatosensory receptive if they responded to electrical stimulation of the sciatic nerve. Most of the recorded RVM cells were excited by vl-PAG stimulation. Some of them responded with a short onset latency (3.6+/-0.9 ms) corresponding to monosynaptic excitation. All of these neurons were also excited by sciatic nerve stimulation at nociceptive intensities. In contrast to this, another proportion of the recorded RVM neurons responded with a four times longer (14.8+/-3 ms) onset latency to the vl-PAG stimulation, corresponding to polysynaptic modulation. All of these neurons were inhibited by sciatic nerve stimulation. The findings show that RVM neurons receive heterogeneous monosynaptic and polysynaptic inputs from the vl-PAG. The results also suggest that the monosynaptic and polysynaptic pathways modulate the activity of functionally distinct groups of RVM neurons.
The ability of 5-HT1 receptor agonists to modulate a chemically induced defence response has been studied in Lister hooded rats. Microinjections of the excitatory amino acidd,l-homocysteic acid (DLH) in both rostral and caudal dorsal periaqueductal gray matter (PAG) caused explosive motor behaviour characteristic of defence. This behaviour was quantified in terms of response duration, arena revolutions and number of defensive jumps. Direct administration into the PAG of either 5-carboxamidotryptamine (5-CT) or 8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT) produced behaviours (decreased exploratory rearing, dose related onset of flat body posture) indicative of 5-HT1A receptor activation. Pretreatment with either 5-CT or 8-OHDPAT directly in the PAG caused a significant attenuation, and in some cases a complete abolition, of the DLH evoked response. These agonists share high affinity in vitro for the 5-HT1A receptor. Thus the results suggest that in vivo activation of 5-HT1A receptors mediates an antiaversive reponse with respect to defensive behaviour elicited by specific chemical stimulation of the dorsal PAG.
Tryptophan (Try) is the only aminoacid present in plasma bound to serum proteins. The administration of Try to rats increased free and total Try in serum. Changes in free Try were much more pronounced and longer lasting than in total Try. Brain Try and 5-hydroxyindoleacetic acid (5-HIAA) underwent changes, parallel and proportional to the changes in free Try in serum. Rats fasted for 24 hours had higher concentrations of free serum tryptophan, brain tryptophan and 5-HIAA than rats fed for 2 hours. In contrast, total serum tryptophan was lower in fasted than in fed rats. These results indicate that brain tryptophan and serotonin turnover are controlled by free serum tryptophan and that free serum tryptophan levels are independent from total serum tryptophan concentrations.
Addition of linoleic acid to rat plasma caused increased uptake of radioactive tryptophan by incubated brain slices. Addition of competing amino acids within the physiological range of their concentrations had negligible effect. Rat midbrain tryptophan concentration in vivo correlated significantly with plasma free tryptophan. These results are consistent with previous work indicating the importance of plasma free tryptophan as a determinant of brain tryptophan concentration.
Previous studies have shown that the midbrain periaqueductal gray (PAG) projects to the ventrolateral medulla (VLM). Here, we studied PAG projections to the area of A1/C1 neurons in the VLM in the rat using phaseolus vulgaris leucoagglutinin (PHA-L) anterograde tracing combined with immunocytochemistry for tyrosine hydroxylase (TH) or phenylethanolamine N-methyl transferase (PNMT). Following PAG injections, PHA-L labeled fibers and terminals were intermingled among TH-immunoreactive (TH-ir) neurons in the VLM. High-power light microscopic examination revealed that some of the PHA-L labeled varicose fibers and boutons were in close contiguity with TH-ir elements. Such apparent appositions appeared more frequently on TH-ir elements in the A1 area than on TH-ir or PNMT-ir neurons in the C1 area. These results indicate that some PAG inputs to the VLM may directly innervate A1/C1 neurons.
There are conflicting results on the function of 5-HT in anxiety and depression. To reconcile this evidence, Deakin and Graeff have suggested that the ascending 5-HT pathway that originates in the dorsal raphe nucleus (DRN) and innervates the amygdala and frontal cortex facilitates conditioned fear, while the DRN-periventricular pathway innervating the periventricular and periaqueductal gray matter inhibits inborn fight/flight reactions to impending danger, pain, or asphyxia. To study the role of the DRN 5-HT system in anxiety, we microinjected 8-OH-DPAT into the DRN to inhibit 5-HT release. This treatment impaired inhibitory avoidance (conditioned fear) without affecting one-way escape (unconditioned fear) in the elevated T-maze, a new animal model of anxiety. We also applied three drug treatments that increase 5-HT release from DRN terminals: 1) intra-DRN microinjection of the benzodiazepine inverse agonist FG 4172, 2) intra-DRN microinjection of the excitatory amino acid kainic acid, and 3) intraperitoneal injection of the 5-HT releaser and uptake blocker D-fenfluramine. All treatments enhanced inhibitory avoidance in T-maze. D-Fenfluramine and intra-DRN kainate also decreased one-way escape. In healthy volunteers, D-fenfluramine and the 5-HT agonist mCPP (mainly 5-HT2C) increased, while the antagonists ritanserin (5-HT2A/2C) and SR 46349B (5-HT2A) decreased skin conductance responses to an aversively conditioned stimulus (tone). In addition, D-fenfluramine decreased, whereas ritanserin increased subjective anxiety induced by simulated public speaking, thought to represent unconditioned anxiety. Overall, these results are compatible with the above hypothesis. Deakin and Graeff have suggested that the pathway connecting the median raphe nucleus (MRN) to the dorsal hippocampus promotes resistance to chronic, unavoidable stress. In the present study, we found that 24 h after electrolytic lesion of the rat MRN glandular gastric ulcers occurred, and the immune response to the mitogen concanavalin A was depressed. Seven days after the same lesion, the ulcerogenic effect of restraint was enhanced. Microinjection of 8-OH-DPAT, the nonselective agonist 5-MeO-DMT, or the 5-HT uptake inhibitor zimelidine into the dorsal hippocampus immediately after 2 h of restraint reversed the deficits of open arm exploration in the elevated plus-maze, measured 24 h after restraint. The effect of the two last drugs was antagonized by WAY-100135, a selective 5-HT1A receptor antagonist. These results are compatible with the hypothesis that the MRN-dorsal hippocampus 5-HT system attenuates stress by facilitation of hippocampal 5-HT1A-mediated neurotransmission. Clinical implications of these results are discussed, especially with regard to panic disorder and depression.
Activation of serotonin-1A receptors (5-HT(1A)R) in the medulla oblongata lowers sympathetic nerve discharge and blood pressure. Binding sites for 5-HT(1A)R ligands are present in ventral medullary nuclei [e.g., rostral ventrolateral medulla (RVLM), raphe pallidus (RPa), and parapyramidal region (PPR)] that project to sympathetic preganglionic neurons in the intermediolateral cell column (IML). However, the projections and the neurochemical contents of the ventral medullary neurons that are likely to be involved in the hypotensive actions of 5-HT(1A) agonists are unclear. Using a sheep antibody to a fragment of the third intracellular loop of the 5-HT(1A)R, we localized 5-HT(1A)R immunoreactivity (ir) to IML-projecting neurons that were retrogradely labeled with rhodamine beads injected into the IML of adult male rats. The percentages of IML-projecting neurons containing 5-HT(1A)R-ir were 49% in RPa, 34% in PPR, and 44% in RVLM. Using multiple-immunofluorescence labeling, we also demonstrated 5-HT(1A)R-ir in serotonergic (5-HT) and in catecholaminergic (tyrosine hydroxylase; TH-ir) neurons of the ventral medulla. The percentages of 5-HT-ir neurons containing 5-HT(1A)R-ir were 28% in RPa, 18% in PPR, and 31% in raphe obscurus. In addition, 5-HT(1A)R-ir was present in 14% of TH-ir neurons of the RVLM. Moreover, some IML-projecting neurons in the PPR and RPa were doubly immunolabeled for 5-HT(1A)R-ir and 5-HT, and some IML-projecting neurons in the RVLM were doubly immunolabeled for 5-HT(1A)R-ir and TH-ir. These data provide anatomical evidence for the presence of 5-HT(1A)R on serotonergic and catecholaminergic bulbospinal neurons and for their potential role in directly modifying the activity of these ventral medullary neurons.
The effects of the selective 5-HT(1A) agonist, 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OHDPAT) and the selective 5-HT(1A) antagonist, N-[2-[4-(2-methoxyphenyl)-1-piperzinyl]ethyl]-N-(pyridinyl) cyclohexanecarboxamide trichloride (WAY100635) on periaqueductal grey (PAG)-stimulated defence behaviour were tested in the rat. Microinjection of the excitatory amino acid, D, L-homocysteic acid (DLH) into the dorsal region of the PAG produced overt aversive behaviour characteristic of the defence response, consisting of explosive motor behaviours which were quantified in terms of their duration and the number of arena revolutions and jumps made by the animal. Intra-PAG pre-treatment with 8-OHDPAT (3, 10 and 25 nmol in 250 nl) 10 min before DLH stimulation significantly attenuated the defence behaviour. This could be reversed by peripheral application of WAY100635 (0.1 mg/kg). In contrast, peripheral 8-OHDPAT (0.03, 0.1 and 0.3mg/kg) produced a significant potentiation of the DLH response which could also be blocked by peripheral WAY100635. When WAY100635 (10 nmol in 250 nl) alone was given into the PAG a significant increase in DLH induced behaviours was observed whereas peripherally applied WAY100635 (0.1 mg/kg) was without effect. These data support previous findings which indicate that serotonergic modulation of aversive behaviours such as defence can be mediated by 5-HT(1A) receptors. Furthermore there is evidence to indicate a differential involvement of pre- and postsynaptic 5-HT(1A) receptors.
In coronal slices of rat midbrain localised injections of FluoroGold or DiO into the dorsolateral periaqueductal grey matter (PAG) labelled cells retrogradely in the dorsal half of the dorsal raphe nucleus (DRN) and the ipsilateral ventrolateral PAG. Low intensity electrical stimulation in the dorsolateral PAG (22.9 +/- 1.9 microA) evoked antidromic responses in neurones recorded intracellularly in the dorsal subnucleus of the DRN. Antidromic responses could also be evoked in neurones in the ventral DRN and its wings but only at much higher currents (40.9 +/- 2.5 microA) which likely spread to activate axons in the ventrolateral PAG that originated from perikarya in the ventral DRN. The findings are discussed in relation to modulation of the excitability of the aversive system in the dorsolateral PAG by the DRN.
Earlier results obtained in one of our laboratories showed that microinjection into the dorsal raphe nucleus (DRN) of the excitatory amino acid kainic acid, the benzodiazepine (BZD) inverse agonist FG 7142, and the 5-HT1A receptor agonist 8-OHDPAT changed the behavior of rats in the elevated T-maze, an animal model of anxiety. The present study investigates biochemical correlates of these results in awake rats by measuring 5-HT release with in vivo microdialysis in two brain structures innervated by the DRN-the amygdala (Am) and the dorsal periaqueductal gray matter (DPAG)-that have been implicated in anxiety. Microinjection of kainic acid (60 pmol) into the DRN significantly increased 5-HT release in both the Am and the DPAG. In the DPAG, the increase was 14-fold higher with respect to the baseline and occurred only at the first sample, which was collected 30 min after the injection. In the Am, the increase was less pronounced (nearly fourfold) but persistent, lasting until the fourth sample, which was collected 120 min from the injection. FG 7142 (40 pmol) and 8-OH-DPAT (8 nmol) were ineffective. Because only intra-DRN kainate both increased inhibitory avoidance and decreased one-way escape in the elevated T-maze, the present behavioral results support the suggestion that 5-HT facilitates conditioned fear in the Am and inhibits unconditioned fear in the DPAG.
Responses of central catecholaminergic systems as well as the Hypothalamic-Pituitary-Adrenocortical (HPA) axis vary during exposure to different stressors. Extracellular norepinephrine (NE) levels in the paraventricular nucleus (PVN) increase markedly with immobilization (IMMO) or with formalin (FORM)-induced pain and relatively little with insulin (INS)-induced hypoglycemia, cold (COLD) stress, or hemorrhage (HEM). Levels of 3,4-dihydroxyphenylacetic acid, a metabolite of dopamine, increase in the locus ceruleus with IMMO or ether but are unchanged during INS-induced hypoglycemia. These and other findings have led to the hypothesis of the existence of stressor-specific central noradrenergic pathways participating in regulation of the HPA axis. In the study described in this chapter, conscious rats have been exposed to one of several stressors-HEM, i.v. INS, s.c. FORM, COLD, or IMMO. Fos immunoreactivity of the immediate early gene c-fos was used to investigate changes in the activity of brain stem neurons. The results were correlated with previous findings about stress-induced central noradrenergic activation in the PVN using in vivo microdialysis and simultaneous measurements of plasma adrenocorticotropic hormone (ACTH) levels. The present results indicate that the magnitude of activation of c-fos in brain catecholaminergic regions and of PVN corticotrophin releasing hormone (CRH) neurons varies widely across stressors. The findings support the notion of stressor-specificity of responses of central catecholaminergic systems and the HPA axis and indicate that different central pathways regulate HPA reactivity.
Pharmacological results obtained in animals tested in approach/avoidance conflict situations have led to the suggestion that 5-HT enhances anxiety by acting on forebrain structures. In contrast, results with intracerebral drug injection associated with aversive electrical brain stimulation indicate that 5-HT inhibits aversion in the dorsal periaqueductal gray (DPAG). To reconcile this evidence, it has been suggested that 5-HT may enhance conditioned fear in the amygdala while inhibiting innate fear in the DPAG. To test this hypothesis, we used three drug treatments known to increase the release of 5-HT from terminals of the dorsal raphe nucleus (DR): (1) intra-DR microinjection of the benzodiazepine inverse agonist FG 7142, (2) intra-DR microinjection of the excitatory amino acid kainic acid and (3) intraperitoneal injection of the 5-HT releaser and uptake blocker D-fenfluramine. All drug treatments enhanced inhibitory avoidance (learned fear) in the elevated T-maze, a new animal model of anxiety. Intra-raphe kainate and D-fenfluramine also decreased one-way escape (innate fear) in the T-maze. In contrast, reduction of 5-HT release by intra-DR injection of 8-OH-DPAT impaired inhibitory avoidance without affecting one-way escape. Overall, these results agree with the above hypothesis. Clinical implications are discussed, especially with regard to panic disorder.
Glucose is a major fuel for body energy metabolism and an essential metabolic fuel for the brain. Consequently, glucose deficit (glucoprivation) elicits a variety of physiological and behavioral responses crucial for survival. Previous work indicates an important role for brain catecholamine neurons in mediation of responses to glucoprivation. This experiment was conducted to identify the specific catecholamine neurons that are activated by glucoprivation. Activation of hindbrain catecholamine neurons by the antimetabolic glucose analogue, 2-deoxy-D-glucose (2DG; 50, 100, 200 or 400 mg/kg, s.c.) was evaluated using double label immunohistochemistry. Fos protein was used as the marker for neuronal activation and the enzymes tyrosine hydroxylase (TH) and phenethanolamine-N-methyl transferase (PNMT) were used as the markers for norepinephrine (NE) and epinephrine (E) neurons. 2-Deoxy-D-glucose (200 and 400 mg/kg) produced selective activation of distinct hindbrain catecholamine cell groups. In the ventrolateral medulla, doubly labeled neurons were concentrated in the area of A1/C1 and were predominantly adrenergic in phenotype. In the dorsal medulla, doubly labeled neurons were limited to C2 and C3 cell groups. In the pons, some A6 neurons were Fos-positive. Neurons in rostral C1, ventral C3, A2, A5 and A7 did not express Fos-ir in response to 2DG. Our results identify specific subpopulations of catecholamine neurons that are selectively activated by 2DG. Previously demonstrated connections of these subpopulations are consistent with their participation in the feeding and hyperglycemic response to glucoprivation. Finally, the predominant and seemingly preferential activation of epinephrine neurons suggests that they may play a unique role in the brain's response to glucose deficit.
Stimulation of the dorsal raphe nucleus (DRN) alters arterial pressure, heart rate and cerebral blood flow, yet projections from the DRN to medullary autonomic nuclei have not been described. We examined whether serotonergic (5-HT) projections from the DRN terminate in the rostral ventrolateral medulla (RVL) and if so, whether the projection mediates cardiovascular responses to DRN stimulation. Studies were performed in adult male Sprague-Dawley rats. Horseradish peroxidase or choleratoxin B was injected unilaterally or bilaterally into the RVL. Levels of 5-HT, its precursors L-tryptophan and 5-hydroxytryptophan and the metabolite 5-hydroxyindole acetic acid were measured in the ventral medulla by HPLC three weeks following placement of electrolytic lesions in DRN. Serotonin transporter (3H-cyanoimipramine binding) was quantified by autoradiography in DRN-lesioned animals. Horseradish peroxidase or choleratoxin B injections into the medulla at the level of the RVL resulted in retrogradely labeled neurons bilaterally, with ipsilateral predominance, in the DRN. Labeled cells were preponderant in rostral ventrolateral portions of the DRN, but were also observed in the dorsal, lateral and interfascicular DRN subnuclei; fewer neurons were observed in caudal portions of the DRN. Three weeks following placement of electrolytic lesions in the DRN, the concentrations of 5-HT and 5-hydroxyindole acetic acid, but not L-tryptophan or 5-hydroxytryptophan, were reduced in the medulla by 45 and 48%, respectively, compared to sham-operated or unoperated controls. DRN lesions reduced binding to the 5-HT transporter in the RVL by approximately 30% compared to unlesioned controls. Unilateral lesions of the RVL reduced the evoked blood pressure response by 53+/-15%; bilateral RVL lesions reduced the response by 86+/-9%. The increase in cortical blood flow elicited by DRN stimulation was unchanged after unilateral or bilateral RVL lesions. These studies demonstrate that there is a descending serotonergic projection from the DRN to the RVL. This projection may mediate autonomic changes elicited by DRN stimulation.
In the present study, renal sympathetic nerve activity was recorded simultaneously with sympathetic nerve activity to skeletal muscle vasculature to determine if the sympatho-inhibition evoked by microinjection of the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)teralin (8-OH-DPAT) into the rostroventrolateral medulla (RVLM) was uniform or regional. Three patterns of sympatho-inhibition were observed in these sympathetic outflows and the type of response depended upon location of microinjection within the subretrofacial nucleus (SRF). Inhibition of renal nerve activity only was elicited by microinjections at rostral sites at the caudal pole of the facial nucleus. In contrast, inhibition of muscle sympathetic nerve activity was evoked from more caudal injections at the rostral pole of the inferior olives. Microinjection in the area between these two regions produced inhibition of both sympathetic outflows. This study demonstrates that differential inhibition of regional sympathetic outflows can be elicited by microinjection of the 5-HT1A receptor agonist 8-OH-DPAT into the RVLM. These data suggests that this modulation is due to differences in anatomical arrangement of the medullary neurons rather than differences in neuron sensitivity to the serotonergic agonist.
Phenylethanolamine-N-methyltransferase (PNMT)-containing neurons in the rostral ventrolateral medulla (RVLM) are believed to play a role in cardiovascular regulation. To determine whether injection of anti-dopamine beta-hydroxylase (DbetaH)-saporin directly into the RVLM in rats could selectively destroy these cells and thereby provide an approach for evaluating their role in cardiovascular regulation, we studied rats 2 wk after unilateral injection of 21 ng anti-DbetaH-saporin into the RVLM. There was an approximately 90% reduction in the number of PNMT-positive neurons in the RVLM, although the number of non-C1, spinally projecting barosensitive neurons of this area was not altered. The A5 cell group was the only other population of DbetaH-containing cells that was significantly depleted. The depressor response evoked by injection of tyramine into the RVLM was abolished by prior injection of toxin. The pressor response evoked by injection of glutamate into the RVLM was attenuated ipsilateral to the toxin injection but was potentiated contralateral to the toxin injection. Thus anti-DbetaH-saporin can be used to make selective lesions of PNMT-containing cells, allowing for the evaluation of their role in cardiovascular regulation.
Results of an earlier study in healthy volunteers suggest that the serotonergic system is involved in anxiety-related mechanisms. We studied the influence of tryptophan depletion on the response to a 35% carbon dioxide challenge. Twenty-four panic disorder patients received a mixture of amino acids, either with or without tryptophan, under double-blind conditions. There was a significant increase in anxiety as well as in neurovegetative symptoms in the depletion group, compared to the placebo condition. Furthermore, when we compare the results of the placebo group with earlier panic provocation studies, it also seems that a balanced amino acid mixture might have a protective effect against a panic provocation. We conclude that the panic-enhancing effect of tryptophan depletion as well as the potential protective effect of tryptophan administration in panic disorder patients can be explained by the Deakin-Graeff theory of anxiety.
The role of 5-hydroxytryptamine 1A (5-HT(1A)) receptors located in the rostral ventrolateral medulla (RVLM) in the mediation of a sympathoinhibitory and depressor response elicited from the ventrolateral periaqueductal gray (vlPAG) matter of the midbrain was examined in pentobarbital sodium-anesthetized rats. Activation of neurons in the vlPAG evoked a decrease in renal and lumbar sympathetic nerve activities and a decrease in arterial blood pressure. After microinjection of the specific 5-HT(1A)-receptor antagonist WAY-100635 into the pressor area of the RVLM, the vlPAG-evoked sympathoinhibition and hypotension was attenuated to control levels (7 of 15 animals) or converted into a sympathoexcitation and pressor response (8 of 15 animals). Baroreflex inhibition of sympathetic nerve activity was not impaired by microinjection of WAY into the sympathoexcitatory region of the RVLM. These data suggest that sympathoinhibition and hypotension elicited by activation of neurons in the vlPAG are mediated by 5-HT(1A) receptors in the RVLM.
Electrical stimulation of the dorsal periaqueductal gray (DPAG) has been used to induce panic-like behavior in rats. In the present study, we investigated the effect of chronic imipramine treatment on the sensitivity of different 5-HT receptor subtypes in inhibiting aversion induced by electrical stimulation of this brain area. For that, the effects of intra-DPAG administration of the endogenous agonist 5-HT (20 nmol), the 5-HT(1A) receptor agonist 8-OH-DPAT (8 nmol) and the 5-HT(2A/2C) receptor agonist DOI (16 nmol) were measured in female Wistar rats given either chronic injection of imipramine (15 mg/kg, 3 weeks, ip) or saline. The results showed that the three receptor agonists raised the threshold of aversive electrical stimulation in both groups of animals, but this antiaversive effect was significantly higher in rats treated with imipramine. Treatment with imipramine did not change the basal threshold of aversive electrical stimulation measured before intra-DPAG injection of the 5-HT agonists. The results suggest that sensitization of both 5-HT(1A) and 5-HT(2) receptors within the DPAG may be involved in the beneficial effect of imipramine in panic disorder (PD).
Double-label fluoresence immunohistochemistry was performed to define serotonergic projections from the raphe and midbrain to the sympathoexcitatory region of the rostroventrolateral medulla (RVLM). Immunolabelling of cholera toxin B subunit retrogradely transported from the pressor region of the RVLM was combined with serotonin (5-HT) immunohistochemistry. Major sources of serotonergic input to the RVLM were shown to include the raphe obscurus, raphe pallidus and raphe magnus with a minor contribution from the ventrolateral, lateral and ventral regions of the periaqueductal gray matter, and the dorsal raphe nucleus. Serotonergic modulation of sympathoexcitatory neurons may establish patterns of sympathetic nerve activity evident in many aspects of cardiovascular regulation.
Serotonergic systems play an important role in the regulation of behavioural, autonomic and endocrine responses to stressful stimuli. This includes modulation of both the hypothalamic-pituitary-adrenal (HPA) axis and the hypothalamic-spinal-adrenal (HSA) axis, which converge at the level of the adrenal cortex to regulate glucocorticoid secretion. Paradoxically, serotonin can either facilitate or inhibit HPA axis activity and stress-related physiological or behavioural responses. A detailed analysis of the brainstem raphé complex and its ascending projections reveals that facilitatory and inhibitory effects of serotonergic systems on glucocorticoid secretion may be due to influences of topographically organized and functionally diverse serotonergic systems. (i) A serotonergic system arising from the middle and caudal dorsal raphé nucleus and projecting to a distributed central autonomic control system and a lateral 'emotional motor system'. Evidence suggests that serotonin can sensitize this subcortical circuit associated with autonomic arousal, anxiety and conditioned fear. (ii) A serotonergic system arising from the median raphé nucleus and projecting extensively and selectively to a ventral subiculum projection system. Evidence suggests that serotonin facilitates this limbic circuit associated with inhibition of ultradian, circadian and stress-induced activity of both the HPA axis and the HSA axis. These new perspectives, based on functional anatomical considerations, provide a hypothetical framework for investigating the role of serotonergic systems in the modulation of ultradian, circadian and stress-induced neuroendocrine function.
Previous research showed that lowering the availability of serotonin to the brain by tryptophan depletion increases the vulnerability of panic disorder patients for an experimental 35% CO(2) panic challenge. The results also suggested that increased availability of serotonin inhibits the response to such a challenge. In the present study, this latter possibility is examined. The reaction of 24 panic disorder patients and 24 healthy volunteers to a 35% CO(2) panic challenge was assessed following administration of 200-mg L-5-hydroxytryptophan (the immediate precursor of serotonin) or placebo. L-5-Hydroxytryptophan significantly reduced the reaction to the panic challenge in panic disorder patients, regarding subjective anxiety, panic symptom score and number of panic attacks, as opposed to placebo. No such effect was observed in the healthy volunteers. L-5-Hydroxytryptophan acts to inhibit panic, which supports a modulatory role of serotonin in panic disorder.
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