Norepinephrine Neuronal Activity Research Articles

Wistar Kyoto rats exhibit decreased serotonin neuronal firing and increased norepinephrine burst activity but dampened hippocampal α2-adrenoceptor sensitivity.

Wistar Kyoto (WKY) rats manifest abnormalities in the function of monoamine receptors and transporters, as well as levels of these neurotransmitters in the brain. The present study assessed alterations in the firing activity of serotonin (5-hydroxytryptamine [5-HT]), norepinephrine (NE), and dopamine (DA) neurons, as well as the activity of 5-HT and NE receptors and transporters in the hippocampus. In vivo electrophysiological recordings were conducted in male WKY and Wistar rats. Extracellular single-unit recordings of 5-HT, NE, and DA neurons were performed. Recordings of pyramidal neurons were conducted in the medial prefrontal cortex (mPFC) and the hippocampus, where direct application of 5-HT and NE by iontophoresis was also carried out. The mean firing rate of 5-HT neurons was significantly decreased in WKY compared to Wistar rats. The burst activity of NE neurons was significantly increased in WKY, while their mean firing activity was not changed. There was no alteration in the firing, burst, and population activity of DA neurons in WKY animals. In the hippocampus, a decrease in sensitivity of α2-adrenoceptors, but not 5-HT receptors, was observed. There was, however, no change in the activity of 5-HT and NE transporters. The firing activity of mPFC pyramidal neurons was similar in WKY versus Wistar rats. In WKY rats, there was a decrease in the firing activity of 5-HT neurons. There was also an enhanced burst activity of NE neurons, accompanied by a reduction in sensitivity of the α2-adrenoceptor in the hippocampus, inferring a decrease in NE transmission.

Ketamine promptly normalizes excess norepinephrine and enhances dopamine neuronal activity in Wistar Kyoto rats.

Ketamine acts primarily by blocking the N-methyl-D-aspartate (NMDA) receptor at the phencyclidine site. The rapid antidepressant properties of ketamine were demonstrated in the clinic and several behavioral models of depression in rodents. We hypothesized that the normalization of abnormal activity of monoamine neurons in Wistar Kyoto (WKY) rats contributes to the rapid antidepressant effects of ketamine. A single administration of ketamine (10mg/kg, i. p) or saline was administered to anesthetized WKY rats before in vivo electrophysiological recordings of dorsal raphe nucleus (DRN) serotonin (5-HT), locus coeruleus (LC) norepinephrine (NE) and ventral tegmental area (VTA) dopamine (DA) neuronal activity. Pyramidal neurons from the medial prefrontal cortex (mPFC) were also recorded before and after a ketamine injection. In the VTA, ketamine elicited a significant increase in the population activity of DA neurons. This enhancement was consistent with findings in other depression-like models in which such a decreased population activity was observed. In the LC, ketamine normalized increased NE neuron burst activity found in WKY rats. In the DRN, ketamine did not significantly reverse 5-HT neuronal activity in WKY rats, which is dampened compared to Wistar rats. Ketamine did not significantly alter the neuronal activity of mPFC pyramidal neurons. These findings demonstrate that ketamine normalized NE neuronal activity and enhanced DA neuronal activity in WKY rats, which may contribute to its rapid antidepressant effect.

Activation of locus coeruleus to rostromedial tegmental nucleus (RMTg) noradrenergic pathway blunts binge-like ethanol drinking and induces aversive responses in mice

There is strong evidence that ethanol entails aversive effects that can act as a deterrent to overconsumption. We have found that in doses that support the development of a conditioned taste aversion ethanol increases the activity of tyrosine hydroxylase (TH) positive neurons in the locus coeruleus (LC), a primary source of norepinephrine (NE). Using cre-inducible AAV8-ChR2 viruses in TH-ires-cre mice we found that the LC provides NE projections that innervate the rostromedial tegmental nucleus (RMTg), a brain region that has been implicated in the aversive properties of drugs. Because the neurocircuitry underlying the aversive effects of ethanol is poorly understood, we characterized the role of the LC to RMTg circuit in modulating aversive unconditioned responses and binge-like ethanol intake. Here, both male and female TH-ires-cre mice were cannulated in the RMTg and injected in the LC with rAVV viruses that encode for a Gq-expressing designer receptor exclusively activated by designer drugs (DREADDs) virus, or its control virus, to directly control the activity of NE neurons. A Latin Square paradigm was used to analyze both 20% ethanol and 3% sucrose consumption using the “drinking-in-the-dark” (DID) paradigm. Chemogenetic activation of the LC to RMTg pathway significantly blunted the binge-ethanol drinking, with no effect on the sucrose consumption, increased the emission of mid-frequency vocalizations and induced malaise-like behaviors in mice. The present findings indicate an important involvement of the LC to RMTg pathway in reducing ethanol consumption, and characterize unconditioned aversive reactions induced by activation of this noradrenergic pathway.This article is part of the special Issue on ‘Neurocircuitry Modulating Drug and Alcohol Abuse'.

Activation of Norepinephrine Neurons in the NTS (A2 population) is Sufficient to Suppress Pulsatile LH Secretion in Female Mice

The overarching goal of this work is to identify neural pathways underlying inhibition of pulsatile luteinizing hormone (LH) secretion during stress. Stress-induced suppression of LH secretion is mediated, at least in part, by suppression of arcuate kisspeptin (ARCKiss1) neurons. The mechanisms by which acute stress suppresses ARCKiss1 cell activity are largely unknown; however, several lines of evidence support the hypothesis that A2 neurons (norepinephrine [NE] neurons in the nucleus of the solitary tract [NTS] of the brainstem) are involved. First, A2 cells are activated during several reactive stress paradigms. Second, NE administered into the paraventricular nucleus, which is innervated by A2 neurons, suppressed pulsatile LH secretion. Finally, ablation of brainstem NE neurons restored estrous cyclicity following chronic glucoprivation (chronic metabolic stress model). The present study employed chemogenetics to test the hypothesis that A2 neurons are sufficient to suppress pulsatile LH secretion in ovariectomized female dopamine beta-hydroxylase (DBH) Cre positive and negative (wild type) mice. Mice received bilateral injections of either a Cre-dependent stimulatory Designer Receptor Exclusively Activated by Designer Drugs (DREADD) virus (AAV1-DIO-hM3Dq-mCherry) or a control virus (AAV1-DIO-mCherry) into the NTS. Mice were randomly assigned to receive either clozapine N-oxide (CNO, specific DREADD agonist; 1mg/kg, i.p.) or saline and blood samples were collected at 6-min intervals for 60 min before and 90 min after injection. Two weeks later, mice received the alternate treatment in a cross-over design (n= 5-10/grp). During the pre-injection period, all mice had clear LH pulses (mean: 6.0 ± 0.2 ng/mL, pulses/60 min: 3.4 ± 1.5). In DBH Cre- (wild type) mice with hM3D virus and DBH Cre+ with mCherry virus (both control groups), neither CNO nor saline altered mean LH or LH pulse frequency. However, DBH Cre+ mice with hM3D virus had a 54% reduction in mean LH (p < 0.05) and 59% reduction in pulse frequency (p < 0.05) following CNO; neither LH metric was altered in response to saline. To assess transduction efficiency, fixed neural tissue was collected. In tissue analyzed thus far, DBH Cre+ mice have mCherry labeling in ~70% of DBH-immunoreactive neurons in the NTS and >90% of mCherry neurons contained DBH immunoreactivity. Three DBH Cre+ mice with hM3D virus mice had no LH response to CNO and may represent missed viral injections, which will be determined when tissue is analyzed. These data demonstrate that activation of A2 neurons is sufficient to impair pulsatile LH secretion in female mice. Moreover, these data support the broad hypothesis that the A2 population of neurons is critical for modulating neuroendocrine function during stress and raises the possibility that A2 neurons directly or indirectly influence ARCKiss1 cell activity.

Repeated but Not Single Administration of Ketamine Prolongs Increases of the Firing Activity of Norepinephrine and Dopamine Neurons.

BackgroundClinical studies have shown that the rapid antidepressant effect of the glutamate N-methyl-D-aspartate receptor antagonist ketamine generally disappears within 1 week but can be maintained by repeated administration. Preclinical studies showed that a single ketamine injection immediately increases the firing and burst activity of norepinephrine (NE) neurons, but not that of serotonin (5-HT) neurons. It also enhances the population activity of dopamine (DA) neurons. In the present study, we investigated whether such alterations of monoamine neuronal firing are still present 1 day after a single injection, and whether they can be maintained by repeated injections.MethodsRats received a single ketamine injection or 6 over 2 weeks and the firing activity of dorsal raphe nucleus 5-HT, locus coeruleus NE, and ventral tegmental area DA neurons was assessed.ResultsOne day following a single injection of ketamine, there was no change in the firing activity of 5-HT, NE, or DA neurons. One day after repeated ketamine administration, however, there was a robust increase of the firing activity of NE neurons and an enhancement of burst and population activities of DA neurons, but still no change in firing parameters of 5-HT neurons. The increased activity of NE neurons was no longer present 3 days after the last injection, whereas that of DA neurons was still present. DA neurons were firing normally 7 days after repeated injections.ConclusionThese results imply that the enhanced activity of NE and DA neurons may play a significant role in the maintenance of the antidepressant action of ketamine.

Enhanced Retrieval of Taste Associative Memory by Chemogenetic Activation of Locus Coeruleus Norepinephrine Neurons.

The ability of animals to retrieve memories stored in response to the environment is essential for behavioral adaptation. Norepinephrine (NE)-containing neurons in the brain play a key role in the modulation of synaptic plasticity underlying various processes of memory formation. However, the role of the central NE system in memory retrieval remains unclear. Here, we developed a novel chemogenetic activation strategy exploiting insect olfactory ionotropic receptors (IRs), termed "IR-mediated neuronal activation," and used it for selective stimulation of NE neurons in the locus coeruleus (LC). Drosophila melanogaster IR84a and IR8a subunits were expressed in LC NE neurons in transgenic mice. Application of phenylacetic acid (a specific ligand for the IR84a/IR8a complex) at appropriate doses induced excitatory responses of NE neurons expressing the receptors in both slice preparations and in vivo electrophysiological conditions, resulting in a marked increase of NE release in the LC nerve terminal regions (male and female). Ligand-induced activation of LC NE neurons enhanced the retrieval process of conditioned taste aversion without affecting taste sensitivity, general arousal state, and locomotor activity. This enhancing effect on taste memory retrieval was mediated, in part, through α1- and β-adrenergic receptors in the basolateral nucleus of the amygdala (BLA; male). Pharmacological inhibition of LC NE neurons confirmed the facilitative role of these neurons in memory retrieval via adrenergic receptors in the BLA (male). Our findings indicate that the LC NE system, through projections to the BLA, controls the retrieval process of taste associative memory.SIGNIFICANCE STATEMENT Norepinephrine (NE)-containing neurons in the brain play a key role in the modulation of synaptic plasticity underlying various processes of memory formation, but the role of the NE system in memory retrieval remains unclear. We developed a chemogenetic activation system based on insect olfactory ionotropic receptors and used it for selective stimulation of NE neurons in the locus coeruleus (LC) in transgenic mice. Ligand-induced activation of LC NE neurons enhanced the retrieval of conditioned taste aversion, which was mediated, in part, through adrenoceptors in the basolateral amygdala. Pharmacological blockade of LC activity confirmed the facilitative role of these neurons in memory retrieval. Our findings indicate that the LC-amygdala pathway plays an important role in the recall of taste associative memory.

Triple reuptake inhibition of serotonin, norepinephrine, and dopamine increases the tonic activation of α2-adrenoceptors in the rat hippocampus and dopamine levels in the nucleus accumbens

Clinical studies have shown the therapeutic efficacy of an increase in dopamine (DA) transmission in treatment of major depressive disorder (MDD). In the present study, we investigated whether blockade of DA transporters in addition to serotonin (5-HT) and norepinephrine (NE) produced additional adaptations of monoaminergic systems. In vivo electrophysiological recordings were carried out in male anesthetized rats. Vehicle, the 5-HT reuptake inhibitor escitalopram, the NE/DA reuptake blocker nomifensine and their combination (triple reuptake inhibition; TRI) were delivered for 2 or 14 days. Firing activity of NE, 5-HT and DA neurons was assessed. Tonic activation of 5-HT1A receptors and α1- and α2-adrenoceptors was determined in the hippocampus and extracellular DA levels in the nucleus accumbens (NAc). Unlike escitalopram, nomifensine and TRI administration increased the tonic activation of α2-adrenoceptors in the hippocampus despite decreasing NE neuronal firing activity after 2 and 14 days of administration. The firing activity of 5-HT neurons was increased after prolonged nomifensine and TRI regimens, while addition of nomifensine to escitalopram prevented the early 2-day suppression of firing by 5-HT reuptake inhibition. The tonic activation of 5-HT1A receptors was enhanced only with escitalopram. Whereas escitalopram and nomifensine decreased firing activity of DA neurons after a 2-day administration, their combination normalized it to baseline level after 14 days; this was accompanied by a robust increase in extracellular DA levels in the NAc. In summary, these results indicate that TRI increases NE and DA but not 5-HT transmission, suggesting a differential efficacy profile in MDD patients.

Involvement of 5-HT1A and 5-HT2A Receptors but Not α 2-Adrenoceptors in the Acute Electrophysiological Effects of Cariprazine in the Rat Brain In Vivo.

Cariprazine, an orally active and potent dopamine D3-preferring D3/D2 receptor partial agonist, is approved to treat adults with schizophrenia (in the United States and Europe) and manic or mixed episodes associated with bipolar I disorder (in the United States). Cariprazine also displays partial agonism at serotonin [5-hydroxytryptamine (5-HT)] 5-HT1A receptors and antagonism at 5-HT2A and 5-HT2B receptors in vitro. The study objective was to determine whether cariprazine leads to functional alterations of monoamine systems in vivo via electrophysiological recordings from anesthetized rats. Dorsal raphe nucleus (DRN), locus coeruleus (LC), and hippocampus pyramidal neurons were recorded, and cariprazine was administered systemically or locally through iontophoresis. In the DRN, cariprazine completely inhibited the firing activity of 5-HT neurons, which was fully reversed by the 5-HT1A receptor antagonist, WAY100635. In the LC, cariprazine reversed the inhibitory effect of the preferential 5-HT2A receptor agonist, 2,5-dimethoxy-4-iodoamphetamine, on norepinephrine (NE) neurons (ED50 = 66 µg/kg) but did not block the inhibitory effect of the α 2-adrenergic receptor agonist, clonidine. Cariprazine, iontophorized into the hippocampus, diminished pyramidal neuronal firing through activation of 5-HT1A receptors, while its concomitant administration did not dampen the suppressant effect of 5-HT. These results indicate that, in vivo, cariprazine acted as a 5-HT1A autoreceptor agonist in the DRN, a 5-HT2A receptor antagonist in modulating the firing activity of LC NE neurons, and a full agonist at 5-HT1A receptors mediating the electrophysiological effect of 5-HT on pyramidal neurons. The modulatory actions of cariprazine on these monoaminergic systems may contribute to its therapeutic effectiveness in patients with depressive episodes.

Partial inhibition of catecholamine activity and enhanced responsiveness to NMDA after sustained administration of vortioxetine

Vortioxetine is a multimodal drug that blocks serotonin (5-HT) reuptake and directly modulates 5-HT receptors. The effects of subacute and long-term administration of vortioxetine on various aspects of catecholamine and glutamate systems were investigated using single-unit extracellular recordings and microiontophoresis in the rat brain. The firing rate of dopamine (DA) neurons was significantly decreased (26%) after 14, but not 4 days of vortioxetine administration (vortioxetine-containing chow, 1.8 g/kg vortioxetine). Same 14- and 4-day regimens of vortioxetine decreased the firing activity of norepinephrine (NE) neurons (by 27% and 41%, respectively). For DA and NE neurons, 14-day vortioxetine exposure also decreased the number of bursts per minute, without changing the number of spikes per burst, percentage of spike firing in burst and the number of spontaneously active neurons per track. However, this vortioxetine-induced suppression of DA and NE neuronal activity is less than that obtained in previous studies with the selective 5-HT reuptake inhibitor (SSRI) escitalopram. In the CA3 region of the hippocampus, 14 days of vortioxetine exposure did not change the sensitivity of postsynaptic α2-adrenoceptors nor did it increase the tonic activation of α1-and α2-adrenoceptors. Vortioxetine administration for 14 days increased the N-methyl-d-aspartate (NMDA)-, but not α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-evoked responses of CA3 pyramidal neurons. Taken together, the results of the current study suggest that vortioxetine might produce a lesser inhibition of DA and NE neuronal activity when compared to those induced by escitalopram as reported in previous studies.

The transition to reproductive senescence is characterized by increase in A6 and AVPV neuron activity with attenuation of noradrenaline content

During the course of life, cyclic females face a state of midlife transition that occurs in a fully functioning neurological system, and results in reproductive senescence. The authors' hypothesis was that changes in the activity noradrenergic neurons may be one of the factors involved in this phenomenon. The aim of this study was to investigate the activity of the neurons in the anteroventral periventricular nucleus (AVPV) and locus coeruleus (LC), to analyze their role in determining reproductive senescence. Adult female Wistar rats in the diestrus phase (4months/cyclic) and old females (18–20months/acyclic) in persistent diestrus, were decapitated or perfused at three different time intervals (10, 14 and 18h) throughout the day. In acyclic rats, the gonadotropin-releasing hormone (GnRH) and noradrenaline (NE) content were reduced; Fos-related antigen (FRA) in AVPV and Fos-related antigen/Tyrosine hydroxylase (FRA/TH) in LC showed immunolabeling of a higher number of neurons in these animals. The 3-methoxy-4-hydroxyphenylglycol/noradrenaline (MHPG/NE) ratio was higher and plasma LH was lower in the acyclic rats. Furthermore, the estradiol level was higher, and the progesterone level was lower after 14h of persistent diestrus. These findings suggested that during the periestropause, there was a higher level of POA/AVPV and NE neuronal activity in the LC of acyclic rats, associated with a lower capacity of synthesis and storage of neurotransmitters and neurohormones contributed to changes in the temporal pattern of neuroendocrine signaling, thereby compromising the accuracy of inhibitory and stimulatory effects, causing irregularity in the estrous cycle and determining reproductive senescence

Altered monoamine system activities after prenatal and adult stress: A role for stress resilience?

IntroductionPrenatal stress (PNS) and stress in adulthood are risk factors for development of major depressive disorder. The present study aimed to 1) confirm previous neuroendocrine and behavioral changes induced by PNS, and 2) to characterize the effect of early- and late life stress on the in vivo activity of monoamine systems. MethodsGestational dams were restrained thrice daily under bright illumination from gestational day (GD)11–20. Behavior and neuroendocrine responses to the forced swim test (FST) were determined in adult (50–80 days) offspring, and electrophysiological single unit recordings of dorsal raphe nucleus serotonin (5-HT), ventral tegmental area dopamine (DA) and locus coeruleus norepinephrine (NE) neurons were obtained at baseline and 24h after the FST. ResultsGestational dams did not habituate to chronic restraint stress, and PNS reduced the birth weight of offspring. In adulthood, swim stress elevated CORT levels longer in PNS animals, while it had no effect on swim behaviors. Baseline firing activity of 5-HT neurons was decreased in PNS animals, while the firing activity of NE and DA neurons was increased. Swim stress had no effect on the firing on 5-HT neurons, but normalized the firing activity of catecholamine neurons in PNS animals. ConclusionThe present data confirm previously established effects on neuroendocrine and physiological measures, and demonstrate an altering effect of PNS and stress on monoamine system activities in adulthood. Since PNS did not result in a depressive-like phenotype, these central changes following PNS might play reflect adaptive changes contributing to stress resilience in adulthood.

The Prevalence and Characteristics of REM Sleep without Atonia (RSWA) in Patients Taking Antidepressants.

The association of REM sleep without atonia (RSWA) as well as REM sleep behavior disorder (RBD) with the intake of selective serotonin reuptake inhibitors (SSRI) and selective norepinephrine reuptake inhibitors (SNRI) is well established. Our study objective was to determine the prevalence of RSWA and RBD among a group of sleep center patients taking SSRI and SNRI. A retrospective chart review was done at our tertiary sleep center, and 10,746 consecutive records from October 1, 2007, through October 31, 2013, were searched for SSRI and SNRI names using the Sleep Cataloguer Software. The search resulted in 1,444 records, which were then reviewed for keywords of RSWA and RBD. The AASM scoring criteria were used to determine RSWA. Reports of 41 patients with known narcolepsy or α-synucleinopathies were excluded. The remaining records were mined for age, sex, presence of obstructive sleep apnea (OSA), type of antidepressant (SSRI or SNRI), and diagnosis for which antidepressant was prescribed. We used logistic regression analysis to adjust for age, OSA, and sex. Of the 1,444 participants on antidepressants, 176 (12.2%) had RSWA (all confirmed by the investigators) compared to 226 of the entire sleep lab population of 10,746 (2.1%), risk ratio (95% CI) 9.978 (8.149, 12.22). Seven of the 176 patients on antidepressants had RBD (0.48%) compared to 108 of 10,746 (1%), p = 0.005. SSRI and SNRI are associated with a higher prevalence of RSWA but not of RBD. This is independent of medication type.

Increase in telencephalic dopamine and cerebellar norepinephrine contents by hydrostatic pressure in goldfish: the possible involvement in hydrostatic pressure-related locomotion

Fish are faced with a wide range of hydrostatic pressure (HP) in their natural habitats. Additionally, freshwater fish are occasionally exposed to rapid changes in HP due to heavy rainfall, flood and/or dam release. Accordingly, variations in HP are one of the most important environmental cues for fish. However, little information is available on how HP information is perceived and transmitted in the central nervous system of fish. The present study examined the effect of HP (water depth of 1.3m) on the quantities of monoamines and their metabolites in the telencephalon, optic tectum, diencephalon, cerebellum (including partial mesencephalon) and vagal lobe (including medulla oblongata) of the goldfish, Carassius auratus, using high-performance liquid chromatography. HP affected monoamine and metabolite contents in restricted brain regions, including the telencephalon, cerebellum and vagal lobe. In particular, HP significantly increased the levels of dopamine (DA) in the telencephalon at 15min and that of norepinephrine (NE) in the cerebellum at 30min. In addition, HP also significantly increased locomotor activity at 15 and 30min after HP treatment. It is possible that HP indirectly induces locomotion in goldfish via telencephalic DA and cerebellar NE neuronal activity.

Serotonin and beyond: therapeutics for major depression.

The serotonin (5-HT, 5-hydroxytryptamine) system has been implicated in the pathogenesis of major depressive disorder (MDD). The case for its contribution to the therapeutic efficacy of a wide variety of antidepressant treatments is, however, much stronger. All antidepressant strategies have been shown to enhance 5-HT transmission in the brain of laboratory animals. Catecholamines, norepinephrine (NE) and dopamine (DA) can also play a pivotal role in the mechanism of action of certain antidepressant strategies. The enhancement of 5-HT transmission by selective serotonin reuptake inhibitors, which leads to a dampening of the activity of NE and DA neurons, may account in part for the low remission rate achieved with these medications and/or the residuals symptoms after remission is achieved. The functional connectivity between the 5-HT, NE and DA systems can be used to understand the mechanism of action of a wide variety of augmentation strategies in treatment-resistant MDD. Proof-of-concept studies have shown that antidepressant medications with complementary mechanisms of action on monoaminergic systems can double the remission rate achieved in a trial of standard duration. Novel approaches are also being used to treat MDD, which also appear to involve the monoaminergic system(s) to a varying extent.

The noradrenergic symptom cluster: clinical expression and neuropharmacology

Signs and symptoms of depression can be linked to one or more monoaminergic systems, specifically the norepinephrine (NE), the dopamine (DA), and the serotonin (5-HT) systems. In particular, the modulation of energy, vigilance, and arousal can be directly linked to the NE system. There is, however, a great deal of overlap in the modulation of the symptoms of depression between these monoaminergic systems. There are considerable reciprocal interactions between the NE, DA, and the 5-HT systems. When using a selective serotonin reuptake inhibitor (SSRI), for example, 5-HT transmission is enhanced, but at the same time there is a dampening of the activity of NE and DA neurons through inhibitory 5-HT2A and 5-HT2C receptors, respectively. This could explain the residual symptoms of fatigue, lack of energy, and anhedonia, often seen after patients present an overall positive response to a SSRI. Using a dual 5-HT and NE reuptake inhibitor (SNRI), such as milnacipran, would result in an additional increase in NE activity. Futhermore, inhibiting NE reuptake increases DA availability in the frontal cortex since DA is mainly cleared by the NE transporters in several brain regions. A risk inherent in increased NE activity is that of provoking anxiety. This is avoided however by the attenuation of the phasic reactivity of the firing of NE neurons through prolonged administration of SSRI and SNRI.

Neuroendocrine and neurochemical impact of aggressive social interactions in submissive and dominant mice: implications for stress-related disorders

Social conflicts may engender stress-related behavioural and physiological disturbances in the victims of aggression. In addition, stress-like neurochemical changes and ensuing depressive and anxiety symptoms might also be evident in the perpetrators of aggressive acts. The present investigation assessed basal levels of circulating corticosterone and of brain serotonin (5-HT) and norepinephrine (NE) in pre-identified submissive and dominant mice. In addition, brain neurochemical changes were determined following a single or three 15-min aggressive episodes both in submissive mice and in those that dominated the aggressive interplay. Three minutes after single and repeated confrontations, plasma corticosterone levels and 5-HT utilization within the prefrontal cortex (PFC) and hippocampus were increased to a comparable extent in submissive and dominant animals. Interestingly, however, NE utilization within the PFC and hippocampus was augmented to a greater level in submissive mice. These results suggest that 5-HT neuronal functioning was generally responsive to aggressive events, irrespective of social rank, whereas NE neuronal activity within the PFC and hippocampus was more sensitive to the submissive/dominance attributes of the social situation. It is possible that NE and 5-HT variations associated with an aggressive experience contribute to depressive- and anxiety-like manifestations typically observed after such psychosocial stressors, particularly in submissive mice. However, given that 5-HT changes occur irrespective of social rank, these data suggest that a toll is taken on both submissive and dominant mice, leaving them vulnerable to stress-related pathology.

An inverse agonist of the histamine H 3 receptor improves wakefulness in narcolepsy: Studies in orexin −/− mice and patients

Narcolepsy is characterized by excessive daytime sleepiness (EDS), cataplexy, direct onsets of rapid eye movement (REM) sleep from wakefulness (DREMs) and deficiency of orexins, neuropeptides that promote wakefulness largely via activation of histamine (HA) pathways. The hypothesis that the orexin defect can be circumvented by enhancing HA release was explored in narcoleptic mice and patients using tiprolisant, an inverse H 3-receptor agonist. In narcoleptic orexin −/− mice, tiprolisant enhanced HA and noradrenaline neuronal activity, promoted wakefulness and decreased abnormal DREMs, all effects being amplified by co-administration of modafinil, a currently-prescribed wake-promoting drug. In a pilot single-blind trial on 22 patients receiving a placebo followed by tiprolisant, both for 1 week, the Epworth Sleepiness Scale (ESS) score was reduced from a baseline value of 17.6 by 1.0 with the placebo ( p > 0.05) and 5.9 with tiprolisant ( p < 0.001). Excessive daytime sleep, unaffected under placebo, was nearly suppressed on the last days of tiprolisant dosing. H 3-receptor inverse agonists could constitute a novel effective treatment of EDS, particularly when associated with modafinil.

Distinct electrophysiological effects of paliperidone and risperidone on the firing activity of rat serotonin and norepinephrine neurons

Paliperidone (9-OH-risperidone) is the main metabolite of the atypical antipsychotic risperidone. While both drugs are potent dopamine (D)2 antagonists, they have quantitative differential affinities for serotonin (5-HT) and norepinephrine (NE) receptor binding sites. The present study aimed to determine if paliperidone exerts distinct effects on 5-HT and NE neuronal activity from those of risperidone. Risperidone and paliperidone were administered to Sprague-Dawley rats. Neuronal activity of 5-HT and NE neurons was assessed using in vivo electrophysiology. Acute administration of risperidone but not paliperidone inhibited the firing of 5-HT neurons, as previously reported. This inhibition was partially antagonized by the NE reuptake inhibitor desipramine, by the 5-HT(1A) receptor antagonist WAY 100635, and completely reversed when both drugs were given consecutively. Risperidone inhibited the firing of 5-HT neurons after 2 and 14 days of administration, with or without escitalopram. Paliperidone did not alter the firing rate of NE neurons by itself, but it reversed the suppression of NE neurons induced by escitalopram, as it was previously reported for risperidone. These results indicate that although risperidone and paliperidone share a qualitatively similar receptor binding profile in vitro, they differentially alter the firing of 5-HT and NE neurons in vivo. The capacity of paliperidone to reverse the selective serotonin reuptake inhibitor (SSRI)-induced inhibition of NE neuronal firing, without interfering with the effect of SSRIs of 5-HT neuronal activity, suggests that paliperidone may be a very effective adjunct in SSRI-resistant depression.

Neurokinin 1 receptor antagonism requires norepinephrine to increase serotonin function

The present studies examined the role of norepinephrine (NE) system in mediating the enhancement of 5-HT function produced by neurokinin (NK)1 receptor antagonism. Dorsal raphe 5-HT and locus coeruleus NE neurons were recorded in vivo in mice lacking NK1 receptors in wildtype mice pretreated with the NK1 antagonist RP67580 and its inactive enantiomer RP 68651. RP67580 and RP68651 were also tested on 5-HT neurons of mice lacking the 5-HT 1A receptor. RP67580 increased the firing rate of 5-HT neurons in wildtype mice and in 5-HT 1A null mutant mice to the same degree, thus indicating that the mechanism by which NK1 antagonists enhances 5-HT firing is independent of 5-HT 1A receptors. NE neuronal burst activity was increased in NK1 null mutant and wildtype mice given RP67580, but not with RP68651. After NE depletion, RP67580 was ineffective in increasing 5-HT neuronal firing activity in NK1 wildtype mice, and the enhancement of 5-HT neuronal firing observed in NK1 null mutant mice was abolished. In conclusion, NE neurons are essential for the action of NK1 antagonists on 5-HT neurons. In addition, the desensitization of 5-HT 1A autoreceptors produced by NK1 receptor antagonism is not critical for enhancing 5-HT neuronal firing.

Effect of neurokinin-1 receptor antagonists on serotoninergic, noradrenergic and hippocampal neurons: Comparison with antidepressant drugs

Neurokinin-1 (NK1) receptor antagonists have been reported to possess antidepressant and anxiolytic properties in controlled trials. Since antidepressant and anxiolytic drugs act mainly by enhancing serotonin (5-HT) and norepinephrine (NE) neurotransmission in forebrain areas, the main focus of the present review is to critically examine the electrophysiological effects of NK1 receptor antagonists on serotoninergic and noradrenergic neurons, and then hippocampal neurons. It is concluded that NK1 antagonists increase the firing and burst activity of 5-HT neurons, increase burst activity of NE neurons, and modulate postsynaptic transmission at the hippocampus level. Further research is needed in order to develop more selective ligands for the human NK1 receptor and to gain better knowledge of required brain penetration and optimal pharmacodynamic conditions for their use in patients.