Extracellular Levels Of Noradrenaline Research Articles

Generation of locus coeruleus norepinephrine neurons from human pluripotent stem cells.

Central norepinephrine (NE) neurons, located mainly in the locus coeruleus (LC), are implicated in diverse psychiatric and neurodegenerative diseases and are an emerging target for drug discovery. To facilitate their study, we developed a method to generate 40-60% human LC-NE neurons from human pluripotent stem cells. The approach depends on our identification of ACTIVIN A in regulating LC-NE transcription factors in dorsal rhombomere 1 (r1) progenitors. In vitro generated human LC-NE neurons display extensive axonal arborization; release and uptake NE; and exhibit pacemaker activity, calcium oscillation and chemoreceptor activity in response to CO2. Single-nucleus RNA sequencing (snRNA-seq) analysis at multiple timepoints confirmed NE cell identity and revealed the differentiation trajectory from hindbrain progenitors to NE neurons via an ASCL1-expressing precursor stage. LC-NE neurons engineered with an NE sensor reliably reported extracellular levels of NE. The availability of functional human LC-NE neurons enables investigation of their roles in psychiatric and neurodegenerative diseases and provides a tool for therapeutics development.

Combined α2- and D2-receptor blockade activates noradrenergic and dopaminergic neurons, but extracellular dopamine in the prefrontal cortex is determined by uptake and release from noradrenergic terminals.

Experimental and clinical evidence indicates a deficit of release and function of dopamine in schizophrenia and suggests that α2-adrenoceptor antagonists rescue dopamine deficit and improve the antipsychotic efficacy of D2-receptor antagonists. In anesthetized male rats, we investigated how the blockade of α2- and D2-receptors by atipamezole and raclopride, respectively, modified the firing of noradrenergic neurons in the locus coeruleus (LC) and dopaminergic neurons in the ventral tegmental area (VTA). In freely moving rats, we studied how atipamezole and raclopride modified extracellular noradrenaline, dopamine, and DOPAC levels in the medial prefrontal cortex (mPFC) through microdialysis. When administered alone, atipamezole activated LC noradrenaline but not VTA dopamine cell firing. Combined with raclopride, atipamezole activated dopamine cell firing above the level produced by raclopride. Atipamezole increased extracellular dopamine to the same level, whether administered alone or combined with raclopride. In the presence of the noradrenaline transporter (NET) inhibitor, atipamezole combined with raclopride increased extracellular dopamine beyond the level produced by either compound administered alone. The results suggest that a) the D2-autoreceptor blockade is required for LC noradrenaline to activate VTA cell firing; b) the level of dopamine released from dopaminergic terminals is determined by NET; c) the elevation of extracellular dopamine levels in the mPFC is the resultant of dopamine uptake and release from noradrenergic terminals, independent of dopaminergic cell firing and release; and d) LC noradrenergic neurons are an important target for treatments to improve the prefrontal deficit of dopamine in neuropsychiatric pathologies.

In vivo microdialysis shows differential effects of prenatal protein malnutrition and stress on norepinephrine, dopamine, and serotonin levels in rat orbital frontal cortex.

Prenatal protein malnutrition (PPM) alters the developing brain including changes in monoaminergic systems and attention. In the present study, we used in vivo microdialysis to examine the relationship between PPM, acute stress, and extracellular serotonin (5HT), dopamine (DA) and norepinephrine (NE) in both hemispheres of lateral orbital frontal cortices (lOFC) in the adult rat. We hypothesized that prenatal protein malnutrition would alter extracellular concentrations of cortical monoamines. The effects of an acute restraint stress were also assessed because PPM alters the brain's response to stress. We used adult male, Long-Evans rats [10 prenatally malnourished (6% casein) and 10 prenatally well-nourished (25% casein)]. Samples were collected from the left and right hemispheres of the lOFC every 20 min for 6 hr total and quantified using high-performance liquid chromatography (HPLC). After 2 hr of sampling, animals were exposed to a 40-min restraint stress. Extracellular levels of NE were significantly higher in PPM animals than in well-nourished controls across both hemispheres at all time-points. In contrast, baseline levels of 5HT and DA levels did not differ between nutritional groups. 5HT levels, but not NE or DA levels, were elevated compared to baseline levels in both nutritional groups and in both hemispheres during the first 20 min of stress exposure. These data highlight the impact of PPM on neuromodulatory systems and the profile of changes in response to acute stress. Additional studies are needed to determine how these basal and stress-related responses impact cognitive performance and whether these differences persist during cognitive testing. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Effect of combined treatment with aripiprazole and antidepressants on the MK-801-induced deficits in recognition memory in novel recognition test and on the release of monoamines in the rat frontal cortex

According to preclinical and clinical studies, the antidepressant-induced increase in the activity of atypical antipsychotics may efficiently improve the treatment of negative and some cognitive symptoms of schizophrenia. In the present study, we aimed to evaluate the effects of the antidepressants escitalopram and mirtazapine and the atypical antipsychotic drug aripiprazole, administered separately or in combination, on the MK-801-induced deficits in the recognition memory test and on the extracellular levels of monoamines and their metabolites in the rat frontal cortex.Based on the results of the behavioral tests, co-treatment with an ineffective dose of aripiprazole (0.1 mg/kg) and escitalopram (2.5 and 5 mg/kg) or mirtazapine (5 mg/kg) abolished the deficits evoked by MK-801 in the novel object recognition test, and those effects were blocked by the 5-HT1A receptor antagonist (WAY 100,635) or the dopamine D1 receptor antagonist (SCH 23,390). Moreover, co-treatment with aripiprazole (0.3 mg/kg) and escitalopram (5 mg/kg) significantly increased the levels of noradrenaline and serotonin, decreased the level of its metabolite, and did not alter level of dopamine, but decreased the levels of its metabolites. In addition, co-treatment with aripiprazole (0.3 mg/kg) and mirtazapine (10 mg/kg) significantly increased the level of noradrenaline, did not change the levels of dopamine and serotonin, but increased the levels of their metabolites. Based on these results, the increase in the extracellular levels of noradrenaline or serotonin in the cortex induced by co-treatment with an antidepressant and aripiprazole may be very important for the pharmacotherapy of negative and some cognitive symptoms of schizophrenia.

Regional Effects of Monoamine Transporter Blockers on Extracellular Monoamine Levels

Monoamine transporter inhibitors are used in the treatment of a number of psychiatric disorders, including major depression and ADHD, and have high abuse potential. These drugs increase extracellular levels of monoamines by blocking the reuptake of monoamines through their respective transporters. Although selective norepinephrine (NE), dopamine (DA) and serotonin (5‐HT) transporter inhibitors increase NE, DA and 5‐HT, respectively, through blockade of their cognate transporter, there is substantial evidence showing that these selective inhibitors can also block the reuptake of monoamines from non‐cognate transporters. For example, studies have shown that norepinephrine transporter (NET) inhibitors can increase extracellular NE and DA levels in the PFC and hippocampus. Studies have also shown increased extracellular NE, DA and 5‐HT levels in the PFC by administration of a selective serotonin reuptake inhibitor (SSRI). Moreover, studies from dopamine transporter (DAT) and serotonin transporter (SERT) KO mice have also shown that selective NET and SERT blockers can increase extracellular DA levels in both the PFC and striatum. Although these non‐selective effects have been reported, there has not been a systematic investigation of brain‐region specific effects of selective monoamine transporter inhibitors on extracellular monoamine levels. We therefore sought to determine the effects of selective inhibitors of monoamine transporters on extracellular monoamine levels in the prefrontal cortex (PFC), nucleus accumbens (NAcc) and dorsal striatum (dStr). We used an ex vivo neurotransmitter release assay to determine the dose‐dependent effects of a NET inhibitor, desipramine, a DAT inhibitor, GRB 12909 and a SERT inhibitor, fluoxetine, on extracellular NE, DA and 5‐HT from PFC, NAcc, and dStr slices of wild‐type (WT) mice. We also examined the dose‐dependent effects of amphetamine on extracellular monoamine levels in the brain regions of interest of WT mice. The findings from WT mice were subsequently compared to those obtained from DAT and NET knockout mice. The results show that selective blockade of NET, DAT and SERT increase extracellular levels of NE, DA, and 5‐HT respectively, as well as alter the extracellular levels of non‐selective monoamines in a brain‐region and genotype specific manner. These findings will guide future studies exploring how region‐specific changes in monoamine levels affect the activity of neuronal circuits, physiology and behavior.Support or Funding InformationBBRF/NARSAD Young Investigator award to Nikhil Urs

Acute restraint stress augments the rewarding memory of cocaine through activation of α1 adrenoceptors in the medial prefrontal cortex of mice

Stress augments the rewarding memory of cocaine, which plays a critical role in inducing cocaine craving. However, the neurobiological mechanisms underlying the enhancing effect of stress remain unclear. Here, we show that noradrenaline (NA) transmission in the medial prefrontal cortex (mPFC) mediates stress-induced enhancement of cocaine craving. When mice were exposed to acute restraint stress immediately before the posttest session of the cocaine-induced conditioned place preference (CPP) paradigm, the CPP score was significantly higher than that in non-stressed mice. Because extracellular NA levels have been reported to be increased in the mPFC during stress exposure, we assessed the effects of NA on mPFC layer 5 pyramidal cell activity. Whole-cell recordings revealed that NA application induces depolarization and a concomitant increase in spontaneous excitatory postsynaptic currents (sEPSCs). The NA effects were inhibited by terazosin, but not by yohimbine or timolol, and the sEPSC increase was not observed in the presence of tetrodotoxin, suggesting the involvement of postsynaptic α1, but not α2 or β, adrenoceptors in the NA effects. Additionally, intra-mPFC injection of terazosin before stress exposure attenuated the stress-induced increase in cocaine CPP. Intra-mPFC injection of phenylephrine, an α1 adrenoceptor agonist, before the posttest session without stress exposure significantly enhanced cocaine CPP. Furthermore, chemogenetic suppression of mPFC pyramidal cells with inhibitory DREADD (designer receptors exclusively activated by designer drugs) also suppressed the stress-induced CPP enhancement. These findings suggest that the stress-induced increase in NA transmission activates mPFC pyramidal cells via α1 adrenoceptor stimulation, leading to enhancement of cocaine craving-related behavior.

Neural mechanisms underlying stress-induced enhancement of cocaine craving behaviors

Stress potentiates craving for addictive drugs including cocaine. To elucidate neural mechanisms underlying this effect of stress, we developed an experimental paradigm combining cocaine-induced conditioned place preference (CPP) with a restraint stress. Acute restraint stress exposure immediately before posttest significantly increased cocaine CPP scores. It has been suggested that the extracellular noradrenaline (NA) level is increased by stress in the laterodorsal tegmental nucleus (LDT), which sends cholinergic projections to dopamine (DA) neurons in the ventral tegmental area (VTA), and medial prefrontal cortex (mPFC), which receives DA input from the VTA. Thus, we investigated the roles of NA in these brain regions. Intra-LDT injection of an α2 or a β adrenoceptor antagonist attenuated the stress-induced enhancement of cocaine CPP. In vitro whole-cell recordings revealed that α2 adrenoceptor stimulation reduced GABAergic inputs to LDT cholinergic neurons that were obtained from cocaine-, but not saline-, treated rats. On the other hand, α1, but not α2 or β, adrenoceptor stimulation excited mPFC pyramidal neurons. Intra-mPFC injection of an α1 adrenoceptor antagonist attenuated the stress-induced enhancement of cocaine CPP. Additionally, chemogenetic silencing of mPFC excitatory neurons also reduced the stress-induced enhancement of cocaine CPP. These findings suggest that stress-induced increases in neuronal activity of the LDT and mPFC may contribute to the enhancement of cocaine craving.

Melanin-concentrating hormone in the Locus Coeruleus aggravates helpless behavior in stressed rats

Animal studies have shown that antagonists of receptor 1 of Melanin-Concentrating Hormone (MCH-R1) elicit antidepressive-like behavior, suggesting that MCH-R1 might be a novel target for the treatment of depression and supports the hypothesis that MCHergic signaling regulates depressive-like behaviors. Consistent with the evidence that MCHergic neurons send projections to dorsal and median raphe nuclei, we have previously demonstrated that MCH microinjections in both nuclei induced a depressive-like behavior. Even though MCH neurons also project to Locus Coeruleus (LC), only a few studies have reported the behavioral and neurochemical effect of MCH into the LC.We studied the effects of MCH (100 and 200 ng) into the LC on coping-stress related behaviors associated with depression, using two different behavioral tests: the forced swimming test (FST) and the learned helplessness (LH). To characterize the functional interaction between MCH and the noradrenergic LC system, we also evaluated the neurochemical effects of MCH (100 ng) on the extracellular levels of noradrenaline (NA) in the medial prefrontal cortex (mPFC), an important LC terminal region involved in emotional processing.MCH administration into the LC elicited a depressive-like behavior evidenced in both paradigms. Interestingly, in the LH, MCH (100) elicited a significant increase in escape failures only in stressed animals. A significant decrease in prefrontal levels of NA was observed after MCH microinjection into the LC.Our results demonstrate that increased MCH signaling into the LC triggers depressive-like behaviors, especially in stressed animals. These data further corroborate the important role of MCH in the neurobiology of depression.

Acute Atomoxetine Selectively Modulates Encoding of Reward Value in Ventral Medial Prefrontal Cortex.

A recent neurocognitive model of attention-deficit hyperactivity disorder (ADHD) has proposed a primary deficit in reward function as well as in executive function to account for underlying neural substrates of ADHD symptoms. Atomoxetine has been widely used as a non-stimulant medication for ADHD with little abuse liability. Although animal studies have reported that atomoxetine increases extracellular levels of both noradrenaline and dopamine in the prefrontal cortex, which receives input from a mesocorticolimbic pathway involved in reward function, there have been few studies in humans concerning the effects of atomoxetine in terms of reward function. Therefore, we investigated whether a single dose of atomoxetine (acute atomoxetine) affects reward processing in healthy adults. We used functional magnetic resonance imaging and adopted the monetary incentive delay task to separately examine neural responses to monetary reward anticipation in the nucleus accumbens and outcome in the ventral medial prefrontal cortex (vmPFC). The experiment was designed as a randomized, placebo-controlled within-subjects cross-over trial. Fourteen healthy adults completed two series of studies, taking either atomoxetine or placebo. Atomoxetine significantly decreased vmPFC activation during gain outcome compared to placebo. In gain anticipation, however, atomoxetine did not show a significant increase in the nucleus accumbens activation compared with placebo. These results suggest that atomoxetine affects reward value encoding through selective modulation of vmPFC activity related to reward outcome. Therefore, such modulatory action may partly contribute to a therapeutic effect of atomoxetine for a group of ADHD patients with increased activity in vmPFC.

Acupuncture reduces nicotine-induced norepinephrine release in the hypothalamus via the solitary NMDA receptor/NOS pathway

Noradrenergic projections from the nucleus tractus solitarius (NTS) to the hypothalamic paraventricular nucleus (PVN) are involved in nicotine (Nic) dependence. Nic induces hypothalamic norepinephrine (NE) release through N-methyl-d-aspartate receptors (NMDARs) and nitric oxide in the NTS. However, acupuncture attenuates Nic withdrawal-induced anxiety. Therefore, this study investigated the effects of acupuncture on Nic-induced hypothalamic NE release. Rats received an intravenous infusion of Nic (90 μg/kg, over 60 s) and extracellular NE levels in the PVN were determined by in vivo microdialysis. Immediately after Nic administration, the rats were bilaterally treated with acupuncture at acupoint HT7 (Shen-Men) or PC6 (Nei-Guan), or a non-acupoint (tail) for 60 s. Acupuncture at HT7, but not at PC6 or the tail, significantly reduced Nic-induced NE release. However, this was abolished by a post-acupuncture infusion of either NMDA or sodium nitroprusside into the NTS. Additionally, acupuncture at HT7, but not the control points, prevented Nic-induced plasma corticosterone secretion and inhibited Nic-induced increases in the phosphorylation of neuronal nitric oxide synthase (nNOS) and endothelial NOS in the NTS. These findings suggest that acupuncture at HT7 reduces Nic-induced NE release in the PVN via inhibition of the solitary NMDAR/NOS pathway.

Role of Cortical Catecholamines in the Paradoxical Action of Psychostimulants

Attention deficit hyperactivity disorder (ADHD) affects young children and manifests symptoms such as hyperactivity, impulsivity and cognitive disabilities. The primary line of treatment for ADHD are the psychostimulant class of drugs including amphetamine (Adderall) and methylphenidate (Ritalin). Several theories have been postulated on the paradoxical calming effect of psychostimulants on ADHD patients, but even after decades of research, their exact mechanism of action is unknown. Clinical studies have shown reduced levels of dopamine (DA) receptor and DA transporters (DAT) in ADHD patients, presumably due to elevated caudate DA levels. Studies using the dopamine (DA) transporter (DAT) knockout mice, which have elevated striatal DA levels and are considered an animal model of ADHD, have suggested that the paradoxical calming effect of psychostimulants might be through the parallel actions of other monoamine neurotransmitters. On the other hand, newer non‐stimulant classes of drugs such as atomoxetine and Intuniv suggest that targeting the norepinephrine (NE) system might explain the paradoxical calming effect. Again, the molecular and cellular mechanisms of action for these drugs or neurotransmitters in ADHD therapy is unknown.Previous work has shown that DA levels in the PFC have a reciprocal effect on striatal DA levels and locomotion. Our preliminary data suggest that PFC D2+ pyramidal neurons project to the striatum and midbrain dopamine neurons and that infusion of D2 agonists in the PFC inhibits locomotion. We hypothesize that PFC DA through the action of PFC D2+ pyramidal neurons regulates striatal DA release and locomotion. To test our hypothesis we use ex vivo neurotransmitter release from mouse PFC slices, microdialysis and locomotor measurements, in NET and DAT knockout mice. Our preliminary data suggest that NET and SERT blockers not only increase extracellular levels of NE and 5HT, but also DA. These data suggest a possible role for cortical catecholamines in regulating the paradoxical effects of psychostimulants. Our future studies will not only shed light on the mechanism of psychostimulant action in ADHD therapy, but will facilitate development of newer therapies based on mechanistic evidence.Support or Funding InformationBrain Behavior Research Foundation 27765 to N. UrsThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Acid sphingomyelinase controls dopamine activity and responses to appetitive stimuli in mice

Alcohol use disorder and depression show a high comorbidity at clinical level with no treatment available selectively for this condition. A hyperfunction of acid sphingomyelinase (ASM) and resulting ceramide overload were recently identified as one pathway into this comorbidity. Here we analyzed the involvement of ASM, one of the main enzymes involved in ceramide synthesis, in the molecular control of monoaminergic systems in their basal activity and in response to pharmacological and natural reinforcers. The effects of alcohol and a palatable food on the extracellular levels of dopamine (DA), serotonin (5-HT), and noradrenaline (NE) were measured by in-vivo microdialysis in ASM overexpressing mice (tgASM). We found reduced basal extracellular DA levels in the nucleus accumbens (Nac) and dorsal hippocampus (DH) of tgASM mice with little effect on 5-HT and NE levels. In contrast, ASM overexpression potentiated the DA response to alcohol (2 g/kg, i.p.) in the DH and Nac, but reduced NE responses. DA and NE responses to a food stimulus were not altered in tgASM mice, but the Nac 5-HT response was enhanced.An immunohistochemical analysis of the DH showed a preserved dopaminergic and serotonergic innervation in tgASM mice and in mice that consumed alcohol for one month. These findings suggest a direct modulation of monoaminergic basal activity and/or responses to reinforcing stimuli by the sphingolipid regulatory enzyme ASM in mice.

Chronic methylphenidate preferentially alters catecholamine protein targets in the parietal cortex and ventral striatum

The psychostimulant methylphenidate (MPH) is the primary drug treatment for attention deficit hyperactivity disorder (ADHD) in children. MPH is well known to acutely block the dopamine (DAT) and noradrenaline (NET) transporters. Its effect on additional catecholamine targets is however less known. This study was aimed at comparing the effects of acute (2 mg/kg, i.p.) and chronic (2 mg/kg twice daily for 2 weeks) MPH treatment to young rats on key catecholamine protein targets in brain regions implicated in the symptoms and treatment of ADHD. For this purpose, the density of DAT, NET, the vesicular monoamine transporter 2 (VMAT2), the rate limiting enzyme for catecholamine synthesis tyrosine hydroxylase (TH) and the dopamine D1 receptor were measured in frontal (FC), parietal cortex (PCx) and the dorsal (DS) and ventral (VS) striatum. The data demonstrate that the effects of MPH depend on duration of treatment and brain region investigated. With the exception of DAT in the VS our results indicate that chronic but not acute administration of MPH increases levels of DAT, NET, TH, VMAT2 and D1. These effects were further more prominent in the VS over DS and in the PCx compared to the FC. In addition, chronic MPH enhanced DAT levels in the left DS but not in right side. To summarize, this study shows new evidence that chronic MPH to young rats preferentially alters catecholamine targets in PCx and VS over DS and FC. The effect of chronic MPH to increase levels of DAT, NET and VMAT2 suggests that the drug might long-term loose some of its acute action to increase extracellular levels of dopamine and noradrenaline. In conclusion, these findings provide novel insights into the mechanism of action by MPH in the treatment of ADHD and further suggest that the long-term effectiveness of the stimulant drug could be limited.

Roles of noradrenergic transmission within the ventral part of the bed nucleus of the stria terminalis in bidirectional brain-intestine interactions.

AimsThe bed nucleus of the stria terminalis (BNST) is a limbic structure mediating autonomic and neuroendocrine responses and negative affective states such as anxiety and fear. We previously demonstrated that noradrenergic transmission via β‐adrenoceptors within the ventral part of BNST (vBNST) is involved in bidirectional interactions between the brain and the upper gastrointestinal (GI) tract. The present study aimed to examine the roles of intra‐vBNST noradrenergic transmission via β‐adrenoceptors in bidirectional interactions between the brain and lower GI tract.MethodsIn vivo microdialysis experiments were performed to examine colorectal distention (CRD)‐induced noradrenaline release within the vBNST of freely moving male Sprague‐Dawley rats. Colonic transit and abdominal pain perception were examined following intra‐vBNST injections of isoproterenol, a β‐adrenoceptor agonist, with and without co‐administration of timolol, a β‐adrenoceptor antagonist.ResultsCRD increased extracellular noradrenaline levels within the vBNST and evoked abdominal contractions in a pressure‐dependent manner (30‐60 mm Hg). Bilateral intra‐vBNST injections of isoproterenol (30 nmol/side) significantly increased CRD (30 mm Hg)‐induced abdominal contractions. Intra‐vBNST injections of isoproterenol (30 nmol/side) significantly increased colonic transit, which was reversed by co‐administration of timolol (30 nmol/side).ConclusionThe results of this study suggest (a) the existence of a positive feedback loop between intra‐vBNST noradrenaline release and abdominal pain perception, and (b) the modulation of colonic motility by intra‐vBNST noradrenergic transmission via β‐adrenoceptors. Dysfunction of the lower GI tract may increase noradrenaline release within the vBNST, which, in turn, may exacerbate impairment of its motility and pain perception.

Effects of cariprazine on extracellular levels of glutamate, GABA, dopamine, noradrenaline and serotonin in the medial prefrontal cortex in the rat phencyclidine model of schizophrenia studied by microdialysis and simultaneous recordings of locomotor activity

RationaleAberrant glutamatergic, dopaminergic, and GABAergic neurotransmission has been implicated in schizophrenia. Cariprazine reverses the behavioral effects observed in the rat phencyclidine (PCP)-induced model of schizophrenia; however, little is known about its in vivo neurochemistry.ObjectivesThe study aims to compare the effects of cariprazine and aripiprazole on PCP-induced changes in the extracellular levels of glutamate, dopamine, serotonin, noradrenaline, and GABA in the rat medial prefrontal cortex (mPFC), and on locomotor activation.MethodsMicrodialysis was performed in awake rats with probes placed into the mPFC. Rats (n = 7/group) received vehicle (saline), cariprazine (0.05, 0.2, or 0.8 mg/kg), or aripiprazole (3 or 20 mg/kg) via gavage. After 60 min, 5 mg/kg PCP was administered intraperitoneally (i.p.). Samples were taken before drug administration, during pretreatment, and after PCP injection. Locomotor activity recording and microdialysis sampling occurred simultaneously.ResultsPCP treatment increased extracellular levels of all the neurotransmitters tested except GABA, for which there were no significant changes. Cariprazine and aripiprazole dose-dependently inhibited the PCP-induced increases of tested neurotransmitters. Overall effects were significant for higher cariprazine doses and both aripiprazole doses for glutamate and noradrenaline, for higher cariprazine doses and 20 mg/kg aripiprazole for dopamine, and for 0.8 mg/kg cariprazine and 20 mg/kg aripiprazole for serotonin and locomotor activity.ConclusionBoth cariprazine and aripiprazole dose-dependently attenuated PCP-induced hyperlocomotion and acute increases in glutamate, dopamine, noradrenaline, and serotonin levels in the mPFC; cariprazine was approximately 5-fold more potent than aripiprazole.

Bidirectional brain-gut interactions: Involvement of noradrenergic transmission within the ventral part of the bed nucleus of the stria terminalis.

IntroductionAlthough the important roles of bidirectional interactions between the brain and gut in stress and emotional responses have long been recognized, the underlying neuronal mechanisms remain unclear. The bed nucleus of the stria terminalis (BNST) is a limbic structure involved in stress responses and negative affective states, such as anxiety and depression. We have previously demonstrated that noradrenergic transmission within the ventral part of the BNST (vBNST) plays a crucial role in anxiety‐like behaviors and pain‐induced aversion.ObjectivesThis study aimed to examine the involvement of noradrenergic transmission via β‐adrenoceptors within the vBNST in bidirectional brain‐gut interactions.MethodsWe measured the gastric distention (GD)‐induced noradrenaline release within the vBNST of freely moving rats using an in vivo microdialysis technique. Gastric emptying and intestinal transit were examined following intra‐vBNST injections of isoproterenol, a β‐adrenoceptor agonist, in the absence or presence of the coadministration of timolol, a β‐adrenoceptor antagonist.ResultsGastric distention at a higher pressure (45 mm Hg) but not at a lower pressure (25 mm Hg) resulted in a significant increase in extracellular noradrenaline levels within the vBNST. Intra‐vBNST injections of isoproterenol (30 nmol/side) induced significant reductions in gastric emptying and small intestinal transit, both of which were reversed by the coadministration of timolol (30 nmol/side).ConclusionNoradrenergic transmission via β‐adrenoceptors within the vBNST was involved in bidirectional brain‐gut interactions. These findings suggest that gastric dysfunction may induce negative affective states via the enhanced release of noradrenaline within the vBNST which, in turn, may cause gastrointestinal impairments.

Methylphenidate induces state-dependency of social recognition learning: Central components.

Methylphenidate (MPH) is a widely prescribed drug for the treatment of attention-deficit hyperactivity disorder. Findings in the literature suggest that the effects of MPH on memory may result from increased extracellular levels of norepinephrine (NE) and dopamine (DA). Here, we report that the systemic administration of MPH before the acquisition phase in a social discrimination task impaired the retrieval of the social recognition memory (SRM), but made it state-dependent: another administration of MPH before the retention test recovered the SRM. We observed that the induction of state dependency by MPH relies on the ventromedial prefrontal cortex (vmPFC), but not on the CA1 region of the hippocampus (CA1). Also, the inhibitors of NE and DA, nisoxetine and GBR12909, respectively, restored the SRM when infused into the vmPFC. Only the GBR12909 was able to restore the SRM in the CA1, whereas nisoxetine could not restore and even caused an impairment on memory retrieval when infused alone before the retention test. The data suggest that the state-dependence of SRM induced by MPH depends on an influence of both catecholamines on the vmPFC, while NE inhibits the retrieval of SRM on the hippocampus.

Effects of α2A Adrenoceptors on Norepinephrine Secretion from the Locus Coeruleus during Chronic Stress-Induced Depression.

Chronic stressors can often lead to the development of psychological disorders, such as depression and anxiety. The locus coeruleus (LC) is a stress sensitive brain region located in the pons, with noradrenergic neurons that project to the hypothalamus, especially the paraventricular nucleus (PVN) of the hypothalamus. The purpose of this paper is to better understand how alpha 2A-adrenoceptors (α2A-ARs) and LC-hypothalamus noradrenergic system participate in the pathophysiological mechanism of depression. In vivo norepinephrine (NE) release in the PVN triggered by electrical stimulation in the LC was detected with carbon fiber electrodes in depression model of rats induced by chronic unpredictable mild stress (CUMS). Also, the extracellular level of NE in the PVN was measured by microdialysis in vivo without any stimulation in the LC. The alpha 2-adrenoceptor (α2-AR) antagonist yohimbine and α2A-ARs antagonist BRL-44408 maleate were systemically administered to rats to determine the effects of α2A-ARs on NE release in the PVN. The peak value of elicited NE release signals in the PVN induced by electrical stimulation in the LC in the CUMS rats were lower than that in the control rats. The extracellular levels of NE in the PVN of the CUMS rats were significantly less than that of the control rats. Intraperitoneal injection of yohimbine or BRL-44408 maleate significantly potentiated NE release in the PVN of the CUMS rats. The CUMS significantly increased protein expression levels of α2A-AR in the hypothalamus, and BRL-44408 maleate significantly reversed the increase of α2A-AR protein expression levels in the CUMS rats. Our results suggest that the CUMS could significantly facilitate the effect of α2-adrenoceptor-mediated presynaptic inhibition and decrease the release of NE in the PVN from LC. Blockade of the inhibitory action of excessive α2A-adrenergic receptors in the CUMS rats could increase the level of NE in the PVN, which is effective in the treatment of depressive disorders.

The effect of atomoxetine on random and directed exploration in humans.

The adaptive regulation of the trade-off between pursuing a known reward (exploitation) and sampling lesser-known options in search of something better (exploration) is critical for optimal performance. Theory and recent empirical work suggest that humans use at least two strategies for solving this dilemma: a directed strategy in which choices are explicitly biased toward information seeking, and a random strategy in which decision noise leads to exploration by chance. Here we examined the hypothesis that random exploration is governed by the neuromodulatory locus coeruleus-norepinephrine system. We administered atomoxetine, a norepinephrine transporter blocker that increases extracellular levels of norepinephrine throughout the cortex, to 22 healthy human participants in a double-blind crossover design. We examined the effect of treatment on performance in a gambling task designed to produce distinct measures of directed exploration and random exploration. In line with our hypothesis we found an effect of atomoxetine on random, but not directed exploration. However, contrary to expectation, atomoxetine reduced rather than increased random exploration. We offer three potential explanations of our findings, involving the non-linear relationship between tonic NE and cognitive performance, the interaction of atomoxetine with other neuromodulators, and the possibility that atomoxetine affected phasic norepinephrine activity more so than tonic norepinephrine activity.

Extinction memory is facilitated by methylphenidate and regulated by dopamine and noradrenaline receptors

Extinction is defined as the learned inhibition of retrieval and is the mainstay of exposure therapy, which is widely used to treat drug addiction, phobias and fear disorders. The psychostimulant, methylphenidate (MPH) is known to increase extracellular levels of noradrenaline and dopamine by blocking their reuptake and studies have demonstrated that MPH can modulate hippocampal physiology and/or functions including long-term potentiation (LTP), learning and memory. However, the influence of MPH on fear extinction memory has been insufficiently studied. Here we investigate the effect of MPH infused into the CA1 region of the hippocampus on extinction memory in animals normally incapable of showing contextual fear conditioning (CFC) extinction because of weak training, and the possible mechanisms through which it acts during this process. For this, male Wistar rats with infusion cannulae stereotaxically implanted in the CA1 region were submitted to a weak extinction protocol in a CFC apparatus. Animals that received intra-CA1 infusion of MPH (12.5μg/side) 20min before the extinction training (Ext Tr) expressed less freezing behavior than Veh-treated animals during both Ext Tr and extinction retention Test (Ext Test). Additionally, the administration of MPH+Timolol (1μg/side) or MPH+SCH23390 (1.5μg/side) intra-CA1 20min before the Ext Tr blocked the enhancing effect of the MPH on extinction learning. These results suggest that MPH in the CA1 region of the hippocampus is able to induce the consolidation of extinction memory and this process occurs through both β-adrenergic and D1/D5 dopaminergic receptors.