Dopaminergic and noradrenergic manipulation of anticipatory reward and probability event-related potentials.

Predicting what will happen in the future in terms of potential reward is essential in daily life. The aim of the current study was to investigate the neurotransmitter systems involved in the anticipation of reward value and probability. We hypothesized that dopaminergic and noradrenergic antagonism would affect anticipation of reward value and probability, respectively. Twenty-three healthy participants were included in a haloperidol (2 mg) × clonidine (0.150 mg) × placebo cross-over design and subjected to a Go/NoGo experimental task during which cues signaled the probability of subsequent target appearance. Reward value (amount of money that could be won for correct and fast responding to the target) as well as probability of target appearance was orthogonally manipulated across four task blocks. Cue-elicited EEG event-related potentials were recorded to assess anticipation of value and probability, respectively. The processing of reward value was affected by dopaminergic antagonism (haloperidol), as evidenced by reduction of the reward-related positivity and P300 to reward cues. This reduction was specifically significant for subjects with high baseline dopamine levels for the P300 and most pronounced for these subjects for the reward-related positivity. In contrast, the processing of reward probability was affected by noradrenergic antagonism (clonidine). In addition, both drugs reduced overall performance (omission rate, response speed variability). We conclude that at least anticipation of reward value and probability, respectively, is specifically affected by dopaminergic versus noradrenergic antagonism.

Effect of monoamine reuptake inhibition and α1 blockade on respiratory arrest and death following electroshock-induced seizures in mice.

OBJECTIVE: Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy. Although the mechanisms for SUDEP are incompletely understood, seizure-induced respiratory arrest (S-IRA) has been strongly and consistently implicated. A body of evidence indicates that serotonin (5-HT), a modulator of breathing, plays a critical role in SUDEP. Because the 5-HT and norepinephrine (NE) systems interact in many biologic processes and NE is known to modulate breathing and seizures, we hypothesized that NE may play a role in S-IRA and SUDEP. METHODS: We examined the effects of pharmacologic manipulation of 5-HT and NE on S-IRA and death following maximal electroshock (MES)-induced seizures in adult wild-type (WT) mice, genetically 5-HT neuron-deficient (Lmx1bf/f/p ) mice, and chemically NE neuron-deficient mice. Mice were treated with pharmacologic agents targeting the serotonergic and noradrenergic systems and subjected to seizure induction via MES while breathing was measured via whole-body plethysmography. RESULTS: S-IRA and death was reduced in WT mice with NE reuptake inhibitors (NRIs), reboxetine and atomoxetine, selective serotonin reuptake inhibitors (SSRIs), fluoxetine and citalopram, and the dual 5-HT/NE reuptake inhibitor (SNRI), duloxetine. S-IRA and death was also reduced in Lmx1bf/f/p mice with reboxetine and fluoxetine. The protective effects of the reuptake inhibitors were prevented by the α1 antagonist, prazosin. Citalopram did not reduce S-IRA and death in NE neuron-deficient mice. SIGNIFICANCE: These data suggest that 5-HT and NE critically interact in the modulation of breathing following a seizure and potentially inform preventive strategies for SUDEP.

Noradrenergic targets for the treatment of alcohol use disorder.

The role of norepinephrine (NE) in the development of alcohol use disorder (AUD) has been studied over the past several decades. However, the NE system has been largely ignored for many years as a potential target for medication development for AUD. More recently, preclinical and clinical studies have demonstrated the potential value of targeting NE signaling for developing new pharmacological treatments for AUD. This review contributes to a special issue of Psychopharmacology focused on promising targets for alcohol addiction. Specifically, this review coalesces preclinical and clinical neuroscience that re-evaluate the noradrenergic system, and in particular the alpha-1 receptor, as a potential target for AUD.

Role of catalpol in ameliorating the pathogenesis of experimental autoimmune encephalomyelitis by increasing the level of noradrenaline in the locus coeruleus.

The endogenous neurotransmitter, noradrenaline, exerts anti-inflammatory and neuroprotective effects in vivo and in vitro. Reduced noradrenaline levels results in increased inflammation and neuronal damage. The primary source of noradrenaline in the central nervous system is tyrosine hydroxylase (TH)­positive neurons, located in the locus coeruleus (LC). TH is the rate­limiting enzyme for noradrenaline synthesis; therefore, regulation of TH protein expression and intrinsic enzyme activity represents the central means for controlling the synthesis of noradrenaline. Catalpol is an iridoid glycoside purified from Rehmannia glutinosa Libosch, which exerts a neuroprotective effect in multiple sclerosis (MS). The present study used an experimental mouse model of autoimmune encephalomyelitis to verify the neuroprotective effects of catalpol. Significant improvements in the clinical scores were observed in catalpol­treated mice. Furthermore, catalpol increased TH expression and increased noradrenaline levels in the spinal cord. In primary cultures, catalpol exerted a neuroprotective effect in rat LC neurons by increasing the noradrenaline output. These results suggested that drugs targeting LC survival and function, including catalpol, may be able to benefit patients with MS.

Pharmacological Modulation of Mucosa-Related Impairment of ß-Adrenoceptor-Mediated Relaxation in Human Detrusor.

OBJECTIVES: The mucosa of human detrusor strips impairs catecholamine-induced relaxation. In order to elucidate which signal transduction pathways are involved in this cross talk between the mucosa and detrusor, we have studied the effects of several pharmacological agonists and antagonists on noradrenaline-mediated relaxation in intact and mucosa-denuded detrusor strips. PATIENTS AND METHODS: Strips of detrusor tissue were obtained from patients who had undergone cystectomy for bladder cancer and were set up for force measurement. KCl- or carbachol-precontracted strips were relaxed with increasing concentrations of noradrenaline in the absence and in the presence of nitric oxide synthase inhibitor, L-NAME; P2X-receptor antagonist, PPADS; ETA-receptor antagonist, BQ-123; ETB-receptor antagonist, BQ-788; cyclooxygenase inhibitor, diclofenac; AT1-receptor antagonist, candesartan; and NK1-receptor antagonist, L-703,606. RESULTS: In intact strips, KCl-stimulated force was enhanced by all blockers; carbachol-stimulated force increased with L-703,606. In denuded strips, only L-NAME augmented the KCl-stimulated contraction. Noradrenaline relaxed the precontracted detrusor strips to a significantly larger extent and at lower concentrations in denuded than in intact strips. L-NAME, PPADS and BQ-123/BQ-788 had little effect on noradrenaline-induced relaxation, whereas diclofenac, candesartan and L-703,606 sensitized intact carbachol-stimulated detrusor strips to noradrenaline-induced relaxation. CONCLUSION: Inhibition of the noradrenaline-induced relaxation of precontracted human detrusor strips by the mucosa is attenuated by diclofenac, candesartan and L-703,606 suggesting the involvement of prostanoids, angiotensin and neurokinin pathways. Further experiments are required to unravel the exact mechanisms.

The role of adrenoceptors in the central nervous system in male and female rat sexual behavior.

Three different phases can be distinguished in rats' sexual cycle, the introductory (precopulatory), the copulatory and the executive (ejaculatory) phases. In this review, a new analysis of existing pharmacological data is made, both in male and female rats, in which the different aspects of sexual behavior are taken into account. An effort is made to distinguish pharmacological effects on sexual behavior from a possible physiological role of noradrenaline. In addition, new data on the role of α2-adrenoceptors on female sexual behavior is presented. The new analysis suggests that noradrenaline has a stimulatory role on the executive phase of male sexual behavior, while the introductory and copulatory phases remain unaffected. Adrenoceptors play a role in the regulation of sexual behavior in the medial preoptic area and the lateral septum. In female rats, noradrenaline also does not play a vital role in the introductory phase. Only the lordosis behavior of the copulatory phase is sometimes affected by adrenergic agents, but only under a certain hormonal condition. The medial preoptic area, the ventromedial nucleus, the arcuate ventromedial nucleus and median eminence are involved in the regulation of female sexual behavior. The new data suggest that α2-adrenoceptors play no major role on any indices of female sexual behavior.

Reactive oxygen species are physiological mediators of the noradrenergic signaling pathway in the mouse supraoptic nucleus.

Free radicals are essential for the vasopressin (AVP) response to plasmatic hyperosmolarity. Noradrenergic afferents are the major projections on the supraoptic nucleus (SON) of the hypothalamus and stimulate the expression of AVP via a nitric oxide (NO) pathway. In this study, we investigated the mechanisms linking free radicals and noradrenaline (NA)-induced regulation of AVP. Analysis of Tg8 transgenic mice, invalidated for the monoamine oxidase-A gene and with consequently high levels of brain monoamines and AVP in the SON, showed that free radicals are more abundant in their SON than in that of wild-type mice (WT). Antioxidant superoxide dismutase 1 and 2 and catalase enzyme activities were also higher in these mice than in WT. This may explain the observed absence of cytotoxicity that would otherwise be associated with such high level of free radicals. Treatment of Tg8 mice with α-MPT, a blocking agent for NA synthesis, decreased both the production of free radicals and the AVP levels in the SON. Furthermore, incubation of ex vivo slices including the SON with NA increased the production of free radicals and AVP levels in wild-type mice. When NA was associated with α-lipoic acid, an antioxidant blocking the production of free radicals, AVP remained at its control level, indicating that free radicals are required for the effect of NA on the expression of AVP. In slices incubated with SNP, a producer of NO, free radicals and AVP levels increased. When NA was associated with L-NAME (a NO synthase blocker), the levels of free radicals and AVP were the same as in controls. Thus, the noradrenaline-NO pathway, which stimulates the expression of vasopressin, involves free radicals. This study provides further evidence of the physiological importance of free radicals, which should no longer be considered solely as cytotoxic factors.

Noradrenergic modulation of neuronal responses to n-methyl-d-aspartate in the vestibular nuclei: an electrophysiological and immunohistochemical study.

Excitatory responses evoked by N-methyl-d-aspartate (NMDA) in the vestibular nuclei (VN) of the rat were studied in vivo during microiontophoretic application of noradrenaline (NA) and/or its agonists and antagonists. Ejection of NA-modified excitatory responses mediated by NMDA receptors (NMDAR) in all neurons tested; the effect was enhancement in 59% of cases and depression in the remaining 41%. Enhancements prevailed in all VN with the exception of the lateral vestibular nucleus, where both effects were recorded in an equal number of cases. The enhancing action of NA on NMDAR-mediated responses was mimicked by the noradrenergic beta-receptor agonist isoproterenol, the beta1 specific agonist denopamine and the alpha2 agonist clonidine. These effects were blocked respectively by the generic beta-receptor antagonist timolol, the beta1 antagonist atenolol and the alpha2 antagonist yohimbine. In contrast, application of the alpha1 receptor agonist cirazoline and the specific alpha1 antagonist prazosin respectively mimicked and partially antagonized the depression of NMDAR-mediated excitations induced by NA. Double-labeling immunohistochemical techniques demonstrated broad colocalization of NMDAR (specifically NR1 and NR2 subunits) with noradrenergic receptors (alpha1, alpha2 and beta1) in many VN neurons; only minor differences were found between nuclei. These results indicate that NA can produce generalized modulation of NMDAR-mediated excitatory neurotransmission in VN, which may in turn modify synaptic plasticity within the nuclei.

Additional antiepileptic mechanisms of levetiracetam in lithium-pilocarpine treated rats.

Several studies have addressed the antiepileptic mechanisms of levetiracetam (LEV); however, its effect on catecholamines and the inflammatory mediators that play a role in epilepsy remain elusive. In the current work, lithium (Li) pretreated animals were administered LEV (500 mg/kg i.p) 30 min before the induction of convulsions by pilocarpine (PIL). Li-PIL-induced seizures were accompanied by increased levels of hippocampal prostaglandin (PG) E2, myeloperoxidase (MPO), tumor necrosis factor-α, and interleukin-10. Moreover, it markedly elevated hippocampal lipid peroxides and nitric oxide levels, while it inhibited the glutathione content. Li-PIL also reduced hippocampal noradrenaline, as well as dopamine contents. Pretreatment with LEV protected against Li-PIL-induced seizures, where it suppressed the severity and delayed the onset of seizures in Li-PIL treated rats. Moreover, LEV reduced PGE2 and MPO, yet it did not affect the level of both cytokines in the hippocampus. LEV also normalized hippocampal noradrenaline, dopamine, glutathione, lipid peroxides, and nitric oxide contents. In conclusion, alongside its antioxidant property, LEV anticonvulsive effect involves catecholamines restoration, as well as inhibition of PGE2, MPO, and nitric oxide.

Noradrenaline increases pain facilitation from the brain during inflammatory pain.

Antidepressants that inhibit the recapture of noradrenaline have variable effects in chronic pain which may be related to the complex role of noradrenaline in pain modulation. Whereas at the spinal cord noradrenaline blocks nociceptive transmission, both antinociception and pronociception were reported after noradrenaline release in the brain. To study the role of noradrenaline in pain modulatory areas of the brain, we elected the dorsal reticular nucleus (DRt), a key pain facilitatory area located at the medulla oblongata. Three studies were performed. First, we show that the infusion in the DRt of nomifensine, which increases local extracellular levels of noradrenaline as shown by in vivo microdialysis, also enhances pain behavioral responses during both phases of the formalin test, a classic inflammatory pain model. Then, we demonstrate that the formalin test triggers the release of noradrenaline in the DRt in a biphasic pattern that matches the two phases of the test. Finally, we show that reducing noradrenaline release into the DRt, using an HSV-1 vector which decreases the expression of tyrosine hydroxylase in noradrenergic DRt-projecting neurons, attenuates pain behavioral responses in both phases of the formalin test. The increased noradrenaline levels induced by the infusion of nomifensine at the DRt, along with the hyperalgesic effects of noradrenaline released at the DRt upon noxious stimulation, indicates that noradrenaline may enhance pain facilitation from the brain. It is important to evaluate if antidepressants that inhibit noradrenaline recapture enhance pain facilitation from the brain herein attenuating their analgesic effects.

PDE3, but not PDE4, reduces ß1 - and ß2-adrenoceptor-mediated inotropic and lusitropic effects in failing ventricle from metoprolol-treated patients.

BACKGROUND AND PURPOSE: PDE3 and/or PDE4 control ventricular effects of catecholamines in several species but their relative effects in failing human ventricle are unknown. We investigated whether the PDE3-selective inhibitor cilostamide (0.3-1 µM) or PDE4 inhibitor rolipram (1-10 µM) modified the positive inotropic and lusitropic effects of catecholamines in human failing myocardium. EXPERIMENTAL APPROACH: Right and left ventricular trabeculae from freshly explanted hearts of 5 non-ß-blocker-treated and 15 metoprolol-treated patients with terminal heart failure were paced to contract at 1 Hz. The effects of (-)-noradrenaline, mediated through ß1 adrenoceptors (ß2 adrenoceptors blocked with ICI118551), and (-)-adrenaline, mediated through ß2 adrenoceptors (ß1 adrenoceptors blocked with CGP20712A), were assessed in the absence and presence of PDE inhibitors. Catecholamine potencies were estimated from -logEC50s. KEY RESULTS: Cilostamide did not significantly potentiate the inotropic effects of the catecholamines in non-ß-blocker-treated patients. Cilostamide caused greater potentiation (P = 0.037) of the positive inotropic effects of (-)-adrenaline (0.78 ± 0.12 log units) than (-)-noradrenaline (0.47 ± 0.12 log units) in metoprolol-treated patients. Lusitropic effects of the catecholamines were also potentiated by cilostamide. Rolipram did not affect the inotropic and lusitropic potencies of (-)-noradrenaline or (-)-adrenaline on right and left ventricular trabeculae from metoprolol-treated patients. CONCLUSIONS AND IMPLICATIONS: Metoprolol induces a control by PDE3 of ventricular effects mediated through both ß1 and ß2 adrenoceptors, thereby further reducing sympathetic cardiostimulation in patients with terminal heart failure. Concurrent therapy with a PDE3 blocker and metoprolol could conceivably facilitate cardiostimulation evoked by adrenaline through ß2 adrenoceptors. PDE4 does not appear to reduce inotropic and lusitropic effects of catecholamines in failing human ventricle.

The noradrenergic pain regulation system: a potential target for pain therapy.

Noradrenaline, through action on α1- and α2-adrenoceptors, is involved in intrinsic control of pain. Peripheral noradrenaline that is mainly released by the sympathetic nervous system has little influence on healthy tissues, whereas in injured or inflamed tissues it has varying effects, including aggravation of pain in neuropathy. The peripheral pronociceptive effect has been associated with injury-induced expression of novel noradrenergic receptors, sprouting of sympathetic nerve fibers, and pronociceptive changes in the ion channel properties on primary afferent nociceptors, whereas an interaction with the immune system may contribute to peripheral antinociceptive effect of noradrenaline. In the spinal dorsal horn, noradrenaline released from descending pathways originating in the pontine A5-A7 cell groups attenuates pain by inhibitory action on α(2A)-adrenoceptors on central terminals of primary afferent nociceptors (presynaptic inhibition), by direct α2-adrenergic action on spinal pain-relay neurons (postsynaptic inhibition), and by α1-adrenergic activation of inhibitory interneurons. Moreover, α(2C)-adrenoceptors on axon terminals of excitatory interneurons might contribute to spinal control of pain. At supraspinal levels, the effect of noradrenergic system on pain has varied depending on many factors such as the type of the adrenoceptor, pathophysiological condition, and the brain area. In general, the baseline pain sensitivity is only little influenced by the noradrenergic system, whereas in injured conditions the noradrenergic system contributes to feedback inhibition of pain. The central as well as the peripheral noradrenergic system is subject to various plastic changes following injury or inflammation that influence its antinociceptive efficiency. α2-Adrenoceptor agonists have proven effective in treating various pain conditions.

Antidepressant-like effect of bis-eugenol in the mice forced swimming test: evidence for the involvement of the monoaminergic system.

Dehydrodieugenol, known as bis-eugenol, is a eugenol ortho dimer, and both compounds were able to exhibit anti-inflammatory and antioxidant activities in previous studies. Furthermore, eugenol showed antidepressant-like effect; however, the biological actions of bis-eugenol on experimental models for screening antidepressant activity are still unknown. The present study investigated a possible antidepressant-like activity of bis-eugenol in the forced swimming test (FST) and tail suspension test (TST) in mice and the involvement in the monoaminergic system in this effect. In addition, a neurochemical analysis on brain monoamines of mice acutely treated with bis-eugenol was also conducted. Bis-eugenol decreased the immobility time in the FST and TST without accompanying changes in ambulation in the open field test at 10 mg/kg, i.p.. Nevertheless, it induced ambulation at 25 and 50 mg/kg doses. The anti-immobility effect of bis-eugenol (10 and 50 mg/kg, i.p.) was prevented by pretreatment of mice with p-chlorophenylalanine (PCPA, 100 mg/kg, i.p., an inhibitor of serotonin synthesis, for four consecutive days), yohimbine (1 mg/kg, i.p., an α2-adrenoceptor antagonist), SCH23390 (15 µg/kg, s.c., a dopamine D1 receptor antagonist) and sulpiride (50 mg/kg, i.p., a dopamine D2 receptor antagonist). Monoamines analysis using high-performance liquid chromatograph revealed significant increase in the 5-HT, NE and DA levels in brain striatum. The present study indicates that bis-eugenol possesses antidepressant-like activity in FST and TST by altering dopaminergic, serotonergic and noradrenergic systems function.

Presynaptic α2-adrenoceptors control the inhibitory action of presynaptic CB1 cannabinoid receptors on prefrontocortical norepinephrine release in the rat.

Endocannabinoids play a crucial neuromodulator role in both physiological and pathological states in various brain regions including the prefrontal cortex (PFC). We examined, whether presynaptic cannabinoid receptors are involved in the modulation of basal and electrical field stimulation-evoked [³H]norepinephrine ([³H]NE) release from rat PFC slices. WIN55,212-2, a nonselective CB1 receptor (CB1R) agonist, inhibited the electrical stimulation-evoked efflux of [³H]NE in a concentration-dependent fashion, which was antagonized by the CB1R antagonist/inverse agonist, AM251 (1 µM). Idazoxan, a selective α2-adrenoceptor antagonist, augmented the evoked [³H]NE release. In the presence of idazoxan, the effect of WIN55,212-2 was exacerbated or attenuated, depending on the applied concentration and stimulation frequency. Moreover their combined, but not individual application elicited a depressive-like phenomenon in the forced-swim test. These data were bolstered with fluorescent and confocal microscopy analysis, which revealed that CB1R immunoreactivity co-localized with dopamine-ß-hydroxylase positive (i.e. noradrenergic) fibers and the inhibitory α(2A) adrenergic autoreceptors (α(2A)R) in the PFC. Furthermore, idazoxan triggered a decrease in CB1R density in the PFC, suggesting that high extracellular level of norepinephrine downregulates CB1Rs.

Does yohimbine hydrochloride facilitate fear extinction in virtual reality treatment of fear of flying? A randomized placebo-controlled trial.

BACKGROUND: Research suggests that yohimbine hydrochloride (YOH), a noradrenaline agonist, can facilitate fear extinction. It is thought that the mechanism of enhanced emotional memory is stimulated through elevated noradrenaline levels. This randomized placebo-controlled trial examined the potential exposure-enhancing effects of YOH in a clinical sample of participants meeting DSM-IV criteria for a specific phobia (fear of flying). METHODS: Sixty-seven participants with fear of flying were randomized to 4 sessions of virtual reality exposure therapy (VRET) combined with YOH (10 mg), or 4 sessions of VRET combined with a placebo. Treatment consisted of 4 weekly 1-hour exposure sessions consisting of two 25-minute virtual flights. At pre- and post- treatment, fear of flying was assessed. The YOH or placebo capsules were administered 1 h prior to exposures. The manipulation of the noradrenaline activity was confirmed by salivary α-amylase (sAA) samples taken pre-, during and post-exposure. RESULTS: Forty-eight participants completed treatment. Manipulation of noradrenaline levels with YOH was successful, with significantly higher levels of sAA in the YOH group when entering exposure. Results showed that both groups improved significantly from pre- to post-treatment with respect to anxiety reduction. However, although the manipulation of noradrenaline activity was successful, there was no evidence that YOH enhanced outcome. CONCLUSIONS: Participants improved significantly on anxiety measures independently of drug condition, after 4 sessions of VRET. These data do not support the initial findings of exposure-enhancing effects of YOH in this dosage in clinical populations.

Compound stimulus presentation and the norepinephrine reuptake inhibitor atomoxetine enhance long-term extinction of cocaine-seeking behavior.

Drug abstinence is frequently compromised when addicted individuals are re-exposed to environmental stimuli previously associated with drug use. Research with human addicts and in animal models has demonstrated that extinction learning (non-reinforced cue-exposure) can reduce the capacity of such stimuli to induce relapse, yet extinction therapies have limited long-term success under real-world conditions (Bouton, 2002; O'Brien, 2008). We hypothesized that enhancing extinction would reduce the later ability of drug-predictive cues to precipitate drug-seeking behavior. We, therefore, tested whether compound stimulus presentation and pharmacological treatments that augment noradrenergic activity (atomoxetine; norepinephrine reuptake inhibitor) during extinction training would facilitate the extinction of drug-seeking behaviors, thus reducing relapse. Rats were trained that the presentation of a discrete cue signaled that a lever press response would result in cocaine reinforcement. Rats were subsequently extinguished and spontaneous recovery of drug-seeking behavior following presentation of previously drug-predictive cues was tested 4 weeks later. We find that compound stimulus presentations or pharmacologically increasing noradrenergic activity during extinction training results in less future recovery of responding, whereas propranolol treatment reduced the benefit seen with compound stimulus presentation. These data may have important implications for understanding the biological basis of extinction learning, as well as for improving the outcome of extinction-based therapies.

Maternal defense is modulated by beta adrenergic receptors in lateral septum in mice.

Maternal defense (offspring protection) is a critical and highly conserved component of maternal care in mammalian systems that involves dramatic shifts in a female's behavioral response to social cues. Numerous changes occur in neuronal signaling and connectivity in the postpartum female, including decreases in norepinephrine (NE) signaling in subregions of the CNS. In this study using a strain of mice selected for maternal defense, we examined whether possible changes in NE signaling in the lateral septum (LS) could facilitate expression of maternal aggression. In separate studies that utilized a repeated measures design, mice were tested for maternal defense following intra-LS injections of either the ß-adrenergic receptor agonist isoproterenol (10 µg or 30 µg) or vehicle (Experiment 1), the ß-adrenergic receptor antagonist propranolol (2 µg) or vehicle (Experiment 2), or the ß1-receptor antagonist, atenolol (Experiment 3). Mice were also evaluated for light-dark performance and pup retrieval. Thirty micrograms of the agonist isoproterenol significantly decreased number of attacks and time aggressive relative to vehicle without affecting pup retrieval or light-dark box performance. In contrast, the antagonist propranolol significantly increased maternal aggression (lowered latency to attack and increased total attack time) without altering light-dark box test. The ß1-specific antagonist, atenolol, significantly decreased latency to attack (1 µg vs. vehicle) without altering other measures. Although the findings were identified in a unique strain of mice, the results of these studies support the hypothesis that changes in NE signaling in LS during the postpartum period contribute to the expression of offspring protection.

Increasing CNS noradrenaline reduces EAE severity.

The endogenous neurotransmitter noradrenaline (NA) is known to exert potent anti-inflammatory effects in glial cells, as well as provide neuroprotection against excitatory and inflammatory stimuli. These properties raise the possibility that increasing levels of NA in the central nervous system (CNS) could provide benefit in neurological diseases and conditions containing an inflammatory component. In the current study, we tested this possibility by examining the consequences of selectively modulating CNS NA levels on the development of clinical signs in experimental autoimmune encephalomyelitis (EAE). In mice immunized with myelin oligodendrocyte glycoprotein peptide to develop a chronic disease, pretreatment to selectively deplete CNS NA levels exacerbated clinical scores. Elevation of NA levels using the selective NA reuptake inhibitor atomoxetine did not affect clinical scores, while treatment of immunized mice with the synthetic NA precursor L-threo-3,4-dihydroxyphenylserine (L-DOPS) prevented further worsening. In contrast, treatment of mice with a combination of atomoxetine and L-DOPS led to significant improvement in clinical scores as compared to the control group. The combined treatment reduced astrocyte activation in the molecular layer of the cerebellum as assessed by staining for glial fibrillary protein but did not affect Th1 or Th17 type cytokine production from splenic T cells. These data suggest that selective elevation of CNS NA levels could provide benefit in EAE and multiple sclerosis without influencing peripheral immune responses.

ACS chemical neuroscience molecule spotlight on Valdoxen.

A new and novel non-SSRI potential treatment option for major depressive disorders is Valdoxen (agomelatine) which is currently in phase III clinical studies. Valdoxen is a norepinephrine disinhibitor (NNDI) and is also an antagonist of the 5-HT(2C) receptor.