Understanding Stimulant Use and Use Disorders in a New Era.

Extending from the triple wave epidemic of opioid-related overdose deaths, a fourth wave of high mortality involving methamphetamine and cocaine use has been gathering force. This article provides a review of the published literature on stimulants including epidemiology, pharmacology, neurobiology, medical and psychiatric consequences, withdrawal management, and medical and behavioral treatments.

Design, Sustainable Synthesis and Biological Evaluation of a Novel Dual α2A/5-HT7 Receptor Antagonist with Antidepressant-Like Properties.

The complex pathophysiology of depression, together with the limits of currently available antidepressants, has resulted in the continuous quest for alternative therapeutic strategies. Numerous findings suggest that pharmacological blockade of α2-adrenoceptor might be beneficial for the treatment of depressive symptoms by increasing both norepinephrine and serotonin levels in certain brain areas. Moreover, the antidepressant properties of 5-HT7 receptor antagonists have been widely demonstrated in a large set of animal models. Considering the potential therapeutic advantages in targeting both α2-adrenoceptors and 5-HT7 receptors, we designed a small series of arylsulfonamide derivatives of (dihydrobenzofuranoxy)ethyl piperidines as dually active ligands. Following green chemistry principles, the designed compounds were synthesized entirely using a sustainable mechanochemical approach. The identified compound 8 behaved as a potent α2A/5-HT7 receptor antagonist and displayed moderate-to-high selectivity over α1-adrenoceptor subtypes and selected serotonin and dopaminergic receptors. Finally, compound 8 improved performance of mice in the forced swim test, displaying similar potency to the reference drug mirtazapine.

Dexmedetomidine maintains blood-brain barrier integrity by inhibiting Drp1-related endothelial mitochondrial dysfunction in ischemic stroke.

Stroke is the second leading cause of death and long-term disability worldwide, which lacks effective treatment. Perioperative stroke is associated with much higher rates of mortality and disability. The neuroprotective role of dexmedetomidine (Dex), a highly selective agonist of alpha2-adrenergic receptor, has been reported in a stroke rat model, and it was found that pretreatment of Dex before stroke could alleviate blood-brain barrier (BBB) breakdown. However, the underlying mechanisms are still unknown. As the brain endothelial cells are the main constituents of BBB and in high demand of energy, mitochondrial function of endothelial cells plays an important role in the maintenance of BBB. Given that dynamin-related protein 1 (Drp1) is a protein mediating mitochondrial fission, with mitochondrial fusion that balances mitochondrial morphology and ensures mitochondria function, the present study was designed to investigate the possible role of Drp1 in endothelial cells involved in the neuroprotective effects of Dex in ischemic stroke. Our results showed that preconditioning with Dex reduced infarction volume, alleviated brain water content and BBB damage, and improved neurological scores in middle cerebral artery occlusion rats. Meanwhile, Dex enhanced cell activity and decreased cell apoptosis in oxygen-glucose deprivation human brain microvascular endothelial cells in vitro. These protective effects of Dex were correlated with the mitochondrial morphology integrality of endothelial cells, mediated by increased phosphorylation of serine 637 in Drp1, and could be reversed by α2-adrenergic receptor antagonist Yohimbine and AMP-activated protein kinase inhibitor Compound C. These findings suggest new molecular pathways involved in the neuroprotective effects of Dex in ischemic stroke. As Dex is routinely used as a sedative drug clinically, our findings provide molecular evidence that it has perioperative neuroprotection from ischemic stroke.

Yohimbine Ameliorates Temporomandibular Joint Chondrocyte Inflammation with Suppression of NF-κB Pathway.

Local joint inflammation plays an important role in the pathogenesis of temporomandibular joint (TMJ) osteoarthrosis (TMJOA). Yohimbine, an alpha-2 adrenergic receptor antagonist, possesses anti-inflammatory properties; however, the ability of Yohimbine to protect against TMJOA-associated chondrocyte inflammation remains unclear. We conducted in vitro and in vivo analyses to investigate whether Yohimbine could ameliorate TMJOA-induced chondrocyte inflammation and to elucidate the mechanisms involved. Chondrocytes of TMJOA mice were stimulated with interleukin (IL)-1ß or noradrenaline (NE), and the resulting production of inflammation-related factors was evaluated in the presence or absence of Yohimbine. Furthermore, two TMJOA mouse models were treated with Yohimbine and the therapeutic effect was quantified. NE (10-6 M) triggered inflammatory cytokine secretion by TMJ chondrocytes, and Yohimbine suppressed IL-1ß- or NE-induced IL-6 upregulation in TMJ chondrocytes with the nuclear factor (NF)-κB pathway inhibition. Yohimbine also ameliorated cartilage destruction in the TMJOA models. Interestingly, αmpT, a tyrosine hydroxylase inhibitor, reversed the effects of Yohimbine by activating the NF-κB pathway. Collectively, these findings show that Yohimbine ameliorated TMJ chondrocyte inflammation and the suppression of NF-κB pathway contributes to this effect.

Mirtazapine, an α2 Antagonist-Type Antidepressant, Reverses Pain and Lack of Morphine Analgesia in Fibromyalgia-Like Mouse Models.

Treatment of fibromyalgia is an unmet medical need; however, its pathogenesis is still poorly understood. In a series of studies, we have demonstrated that some pharmacological treatments reverse generalized chronic pain but do not affect the lack of morphine analgesia in the intermittent cold stress (ICS)-induced fibromyalgia-like pain model in mice. Here we report that repeated intraperitoneal treatments with mirtazapine, which is presumed to disinhibit 5-hydroxytriptamine (5-HT) release and activate 5-HT1 receptor through mechanisms of blocking presynaptic adrenergic α2 and postsynaptic 5-HT2 and 5-HT3 receptors, completely reversed the chronic pain for more than 4 to 5 days after the cessation of treatments. The repeated mirtazapine treatments also recovered the morphine analgesia after the return of nociceptive threshold to the normal level. The microinjection of small interfering RNA (siRNA) adrenergic α2a receptor (ADRA2A) into the habenula, which showed a selective upregulation of α2 receptor gene expression after ICS, reversed the hyperalgesia but did not recover the morphine analgesia. However, both reversal of hyperalgesia and recovery of morphine analgesia were observed when siRNA ADRA2A was administered intracerebroventricularly. As the habenular is reported to be involved in the emotion/reward-related pain and hypoalgesia, these results suggest that mirtazapine could attenuate pain and/or augment hypoalgesia by blocking the habenular α2 receptor after ICS. The recovery of morphine analgesia in the ICS model, on the other hand, seems to be mediated through a blockade of α2 receptor in unidentified brain regions. SIGNIFICANCE STATEMENT: This study reports possible mechanisms underlying the complete reversal of hyperalgesia and recovery of morphine analgesia by mirtazapine, a unique antidepressant with adrenergic α2 and serotonergic receptor antagonist properties, in a type of intermittently repeated stress (ICS)-induced fibromyalgia-like pain model. Habenula, a brain region which is related to the control of emotional pain, was found to play key roles in the antihyperalgesia, whereas other brain regions appeared to be involved in the recovery of morphine analgesia in the ICS model.

α 2-Adrenoceptors: Challenges and Opportunities-Enlightenment from the Kidney.

It was indeed a Don Quixote-like pursuit of the mechanism of essential hypertension when we serendipitously discovered α 2-adrenoceptors (α 2-ARs) in skin-lightening experiments in the frog. Now α 2-ARs lurk on the horizon involving hypertension causality, renal denervation for hypertension, injury from falling in the elderly and prazosin's mechanism of action in anxiety states such as posttraumatic stress disorder (PTSD). Our goal here is to focus on this horizon and bring into clear view the role of α 2-AR-mediated mechanisms in these seemingly unrelated conditions. Our narrative begins with an explanation of how experiments in isolated perfused kidneys led to the discovery of a sodium-retaining process, a fundamental mechanism of hypertension, mediated by α 2-ARs. In this model system and in the setting of furosemide-induced sodium excretion, α 2-AR activation inhibited adenylate cyclase, suppressed cAMP formation, and caused sodium retention. Further investigations led to the realization that renal α 2-AR expression in hypertensive animals is elevated, thus supporting a key role for kidney α 2-ARs in the pathophysiology of essential hypertension. Subsequent studies clarified the molecular pathways by which α 2-ARs activate prohypertensive biochemical systems. While investigating the role of α 1-adrenoceptors (α 1-ARs) versus α 2-ARs in renal sympathetic neurotransmission, we noted an astonishing result: in the kidney α 1-ARs suppress the postjunctional expression of α 2-ARs. Here, we describe how this finding relates to a broader understanding of the role of α 2-ARs in diverse disease states. Because of the capacity for qualitative and quantitative monitoring of α 2-AR-induced regulatory mechanisms in the kidney, we looked to the kidney and found enlightenment.

Evaluation of the Effect of Prazosin Treatment on α-2c Adrenoceptor and Apoptosis Protein Levels in the Predator Scent-Induced Rat Model of Post-Traumatic Stress Disorder.

The predator scent-induced (PSI) stress model is a rat model used to mimic post-traumatic stress disorder (PTSD) symptoms in humans. There is growing evidence that prazosin, which blocks α-1 and is approved by the FDA as an anti-hypertensive drug, can potentially be of use in the treatment of PTSD-related sleep disorders. The aim of this study was to investigate the role of prazosin treatment on behavioral parameters (freezing time, total transitions, and rearing frequency measured from the open field; anxiety index, total entries and time spent in open arms calculated from the elevated plus maze), apoptotic proteins and α-2c-AR in fear memory reconsolidation in the PSI stress rat model. We used western blot analysis to determine the effect of prazosin (0.5 mg/kg/ip) on α-2c-AR and apoptotic protein expression changes in the frontal cortex, hippocampus, and amygdala. It was determined that in the stress group, there was increased freezing time and anxiety index, and decreased rearing frequency, total transitions, total entries, and time spent in open arms compared to the control groups. Following PSI-stress, pro-apoptotic (bax) protein expression levels increased and α-2c AR and anti-apoptotic protein (bcl-2) levels decreased in investigated all brain regions. The majority of stress-induced changes were recovered with prazosin treatment. The results of our study may potentially be useful in understanding the effect of prazosin treatment, given the fact that the amygdala, frontal cortex, and hippocampus regions are affected for stress conditions.

α2-Adrenergic Receptor in Liver Fibrosis: Implications for the Adrenoblocker Mesedin.

The noradrenergic system is proposed to play a prominent role in the pathogenesis of liver fibrosis. While α1- and ß-adrenergic receptors (ARs) are suggested to be involved in a multitude of profibrogenic actions, little is known about α2-AR-mediated effects and their expression pattern during liver fibrosis and cirrhosis. We explored the expression of α2-AR in two models of experimental liver fibrosis. We further evaluated the capacity of the α2-AR blocker mesedin to deactivate hepatic stellate cells (HSCs) and to increase the permeability of human liver sinusoidal endothelial cells (hLSECs). The mRNA of α2a-, α2b-, and α2c-AR subtypes was uniformly upregulated in carbon tetrachloride-treated mice vs the controls, while in bile duct-ligated mice, only α2b-AR increased in response to liver injury. In murine HSCs, mesedin led to a decrease in α-smooth muscle actin, transforming growth factor-ß and α2a-AR expression, which was indicated by RT-qPCR, immunocytochemistry, and Western blot analyses. In a hLSEC line, an increased expression of endothelial nitric oxide synthase was detected along with downregulated transforming growth factor-ß. In conclusion, we suggest that the α2-AR blockade alleviates the activation of HSCs and may increase the permeability of liver sinusoids during liver injury.

The association between tic medication therapy and psychiatric comorbidities among patients with Tourette syndrome: A national population-based study in Taiwan.

BACKGROUND: Tourette syndrome (TS) is often comorbid with attention deficit hyperactivity disorder, obsessive-compulsive disorder, and depression. Medications are the main treatment for TS. Relationships between TS medication therapy and psychiatric comorbidities remain unclear. This study explored the impacts of TS medication on the risk of psychiatric comorbidities using a nationally representative sample of TS in Taiwan. METHODS: Data from National Health Insurance Research Database in Taiwan was used to identify 997,213 children and adolescents aged 6-18 years who had received a diagnosis of TS based on ICD-9-CM codes in 2000-2010. Cox's proportional hazard regression analysis was conducted to estimate the risk of comorbidities among subjects with and without tic medication therapy. RESULTS: We found that in TS patients, a lower risk of psychiatric comorbidities occurred in the tic medication therapy group (p = 0.012) and the crude hazard ratio (HR) was 0.6 (95% confidence interval (CI) = 0.4-0.8, p < 0.001). After adjusting for potential confounders of gender, age, income, level of care, department visited, brain injury, and the number of suicide attempts, the risk of comorbidities was still significantly lower in the tic medication therapy group (adjusted HR = 0.5, 95% CI = 0.3-0.6, p < 0.001). DISCUSSION: One limitation was that we did not include all mediations used to treat psychiatric comorbidities among TS patients. This study found the effectiveness of TS medications on improving psychiatric comorbidities. CONCLUSIONS: Compared to those without medication, medication therapy appears to have a benefit of decreasing the risk of psychiatric comorbidities. Strategies to improve medication regimens should be considered in clinical settings.

Evaluation of atipamezole as a treatment for dexmedetomidine-induced cardiovascular depression in anesthetized cats.

OBJECTIVE: To evaluate the cardiovascular effects of atipamezole administered at half the volume or the same volume as dexmedetomidine to isoflurane-anesthetized cats. ANIMALS: 6 adult (1 to 2 years old) domestic shorthair cats (body weight, 3 to 6 kg). PROCEDURES: Each cat was anesthetized with isoflurane and rocuronium 3 times; there was a 1-week washout period between successive anesthetic procedures. For each anesthetic procedure, dexmedetomidine (5 µg/kg) was administered IV. Five minutes after dexmedetomidine was administered, atipamezole (25 or 50 µg/kg) or saline (0.9% NaCl) solution was administered IM. Pulse rate, mean arterial blood pressure (MAP), cardiac output (CO), and systemic vascular resistance (SVR) were measured during anesthesia before dexmedetomidine administration (baseline), after dexmedetomidine administration, and 15, 30, 60, and 120 minutes after administration of atipamezole or saline solution. Pulse rate and MAP were also recorded when MAP was at its lowest value. Hemodynamic variables were compared among treatments at baseline, after dexmedetomidine administration, and after administration of atipamezole or saline solution. Effects of treatment and time on all variables were assessed with mixed-effects models. RESULTS: Both doses of atipamezole resulted in a significantly lower MAP than did saline solution. Pulse rate, CO, and SVR were not significantly different among treatments after atipamezole or saline solution were administered. CONCLUSIONS AND CLINICAL RELEVANCE: Atipamezole administered IM at half the volume or the same volume as dexmedetomidine was ineffective at increasing pulse rate or CO in anesthetized cats that received dexmedetomidine. However, atipamezole caused short-lasting but severe arterial hypotension.

Alpha2 -adrenoceptor agonists inhibit form-deprivation myopia in the chick.

BACKGROUND: The putative myopia-controlling receptor is thought to be muscarinic acetylcholine receptor subtype M4 , because mamba toxin-3 can inhibit form-deprivation myopia in chicks at a far lower concentration than atropine. However, mamba toxin-3 is equally potent at the human α1A -, α1D -, and α2A -adrenoceptors. To test the hypothesis that α-adrenoceptors might be involved in regulation of eye growth, the treatment effects of α2 -adrenoceptor agonists brimonidine, clonidine, and guanfacine, and antagonist yohimbine, on form-deprivation myopia in the chick were measured. METHODS: Right eyes of White Leghorn chicks were goggled with diffusers to induce form-deprivation myopia; left eyes were left open as controls. Goggled eyes were injected intravitreally with 20 µL of vehicle, or 2, 20, or 200 nmol of brimonidine, clonidine, guanfacine, or yohimbine, 24, 72, and 120 hours after goggle application. Alternatively, myopia was inhibited physiologically by goggle removal for two hours, and the α2 -adrenoceptor antagonist, yohimbine, was injected to test whether it could block this type of myopia inhibition. One day after the last injection, refractive error and axial length were measured. RESULTS: Brimonidine (20 and 200 nmol) and clonidine (200 nmol) effectively inhibited experimentally induced increases in negative refractive error and axial elongation. All doses of guanfacine significantly inhibited induced negative refractive error, but only 20 and 200 nmol significantly inhibited axial elongation. Yohimbine had no effect on form-deprivation myopia, but 200 nmol reduced the myopia-inhibiting effect of goggle removal. CONCLUSION: High concentrations of α2 -adrenoceptor agonists, similar to those required by atropine, inhibited chick form-deprivation myopia; antagonism by yohimbine had no effect. High-concentration yohimbine partially interfered with emmetropisation in form-deprived chicks experiencing normal vision for two hours per day. These data support the hypothesis that treatment with high concentrations of adrenergic drugs can affect experimentally induced myopia and normal visual processes.

Mirtazapine for chronic breathlessness? A review of mechanistic insights and therapeutic potential.

INTRODUCTION: Chronic breathlessness is a common and distressing symptom of advanced disease with few effective treatments. Central nervous system mechanisms are important in respiratory sensation and control. Consequently, drugs which may modify processing and perception of afferent information in the brain may have a role. Antidepressants have been proposed; however, current evidence is limited. Of potentially suitable antidepressants, mirtazapine is an attractive option given its tolerability profile, low cost, and wide availability, along with additional potential benefits. Areas covered: The paper provides an overview of the physiology of breathlessness, with an emphasis on central mechanisms, particularly the role of fear circuits and the associated neurotransmitters. It provides a potential rationale for how mirtazapine may improve chronic breathlessness and quality of life in patients with advanced disease. The evidence was identified by a literature search performed in PubMed through to October 2018. Expert opinion: Currently, there is insufficient evidence to support the routine use of antidepressants for chronic breathlessness in advanced disease. Mirtazapine is a promising candidate to pursue, with definitive randomized controlled trials required to determine its efficacy and safety in this setting.

EXPERIMENTAL STUDY OF PAIN-RELIEVING MECHANISMS OF 4-[4-OXO-(4H)-QUINAZOLIN-3-YL]-BENZOIC ACID (PK-66 COMPOUND).

An in-depth study of the pharmacological properties of 4-[4-oxo-(4h)-quinazolin-3-yl]-benzoic acid as an analgesic agent established that it had a sufficiently high analgesic effect on models of somatic and neuropathic pain syndromes. Study objective was to study the mechanisms of analgesic action of PK-66 compound in rats using the pharmacological analysis. We evaluated the mechanisms of analgesic effect of PK-66 (1 mg/kg, intraperitoneal) compound on the thermal irritation model on Hours 1, 2, 4 and 6 after administration of study compounds. To evaluate the mechanisms of PK-66 compound pain killing, we determined the changes in its efficacy against the effects of pharmacological analyzers - Naloxon, Tramadolum, Clophelinum (Clonidine), Yohimbine, Noraepinephrine, Reserpinum, Chlorpromazine (Aminazin), Levodopa, Diazepam, and Memantine). The anti-nociceptive effect of PK-66 compound was virtually unchanged during all study terms with underlying administration of Naloxon, an opioid receptor antagonist. The results of administration of Reserpinum in rats and the concomitant administration of Noradrenaline, Clophelinum, Yohimbine and quinazoline derivative demonstrated that the adrenergic system, in particular alpha-2 adrenergic receptors, was involved in the mechanisms of PK-66 activity. Changes in the PK-66 compound effect with underlying previous administration of Levodopa and Chlorpromazine suggested that the dopaminergic system was unquestionably involved in the analgesic activity of the compound. Further study of the involvement of inhibitory and exhilarating amino acids, GABA and glutamate, showed that administration of Diazepam potentiated and extended the PK-66 analgesic effect on the thermal nociception models throughout the experiment. At the same time, increased antinociception with underlying Memantine administration preceding PK-66 was observed only in the first hours of the experiment. Therefore, the studies conducted have shown that the adrenergic system, in particular alpha-2 adrenergic receptors, dopaminergic and GABAergic systems, is involved in the mechanisms of analgesic action of 4-[4-oxo-(4h) -quinazolin-3-yl]-benzoic acid (PK-66) without any effect of PK-66 on opioid receptors.

Inhibition of α2C-adrenoceptors ameliorates cisplatin-induced acute renal failure in rats.

Nephrotoxicity is a major adverse reaction of the anticancer drug, cisplatin. We investigated the renoprotective effects of the α2-adrenoceptor antagonist, yohimbine and selective α2C-adrenoceptor antagonist, JP-1302, in cisplatin-treated Sprague Dawley rats. Rats were given a single intravenous dose of 7.5 mg/kg cisplatin and then yohimbine or JP-1302 was administered intraperitoneally at 0.1 or 3 mg/kg/day, respectively, for four days. Renal functional parameters, such as blood urea nitrogen, plasma creatinine, creatinine clearance and renal venous norepinephrine concentrations were measured. Kidney tissue damage and tumour necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1) mRNA levels were assessed after the animals were euthanized. Cisplatin treatment aggravated the kidney functional parameters of blood urea nitrogen, plasma creatinine and creatinine clearance. Renal venous norepinephrine concentrations were also elevated after cisplatin administration. Treatment with yohimbine or JP-1302 clearly ameliorated kidney function and cell apoptosis. These treatments suppressed elevated renal plasma norepinephrine, TNF-α, MCP-1 and cleaved caspase 3 expressions which occurred after administration of cisplatin. These results suggest that yohimbine can prevent cisplatin-induced renal toxicity associated with acute kidney injury by suppressing cytokine expression through α2C-adrenoceptors.

Dexmedetomidine restores septic renal function via promoting inflammation resolution in a rat sepsis model.

BACKGROUND: Acute kidney injury occurred after sepsis, resulting in high mortality. This research aims to elucidate the mechanistic effect of DEX on the renal inflammation resolution during sepsis in rats. METHODS: The rats were randomly divided into a sham group and the other three cecal ligation and puncture (CLP) model groups, based on different treatments: placebo, DEX and 2-adrenergic receptor (AR) inhibitor atipamezole (AT) treatment (DEX + AT) groups. The survival of septic rats within 24 h was recorded. Tissue pathology, plasma IL-1ß, IL-6, TNF-α, lipoxygenase-5 and lipoxin A4 were evaluated. Western blotting and immunostaining was used to determine expression of TLR4, IκB, IKK, NF-κB p65 and pp65 in kidney tissue. Then qPCR was used to analyze the mRNA expression of renal α2A-AR, α2B-AR and α2C-AR. RESULTS: Rat mortality and kidney inflammation were significantly increased in septic rats. Specifically, IL-1ß, IL-6 and TNF-α plasma levels, NF-κB activity, and TLR4 expression in rat kidney tissues were increased after CLP. In the DEX treatment group, mortality was reduced, histology changes were minor, and lipoxygenase-5, and lipoxin A4 expression were increased. The expression of IL-1ß, IL-6 and TNF-α, NF-κB activity and TLR4 expression in rat kidney tissues were also decreased. These results indicated that DEX treatment alleviates acute kidney injury induced by CLP. However, the effects of DEX were apparently suppressed by atipamezole in the DEX + AT group. CONCLUSION: The current study demonstrated the protective effect of DEX on CLP-induced kidney injury, which may be effective by attenuating NF-κB pathway activation with lipoxin A4.

α2A-adrenergic blockade attenuates septic cardiomyopathy by increasing cardiac norepinephrine concentration and inhibiting cardiac endothelial activation.

Cardiomyopathy is a common complication associated with increased mortality in sepsis, but lacks specific therapy. Here, using genetic and pharmacological approaches, we explored the therapeutic effect of α2A-adrenergic receptor (AR) blockade on septic cardiomyopathy. CLP-induced septic rats were treated with BRL44408 (α2A-AR antagonist), prazosin (α1-AR antagonist) and/or reserpine. CLP-induced cardiomyopathy, indicated by reduced dP/dt and increased cardiac troponin I phosphorylation, was attenuated by BRL44408, this was associated with reduced cardiac TNF-α and endothelial VCAM-1 expression, cardiomyocyte apoptosis and related signal molecule phosphorylation. BRL44408 increased cardiac norepinephrine (NE) concentration in CLP rats. Pretreatment with reserpine that exhausts cardiac NE without affecting the circulating NE concentration or with prazosin partially abolished the cardioprotection of BRL44408 and reversed its inhibitory effects on myocardial TNF-α, apoptosis and related signal molecule phosphorylation, but not on VCAM-1 expression in septic rats. These effects of BRL44408 were confirmed by α2A-AR gene deletion in septic mice. Furthermore, α2-AR agonist not only enhanced LPS-induced TNF-α and VCAM-1 expression in cardiac endothelial cells that express α2A-AR, but also enhanced LPS-induced cardiac dysfunction in isolated rat hearts. Our data indicate that α2A-AR blockade attenuates septic cardiomyopathy by promoting cardiac NE release that activates myocardial α1-AR and suppressing cardiac endothelial activation.

Augmenting treatment efficiency in exposure therapy for PTSD: a randomized double-blind placebo-controlled trial of yohimbine HCl.

The alpha-2 adrenergic receptor antagonist, yohimbine, can facilitate fear extinction in animals and humans. One potential mechanism is increased noradrenergic activity and associated arousal in the presence of conditioned stimuli. Accordingly, yohimbine might augment prolonged exposure (PE) therapy for posttraumatic stress disorder (PTSD), where heightened exposure-oriented arousal is a theorized driver and empirical predictor of treatment success. A double-blind placebo-controlled randomized trial (NCT 01031979) piloted yohimbine augmentation in 26 males with combat-related PTSD. Participants were given one-time dose of yohimbine or placebo prior to the first imaginal exposure. Subsequently, both arms completed standard PE. The primary outcome was trauma-cued heart-rate reactivity a week after the drug/exposure visit, a highly specified, objective measure sensitive to incremental change. Secondary outcomes included arousal during the drug/exposure visit and slope of distress, PTSD, and depression over the course of PE. Consistent with hypothesis, yohimbine led to higher objective and subjective arousal during the drug/exposure visit and to lower trauma-cued heart-rate reactivity one-week later. One dose of yohimbine also led to greater between-session habituation and more rapid improvement on depression, but not PTSD, over the course of care. Results of this controlled pilot indicate support for continued investigation of yohimbine-augmented exposure therapy for PTSD.

Treatment with the noradrenaline re-uptake inhibitor atomoxetine alone and in combination with the α2-adrenoceptor antagonist idazoxan attenuates loss of dopamine and associated motor deficits in the LPS inflammatory rat model of Parkinson's disease.

The impact of treatment with the noradrenaline (NA) re-uptake inhibitor atomoxetine and the α2-adrenoceptor (AR) antagonist idazoxan in an animal model of Parkinson's disease (PD) was assessed. Concurrent systemic treatment with atomoxetine and idazoxan, a combination which serves to enhance the extra-synaptic availability of NA, exerts anti-inflammatory and neuroprotective effects following delivery of an inflammatory stimulus, the bacterial endotoxin, lipopolysaccharide (LPS) into the substantia nigra. Lesion-induced deficits in motor function (akinesia, forelimb-use asymmetry) and striatal dopamine (DA) loss were rescued to varying degrees depending on the treatment. Treatment with atomoxetine following LPS-induced lesion to the substantia nigra, yielded a robust anti-inflammatory effect, suppressing microglial activation and expression of the pro-inflammatory cytokine TNF-α whilst increasing the expression of neurotrophic factors. Furthermore atomoxetine treatment prevented loss of tyrosine hydroxylase (TH) positive nigral dopaminergic neurons and resulted in functional improvements in motor behaviours. Atomoxetine alone was sufficient to achieve most of the observed effects. In combination with idazoxan, an additional improvement in the impairment of contralateral limb use 7 days post lesion and a reduction in amphetamine-mediated rotational asymmetry 14 days post-lesion was observed, compared to atomoxetine or idazoxan treatments alone. The results indicate that increases in central NA tone has the propensity to regulate the neuroinflammatory phenotype in vivo and may act as an endogenous neuroprotective mechanism where inflammation contributes to the progression of DA loss. In accordance with this, the clinical use of agents such as NA re-uptake inhibitors and α2-AR antagonists may prove useful in enhancing the endogenous neuroimmunomodulatory potential of NA in conditions associated with brain inflammation.

Duloxetine Protects against Oxaliplatin-Induced Neuropathic Pain and Spinal Neuron Hyperexcitability in Rodents.

Oxaliplatin is a widely used chemotherapy agent, but induces serious peripheral neuropathy. Duloxetine is a dual reuptake inhibitor of serotonin and norepinephrine, and is shown to be effective against pain. However, whether and how duloxetine can attenuate oxaliplatin-induced allodynia in rodents is not clearly understood. A single injection of oxaliplatin (6 mg/kg, intraperitoneal; i.p.) induced a cold and mechanical allodynia, which was assessed by acetone and von Frey filament tests, respectively. When significant allodynic signs were observed, three different doses of duloxetine (10, 30, and 60 mg/kg, i.p.) were injected. Administration of 30 and 60 mg/kg of duloxetine significantly reduced the allodynia, whereas 10 mg/kg did not. By using an in vivo extracellular recording method, we further confirmed that 30 mg/kg of duloxetine could significantly inhibit the hyperexcitability of spinal wide dynamic range (WDR) cells. The anti-allodynic effect of duloxetine was completely blocked by an intrathecal injection of phentolamine (non-selective α-adrenergic receptor antagonist, 20 µg), or prazosin (α1-adrenergic receptor antagonists, 10 µg); however, idazoxan (α2-adrenergic receptor antagonist, 10 µg) did not block it. In conclusion, we suggest that duloxetine may have an effective protective action against oxaliplatin-induced neuropathic pain and spinal hyperexcitability, which is mediated by spinal α1-adrenergic receptors.