Alpha-adrenergic Receptors Research Articles

The New Stealth Drug on the Street: A Narrative Review of Xylazine as a Street Drug.

Xylazine is an alpha-adrenergic receptor agonist approved for use only in animals with a prescription from a veterinarian. It is a powerful sedative that is slowly infiltrating the recreational street drug scene and is often used by polysubstance abusers. Known as "tranq," it can be fatal, and xylazine-induced toxicity cannot be reversed with naloxone or nalmefene. Due to its vasoconstrictive effects, chronic use of xylazine is associated with necrotic skin lesions and general deterioration of health. Since xylazine is not approved for human use and is not scheduled as a controlled substance, there are no human studies to provide evidence of drug-drug interactions, lethal doses, or reversal protocols. Xylazine is available online without a prescription. Street drug users may take xylazine knowingly or unknowingly, as it is often combined with other illicit substances such as fentanyl. There are no rapid tests for xylazine, although there are specialty tests that can be ordered. Xylazine represents a major threat to street drug users and another challenge to emergency healthcare workers, first responders, and others who care for those who have taken this "new" street drug.

Assessing attention and impulsivity in the variable stimulus duration and variable intertrial interval rodent continuous performance test schedules using noradrenaline receptor antagonists in female C57BL/6JRj mice

RationaleNoradrenergic dysfunction is associated with disorders of impulsivity and inattention. The rodent continuous performance test (rCPT) quantifies changes in attention and impulsivity.ObjectiveTo use NA receptor antagonists to examine the roles of NA on attention and impulsivity behaviours measured in the rCPT variable stimulus duration (vSD) and the variable intertrial interval (vITI) schedules.MethodsTwo cohorts of 36 female C57BL/6JRj mice were examined separately in the rCPT vSD and vITI schedules. Both cohorts received antagonists of the following adrenoceptors: α1 (doxazosin, DOX: 1.0, 3.0, 10.0 mg/kg), α2 (yohimbine, YOH: 0.1, 0.3, 1.0 mg/kg), and β1/2 (propranolol, PRO: 1.0, 3.0, 10.0 mg/kg) in consecutive balanced Latin square designs with flanking reference measurements. The antagonists were subsequently examined for effects on locomotor activity.ResultsDOX showed similar effects in both schedules, improving discriminability and accuracy, and reducing responding and impulsivity, and DOX also reduced locomotor activity. YOH showed prominent effects in the vSD schedule to increase responding and impulsivity, while impairing discriminability and accuracy. YOH did not affect locomotor activity. PRO increased responding and impulsivity, decreased accuracy, but did not affect discriminability or locomotor activity.ConclusionAntagonism of α2 or β1/2 adrenoceptors caused similar increases in responding and impulsivity and worsened attentional performance, while α1 adrenoceptor antagonism showed the opposite effects. Our results suggest that endogenous NA exerts bidirectional control of most behaviours in the rCPT. The parallel vSD and vITI studies showed a substantial overlap in effects, but also some differences that indicate differing sensitivity towards noradrenergic manipulations.

Repeated Traumatic Brain Injury is Associated with Neurotoxic Plasma Autoantibodies Directed against the Serotonin 2A and Alpha 1 Adrenergic Receptors.

Traumatic brain injury (TBI) was associated with increased plasma agonist autoantibodies targeting the serotonin 2A receptor. Repeated TBI exposure is associated with high risk for neurodegenerative and neuropsychiatric complications. Here we tested a hypothesis that repeated TBI is associated with plasma agonist autoantibodies targeting more than one kind of catecholamine G-protein coupled receptor. Protein-A affinity chromatography was used to isolate the IgG fraction of plasma in forty-two middle-aged and older adults who had experienced one or more TBI exposures. The Ig (1/40th dilution=7.5 ug/mL) were tested for neurotoxicity in mouse neuroblastoma cells using an acute neurite retraction assay indicative of Gq11/IP3/Ca2+ and RhoA/Rho kinase signaling pathways' activation. Three different linear synthetic peptides corresponding to the second extracellular loop of the alpha 1A, alpha 2A or serotonin 2A receptors were used as target antigen in different enzyme-linked immunoassays. The second extracellular loop receptor peptides themselves (alpha 1A, alpha 2A) or a fragment (serotonin 2A) were tested for ability to prevent Ig-induced neurite retraction. Patients who had experienced either repeated TBI (N=10) or a single TBI with a co-morbid autoimmune disease (N=5) were significantly more likely to harbor neurotoxic plasma autoantibodies targeting both alpha 1 adrenergic and serotonin 2A receptors vs. patients having only a single TBI. Ig-induced neurotoxicity was significantly prevented by co-incubation with either 850 nM prazosin (alpha 1 adrenergic receptor) and/or 500 nM M100907 (serotonin 2A receptor) antagonists. Alpha 1 adrenergic receptor and serotonin 2A receptor Ig immunoreactive level and titer were significantly increased in repeated TBI and single TBI/autoimmune patients (N=7-8) compared to age-matched TBI patients without neurotoxic plasma Ig (N=4). SN.8, a linear synthetic peptide corresponding to a conserved region of the second extracellular loop (ECL) of the serotonin 2A receptor completely prevented neurite retraction induced by repeated TBI plasma Ig. A repeated TBI patient harboring alpha adrenergic receptor AAB alone experienced prospective steep decline in cognitive function over two years. Repeated TBI and TBI with associated autoimmunity harbored more than one kind of neurotoxic catecholaminergic agonist GPCR autoantibody each associated with high risk for steep rate of cognitive decline. Specific immunoassays using the second extracellular receptor loop as target antigen are needed to detect each specific different GPCR autoantibody. A fragment of the second ECL of the serotonin 2A receptor (SN.8) neutralized Ig-induced neurotoxicity in repeated TBI or TBI with associated systemic autoimmunity.

Ocular Posterior Segment Distribution and Pharmacokinetics of Brimonidine After Intravitreal Administration in Guinea Pigs.

Purpose: Brimonidine is a highly alpha-2 adrenergic agonist, which provides a potential myopia control effect. This study aimed to examine the pharmacokinetics and concentration of brimonidine in the posterior segment tissue of eyes in guinea pigs. Methods: A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was successfully used for brimonidine pharmacokinetics and tissue distribution research in guinea pigs following intravitreal administration (20 μg/eye). Results: Brimonidine concentrations in the retina and sclera were maintained at a high level (>60 ng/g) at 96 h postdosing. Brimonidine concentration peaked in the retina (377.86 ng/g) at 2.41 h and sclera (306.18 ng/g) at 6.98 h. The area under curve (AUC0-∞) was 27,179.99 ng h/g in the retina and 39,529.03 ng h/g in the sclera. The elimination half-life (T1/2e) was 62.43 h in the retina and 67.94 h in the sclera. Conclusions: The results indicated that brimonidine was rapidly absorbed and diffused to the retina and sclera. Meanwhile, it maintained higher posterior tissue concentrations, which can effectively activate the alpha-2 adrenergic receptor. This may provide pharmacokinetic evidence for the inhibition of myopia progression by brimonidine in animal experiments.

Brain regions with higher noradrenergic innervation show greater vulnerability to degeneration in preclinicial Alzheimer’s disease

AbstractBackgroundThe noradrenergic (NA) system comprises several cortical and subcortical brain areas with differential densities of NA transporters and receptors. A decline in the NA system, together with additional risk factors such as ApoE4‐status, gender, age, vascular changes and years of education may contribute to the development of Alzheimer’s disease (AD). The aim of this study was to examine whether brain areas known to be rich in NA receptors and transporters are particularly vulnerable to degeneration in preclinical AD.MethodWe examined interindividual differences in volumes of specific brain areas grouped into high and low NA density regions (NA‐high/NA‐low) for healthy controls (HC) and AD relatives (n = 122), individuals with subjective cognitive decline (SCD) (n = 152) and mild cognitive impairment (MCI) (n = 78). Structural equation modeling (SEM) was used to simultaneously examine associations between NA‐high and NA‐low regions across clinical groups. We investigated whether brain volumes in NA‐high and NA‐low areas were differentially related to known AD risk factors (ApoE4 status, CSF amyloid‐ß (Aß) 42/40 and phosphorylated tau (pTau)), and whether these links differed in HC, SCD and MCI.ResultEstimating a two‐factor model with NA‐high and NA‐low revealed a better model fit than estimating one general factor. ApoE4‐carriers were associated with a lower ratio of Aß42/40 (‐0.472***) and a higher level of pTau (0.263***). In the whole sample, a low ratio of Aß42/40 was associated with lower brain volume in NA‐high (0.157***), but not NA‐low areas. pTau showed no significant association to NA‐high or NA‐low areas.The group analysis revealed an increasing association between ApoE4, pTau and Aß42/40 in HC, SCD and MCI. An association between Aß42/40 and NA‐high areas was observed in all groups, whilst for an additional positive association to NA‐low in HC (0.125*), but negative association in SCD (‐0.184*). Finally, the negative association between pTau and Aß42/40 is true for SCD and MCI, but not for HC.ConclusionSEM can be used to separate brain regions into NA‐high and NA‐low areas. Higher risk status Aß42/40 is linked to lower brain volume in high NA density areas, suggesting a particular vulnerability of brain areas likely more affected by NA decline in AD.

Multiscale model of primary motor cortex circuits predicts in vivo cell-type-specific, behavioral state-dependent dynamics

Understanding cortical function requires studying multiple scales: molecular, cellular, circuit, and behavioral. We develop a multiscale, biophysically detailed model of mouse primary motor cortex (M1) with over 10,000 neurons and 30 million synapses. Neuron types, densities, spatial distributions, morphologies, biophysics, connectivity, and dendritic synapse locations are constrained by experimental data. The model includes long-range inputs from seven thalamic and cortical regions and noradrenergic inputs. Connectivity depends on cell class and cortical depth at sublaminar resolution. The model accurately predicts invivo layer- and cell-type-specific responses (firing rates and LFP) associated with behavioral states (quiet wakefulness and movement) and experimental manipulations (noradrenaline receptor blockade and thalamus inactivation). We generate mechanistic hypotheses underlying the observed activity and analyzed low-dimensional population latent dynamics. This quantitative theoretical framework can be used to integrate and interpret M1 experimental data and sheds light on the cell-type-specific multiscale dynamics associated with several experimental conditions and behaviors.

Functional Involvement of ADRA1D in Cutaneous Melanoma Progression and Angiogenesis.

Cutaneous melanoma is a highly aggressive and malignant skin cancer, and its high recurrence rate and drug resistance increase the difficulty of treating advanced-stage patients. Studies have revealed that treatment via stimulation of alpha-1 adrenergic receptor (ADRA1) subtypes inhibits melanoma growth in mice. However, the associations between alpha-1D adrenergic receptor (ADRA1D) and cutaneous melanoma are poorly understood. Tissue specimens from 16 pairs of patients with a pigmented nevus and cutaneous melanoma were analyzed for ADRA1D expression using immunohistochemical staining. Western blotting and RT-qPCR were carried out in order to detect ADRA1D expression levels in melanoma cells and human epidermal melanocytes (HEMs), hypoxia-inducible factor-1α (HIF-1α), and vascular endothelial growth factor (VEGF) levels in HUVECS. A375 cells were transfected with a lentivirus overexpressing ADRA1D. Wound-healing, Transwell, and cell proliferation assays were utilized to identify the ADRA1D effect on the migration, invasion, and proliferation of the two groups of A375 cells in vitro. In order to evaluate the function of ADRA1D in vivo, a melanoma xenograft model was developed in immunodeficient mice. ADRA1D was low expressed in cutaneous melanoma tissues. Overexpression of ADRA1D inhibited the tubulation and migration of HUVECs in vitro. Overexpression of ADRA1D significantly decreased the HIF-1α and VEGF expression. Overexpression of ADRA1D inhibited the invasion and proliferation of A375 melanoma cells in vitro and reduced its angiogenesis in vivo. ADRA1D inhibits cutaneous melanoma growth and angiogenesis. It attenuates melanoma cell proliferation and invasion. Meanwhile, its anti-angiogenic effect is achieved by negatively regulating the HIF-1α/VEGF axis in melanoma tissue, thereby attenuating the growth of cutaneous melanoma and reducing the potential of metastasis.

The Role of Alpha-2 Agonists for Attention Deficit Hyperactivity Disorder in Children: A Review.

Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common neurodevelopmental disorders, characterized by the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), which is marked by symptoms such as inappropriate levels of inattention, hyperactivity, and impulsivity that can affect academic, social, and personal functioning in children and adolescents. This review summarizes clinical trials demonstrating the effectiveness of Alpha-2 agonists in reducing symptoms of inattention, hyperactivity, and impulsivity in children with ADHD. Studies were identified through a systematic search of PubMed and Cochrane databases. However, these medications' long-term safety and efficacy remain uncertain, with a lack of data on their effects on growth, cardiovascular function, and other adverse events. Further studies are required to determine these medications' optimal dose and treatment duration. Medications that target the noradrenergic system, such as Alpha-2 agonists, have been increasingly used as a treatment option for ADHD, with guanfacine and clonidine being two of the most commonly used medications. They function by selectively targeting Alpha-2 adrenergic receptors in the brain leading to improved attention and reduced hyperactivity and impulsivity symptoms in children with ADHD. Clinical trials have demonstrated the effectiveness of Alpha-2 agonists in treating ADHD in children by reducing symptoms of inattention, hyperactivity, and impulsivity. However, these medications' long-term safety and efficacy still need to be completely understood. Due to a lack of information on the effects of Alpha-2 agonists on growth, cardiovascular function, and other long-term adverse events, more studies must investigate the optimal dose and treatment duration for these medications. Despite these concerns, Alpha-2 agonists remain a valuable treatment option for ADHD in children, especially those unable to tolerate stimulant medications or who have coexisting conditions such as tic disorders. Future research should continue to explore the safety and efficacy of Alpha-2 agonists in the long term. In conclusion, Alpha-2 agonists show promise as a treatment for ADHD in children; however, the safety and efficacy of these drugs in the long term are not yet completely understood. Additional studies are required to investigate the optimal dose and treatment duration for these medications in their use as a treatment for this debilitating disease.

(230) Chronic Unpredictable Stress Impairs Corpus Cavernosum Reactivity in Mice

Abstract Introduction Stress is associated with erectile dysfunction (ED), however, it is not clear whether psychological stressors affect the vasculature and the erectile tissue in a manner that could contribute to a vasculogenic erectile dysfunction. A positive correlation between hyperprolactinemia, stress and erectile dysfunction has been demonstrated, and interestingly, prolactin was shown to decrease endothelium nitric oxide and endothelium- dependent vasorelaxation in different vascular beds. In this study, we aimed to evaluate the relaxation of the corpus cavernosum of male and pudendal artery of male and female mice undergoing chronic unpredictable stress (CUS). Objective We aimed to test the hypothesis that vascular impairment caused by CUS leads to impaired relaxation of the pudendal artery and corpus cavernosum which may cause erectile dysfunction. Methods Male and female C57Bl/6 mice were submitted to 28 days of chronic unpredictable stress (CUS). The pudendal artery and corpus cavernosum were removed and mounted in a myograph to evaluate reactivity. Tissues were kept in physiological salt solution at 37°C, constantly aerated with 95%O2/5%CO2 and concentration-response curves to acetylcholine (ACh; 1 nM – 30 uM) and phenylephrine (PE; 1 nM – 30 uM) were obtained. Using non-linear regression, we obtained the maximal response (Emax) and potency (pEC50) of ACh and PE. Data are expressed as mean ± S.E.M. P<0.05 was considered statistically different. Results In the pudendal artery, neither the potency nor the maximal response to ACh was changed by the stress. Contraction to PE was higher in males, compared to females, and there was a trend to be further increased in stressed males. On the other hand, in the corpus cavernosum of stressed males there was a significant decrease in the maximal relaxation induced by acetylcholine (control: 88 ± 4% vs stress: 75 ± 4%, n=7 each group) as well as impaired contraction to PE (control: 1.72 ± 0.17% vs stress: 1.07 ± 0.15%, n= 7 each group). The impaired relaxation might be associated with impaired nitric oxide availability, whereas impaired contraction can be associated with a desensitization of alpha-adrenergic receptors in response to stress. Conclusions Our findings demonstrate that stress impairs the reactivity of the corpus cavernosum, which may contribute to the development of erectile dysfunction in stressed males. Disclosure No

Cognitive Test Solution in Mice with Different Brain Weights after Atomoxetine.

In this paper, the data are presented concerning different reactions to seven daily injections of atomoxetine in two mouse strains differing in relative brain weight. Atomoxetine affected the performance in a puzzle-box cognitive test in a complicated way-the large brain mice were less successful at task solutions (presumably because they were not afraid of the brightly lit test box), while the small brain strain of atomoxetine treated mice solved the task more successfully. The behavior of all atomoxetine treated animals was more active in an aversive situation (an unescapable slippery funnel, (analogous to the Porsolt test) and the time of immobility decreased significantly in all atomoxetine treated mice. The general patterns of behavioral reactions to atomoxetine in the cognitive test and other interstrain differences demonstrated in these experiments made it possible to suggest that differences in ascending noradrenergic projections between the two strains used exist. Further analysis of the noradrenergic system in these strains is needed (and further analysis of the effects of drugs which affect noradrenergic receptors).

Alpha-methyltyrosine reduces the acute cardiovascular and behavioral sequelae in a murine model of traumatic brain injury.

Increased catecholamines contribute to heightened cardiovascular reactivity and behavioral deficits after traumatic brain injury (TBI); adrenergic receptor blockade has limited success in reducing adverse sequelae of TBI. Injury-induced increases in the synthesis of catecholamines could contribute to adverse outcomes in TBI. Inhibition of catecholamine synthesis with alpha-methyltyrosine (αMT) could offer a benefit after TBI. Original research trial in mice randomized to αMT (50 mg·kg -1 ·d -1 ) or vehicle for 1 week after TBI induced by controlled cortical impact. Primary outcomes of cardiovascular reactivity and behavioral deficits were assessed after 1 week. Secondary outcomes included blood brain barrier permeability and quantification of gene transcription whose products determine intraneuronal chloride concentrations, the release of catecholamines, and activation of the sympathetic nervous system. These genes were the alpha-2 adrenergic receptor ("Adra2c"), the sodium-potassium-chloride cotransporter ("Nkcc1"), and the potassium chloride cotransporter ("Kcc2"). We also assessed the effect of TBI and αMT on the neuronal chloride/bicarbonate exchanger ("Ae3"). Traumatic brain injury-induced increases in blood pressure and cardiac reactivity were blocked by αMT. Inhibition of catecholamine synthesis decreased blood brain barrier leakage and improved behavioral outcomes after TBI. Traumatic brain injury diminished the transcription of Adra2c and enhanced expression of Nkcc1 while reducing Kcc2 transcription; αMT prevented the induction of the Nkcc1 by TBI without reversing the effects of TBI on Kcc2 expression; αMT also diminished Ae3 transcription. Traumatic brain injury acutely increases cardiovascular reactivity and induces behavioral deficits in an αMT-sensitive manner, most likely by inducing Nkcc1 gene transcription. Alpha-methyltyrosine may prove salutary in the treatment of TBI by attenuating the enhanced expression of Nkcc1, minimizing blood brain barrier leakage, and diminishing central catecholamine and sympathetic output. We also found an unreported relationship between Kcc2 and the chloride/bicarbonate exchanger, which should be considered in the design of trials planned to manipulate central intraneuronal chloride concentrations following acute brain injury.

Development of the vasoactive intestinal peptide receptor 2 (VIPR2) antagonist peptide for the treatment of schizophrenia

Schizophrenia affects approximately 24 million people worldwide. Existing medications for the treatment of schizophrenia work primarily by improving positive symptoms such as agitation, hallucinations, delusions, and aggression. They possess common mechanism of action (MOA), blocking to neurotransmitter receptors such as dopamine, serotonin, and adrenaline receptors. Although multiple agents are available for the treatment of schizophrenia, the majority do not address negative symptoms or cognitive dysfunction. In other cases, patients have drug-related adverse effects. The vasoactive intestinal peptide receptor 2 (VIPR2, also known as VPAC2 receptor) might be an attractive drug target for the treatment of schizophrenia because both clinical and preclinical studies have demonstrated a strong link between high expression/overactivation of VIPR2 and schizophrenia. Despite these backgrounds, the proof-of-concept of VIPR2 inhibitors has not been examined clinically. A reason might be that VIPR2 belongs to class-B GPCRs, and the discovery of small-molecule drugs against class-B GPCRs is generally difficult. We have developed a bicyclic peptide KS-133, which shows VIPR2 antagonist activity and suppresses cognitive decline in a mouse model relevant to schizophrenia. KS-133 has a different MOA from current therapeutic drugs and exhibits high selectivity for VIPR2 and potent inhibitory activity against a single-target molecule. Therefore, it may contribute to both the development of a novel drug candidate for the treatment of psychiatric disorders such as schizophrenia and acceleration of basic studies on VIPR2.

Vagal nerve activity and sympathetic nerve activity are suppressed by alpha-2 adrenergic receptor agonists in conscious rats

Vagal nerve activity (VNA) and sympathetic nerve activity (SNA) have been known to influence each other and changes in their activity directly, but details on this remain unknown. This study used an alpha-2 adrenergic receptor agonist (dexmedetomidine) to study how SNA affects VNA in the conscious state. Electroencephalography, electromyography, electrocardiography, cervical VNA, renal SNA, and catheters for arterial pressure measurement and intravenous drug administration were measured after male Wistar rats were anesthetized and implanted with electrodes. Dexmedetomidine (50 micro g/kg) was intravenously administered in conscious rats. Cervical VNA decreased and reached its lowest values about 10 min after intravenous dexmedetomidine administration. However, renal SNA, electromyography, and heart rate decreased immediately after administration, whereas arterial pressure increased immediately. These results show that alpha-2 adrenergic receptor agonists simultaneously inhibit VNA and SNA. Furthermore, the present data suggest that excessive SNA activation increases norepinephrine release, inducing an increase in the concentration of circulating norepinephrine, which in turn inhibits SNA via negative feedback and suppresses VNA. JST (JPMJMS2023) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

In Vivo Real-Time Study of Drug Effects on Carotid Blood Flow in the Ovine Fetus.

The ability of an organism to maintain a constant blood flow to the brain in response to sudden surges in systemic blood pressure (BP) is known as cerebral autoregulation (CAR), which occurs in the carotid artery. In contrast to full-term neonates, preterm neonates are unable to reduce the cerebral blood flow (CBF) in response to increased systemic BP. In preterm neonates, this exposes the fragile cerebral vessels to high perfusion pressures, leading to their rupture and brain damage. Ex vivo studies using wire myography have demonstrated that carotid arteries from near-term fetuses constrict in response to the activation of adrenergic alpha1 receptors. This response is blunted in the preterm fetus. Thus, to examine the role of alpha1-AR in vivo, presented here is an innovative approach to determine the effects of drugs on a carotid arterial segment in vivo in an ovine fetus during the developmental progression of gestation. The presented data demonstrate the simultaneous measurement of fetal blood flow and blood pressure. The perivascular delivery system can be used to conduct a long-term study over several days. Additional applications for this method could include viral delivery systems to alter the expression of genes in a segment of the carotid artery. These methods could be applied to other blood vessels in the growing organism in utero as well as in adult organisms.

The role of beta- and alpha-adrenergic receptors on alcohol drinking

Alcohol Use Disorders (AUD) is characterized by compulsion-like alcohol drinking (CLAD), where intake despite negative consequences can be a major clinical obstacle. With few treatment options available for AUD, there is a significant need for novel therapies. The noradrenergic system is an important hub for regulating stress responses and maladaptive drives for alcohol. Studies have shown that drugs targeting α1 adrenenergic receptors (ARs) may represent a pharmacological treatment for pathological drinking. However, the involvement of β ARs for treating human drinking has received scant investigation, and thus we sought to provide pre-clinical validation for possible AR utility for CLAD by analyzing whether β AR antagonists propranolol (β1/2), betaxolol (β1), and ICI, 118,551 (β2) impacted CLAD and alcohol-only drinking (AOD) in male Wistar rats. We found that the highest dose of propranolol tested systemically (10 mg/kg) reduced alcohol drinking, while 5 mg/kg propranolol reduced drinking with a trend to impact CLAD more than AOD, and with no effects of 2.5 mg/kg. Betaxolol (2.5 mg/kg) also decreased drinking, while ICI 118.551 had no effects. Also, while AR compounds might have utility for AUD, they can also lead to undesirable side effects. Here, a combination of ineffective doses of propranolol and prazosin reduced both CLAD and AOD. Finally, we investigated the effect of propranolol and betaxolol in two brain areas related to pathological drinking, the anterior insula (aINS) and medial prefrontal cortex (mPFC). Surprisingly, propranolol (1–10 μg) in aINS or mPFC did not affect CLAD or AOD. Together, our findings provide new pharmacological insights into noradrenergic regulation of alcohol consumption, which may inform AUD therapy.

Lurasidone for Treating Schizophrenia and Bipolar Depression: A Review of Its Efficacy.

Lurasidone is an antipsychotic medication that blocks dopamine D2 and serotonin 5-hydroxy-tryptamine (5-HT)2Areceptors and affects other serotoninergic and noradrenergic receptors. It has rapid absorption and linear pharmacokinetics. The rates of metabolic syndrome for patients taking lurasidone are comparable to placebo groups. Lurasidone is a safe and effective treatment for patients with acute schizophrenia and bipolar depression. It has been found to improve the brief psychiatric rating scale and other secondary measures in schizophrenic patients and reduce depressive symptoms in bipolar I depression. The once-daily administration of lurasidone is generally well-tolerated and does not cause clinically significant differences in extrapyramidal symptoms, adverse effects, or weight gain compared to a placebo. However, lurasidone's effectiveness in combination with lithium or valproate has been mixed. Further research is needed to determine optimal dosing, treatment duration, and combination with other mood stabilizers. Long-term safety and effectiveness and its use in different subpopulations should also be evaluated.

Prenatal Morphine Exposure Increases Cardiovascular Disease Risk and Programs Neurogenic Hypertension in the Adult Offspring.

The opioid overdose and opioid use disorder epidemics are concomitant with increased metabolic and CVD risk. Although opioid use disorder causes adverse pregnancy outcomes, the offspring's cardiovascular health is understudied. We hypothesized that offspring exposed to in utero morphine exposure (IUME) would show increased CVD risk factors and endogenous opioid system dysregulation. Sprague Dawley dams were treated with saline (vehicle, n=10) or escalating doses of morphine (5-20 mg/kg per day, SC, n=10) during gestation. Cardiovascular and metabolic parameters were assessed in adult offspring. Litter size and pups' birth weight were not different in response to IUME. Female and male IUME offspring showed reduced body length at birth (P<0.05) and body weight from weeks 1 to 3 of life (P<0.05), followed by a catch-up growth effect. By week 16, female and male IUME rats showed reduced tibia length (P<0.05) and fat mass. IUME increases the mean arterial pressure and the depressor response to mecamylamine (5 mg/kg per day, IP) induced by IUME were abolished by a chronic treatment with an alpha-adrenergic receptor blocker (prazosin; 1 mg/kg per day, IP). Although circulating levels of angiotensin peptides were similar between groups, IUME exacerbated maximal ex vivo Ang (angiotensin) II-induced vasoconstriction (P<0.05) and induced endothelial dysfunction in a sex-specific manner (P<0.05). Proenkephalin, an endogenous opioid peptide that lowers blood pressure and sympathetic-mediated vasoconstriction, showed reduced mRNA expression in the heart, aorta, and kidneys from morphine versus vehicle group (P<0.05). Among the effects of IUME, neurogenic hypertension, vascular dysfunction, and metabolic dysfunction could be associated with the dysregulation of the endogenous opioid system.

Emotion-related impulsivity moderates the role of arousal on reflection impulsivity

Emotion-related impulsivity is an important behavioural phenotype in clinical psychology and public health. Here, we test the hypothesis that emotion-related impulsivity moderates the effects of arousal on cognition using pharmacological manipulation. Participants completed a measure of emotion-related impulsivity, four cognitive tasks tapping onto different facets of impulsive behaviours, and a blinded arousal manipulation using yohimbine hydrochloride, which acts on noradrenergic receptors. Our findings suggest that emotion-related impulsivity moderates the role of arousal on impulsive performance on the Information Sampling Task. As expected, more severe emotion-related impulsivity was related to more impulsive decisions in the yohimbine but not in the placebo group. Results provide some of the first experimental evidence that emotion-related impulsivity is related to differential behavioural responses in the face of high arousal. Despite this preliminary support, we discuss findings for one task that did not fit hypotheses, and provide suggestions for replication and extension.

Number Needed to Treat and Number Needed to Harm From Two Phase 3 Studies of Sublingual Dexmedetomidine for Treating Acute Agitation in Patients With Schizophrenia and Bipolar Disorder

AbstractBackgroundEpisodes of acute agitation can occur in individuals who suffer from schizophrenia or bipolar disorder and these can be a significant challenge for patients and for those who provide care to them. Sublingual dexmedetomidine is a selective alpha2-adrenergic receptor agonist that was recently approved by the US Food and Drug Administration for the treatment of agitation in adults with schizophrenia or bipolar disorder. The sublingual form of dexmedetomidine does not undergo first-pass hepatic metabolism, thus resulting in greater absorption than when ingested. In two Phase 3 studies of adults with schizophrenia or bipolar disorder, sublingual dexmedetomidine significantly reduced acute agitation at 2 hours, as measured by the five-item Positive and Negative Syndrome Scale-Excited Component (PEC). When initially appraising the potential utility of a new medication, number needed to treat (NNT) and needed to harm (NNH) can be helpful to assess the size of the treatment effect and, hence, clinical relevance.ObjectiveCalculation of NNT and NNH through post hoc analysis of Phase 3 data.MethodsPost hoc analysis of data were performed on data from two double-blind, randomized, placebo-controlled studies of sublingual dexmedetomidine in adults with schizophrenia or bipolar disorder experiencing acute agitation. Patients were randomized to a single dose of sublingual dexmedetomidine 180 μg, 120 μg, or placebo. The primary endpoint was mean change from baseline in the PEC total score. A therapeutic response was defined as a ≥40% reduction from baseline in PEC total score at 2 hours. NNT was calculated for PEC response rate for sublingual dexmedetomidine versus placebo. NNH was calculated using the incidence of adverse events for sublingual dexmedetomidine versus placebo. Likelihood to be helped or harmed (LHH) was calculated as the ratio of NNH to NNT.ResultsNNT (95% CI) was 3 (2, 3) for 180 mcg and 3 (3, 4) for 120 ug in patients with schizophrenia and 3 (2, 3) for 180 mcg and 4 (3, 6) for 120 ug in patients with bipolar disorder. NNH was greater than 10 for all AEs except somnolence, where NNH was 7 (5, 10) for all doses pooled from both studies. LLH values were greater than 1 for efficacy versus applicable tolerability outcomes in all cases.ConclusionsThis post hoc analysis demonstrated favorable NNT and NNH values for sublingual dexmedetomidine. In all instances therapeutic response was encountered more frequently than any adverse event. These values compare favorably to similar analyses for other approved agents for the treatment of agitation associated with schizophrenia or bipolar disorder, including intramuscular and inhaled formulations.FundingBioXcel Therapeutics, Inc.

Divergent projections from locus coeruleus to the corticobasal ganglia system and ventral tegmental area of the adult male zebra finch.

The locus coeruleus (LC) is a small noradrenergic brainstem nucleus that plays a central role in regulating arousal, attention, and performance. In the mammalian brain, individual LC neurons make divergent axonal projections to different brain regions, which are distinguished in part by which noradrenaline (NA) receptor subtypes they express. Here, we sought to determine whether similar organizational features characterize LC projections to corticobasal ganglia (CBG) circuitry in the zebra finch song system, with a focus on the basal ganglia nucleus Area X, the thalamic nucleus DLM, as well as the cortical nuclei HVC, LMAN, and RA. Single and dual retrograde tracer injections reveal that single LC-NA neurons make divergent projections to LMAN and Area X, as well as to the dopaminergic VTA/SNc complex that innervates this CBG circuit. Moreover, in situ hybridization revealed that differential expression of mRNA encoding α2A and α2C adrenoreceptors distinguishes LC-recipient CBG song nuclei. Therefore, LC-NA signaling in the zebra finch CBG circuit employs a similar strategy as in mammals, which could allow a relatively small number of LC neurons to exert widespread yet distinct effects across multiple brain regions.