A PAM of the α1A-Adrenergic receptor rescues biomarker, long-term potentiation, and cognitive deficits in Alzheimer's disease mouse models without effects on blood pressure.

α1-Adrenergic Receptors (ARs) regulate the sympathetic nervous system by the binding of norepinephrine (NE) and epinephrine (Epi) through different subtypes (α1A, α1B, α1D). α1A-AR activation is hypothesized to be memory forming and cognitive enhancing but drug development has been stagnant due to unwanted side effects on blood pressure. We recently reported the pharmacological characterization of the first positive allosteric modulator (PAM) for the α1A-AR with predictive pro-cognitive and memory properties. In this report, we now demonstrate the in vivo characteristics of Compound 3 (Cmpd-3) in two genetically-different Alzheimer's Disease (AD) mouse models. Drug metabolism and pharmacokinetic studies indicate sufficient brain penetrance and rapid uptake into the brain with low to moderate clearance, and a favorable inhibition profile against the major cytochrome p450 enzymes. Oral administration of Cmpd-3 (3-9 mg/kg QD) can fully rescue long-term potentiation defects and AD biomarker profile (amyloid ß-40, 42) within 3 months of dosing to levels that were non-significant from WT controls and which outperformed donepezil (1 mg/kg QD). There were also significant effects on paired pulse facilitation and cognitive behavior. Long-term and high-dose in vivo studies with Cmpd-3 revealed no effects on blood pressure. Our results suggest that Cmpd-3 can maintain lasting therapeutic levels and efficacy with disease modifying effects with a once per day dosing regimen in AD mouse models with no observed side effects.

α1-Adrenergic Receptors: Insights into Potential Therapeutic Opportunities for COVID-19, Heart Failure, and Alzheimer's Disease.

α1-Adrenergic receptors (ARs) are members of the G-Protein Coupled Receptor superfamily and with other related receptors (ß and α2), they are involved in regulating the sympathetic nervous system through binding and activation by norepinephrine and epinephrine. Traditionally, α1-AR antagonists were first used as anti-hypertensives, as α1-AR activation increases vasoconstriction, but they are not a first-line use at present. The current usage of α1-AR antagonists increases urinary flow in benign prostatic hyperplasia. α1-AR agonists are used in septic shock, but the increased blood pressure response limits use for other conditions. However, with the advent of genetic-based animal models of the subtypes, drug design of highly selective ligands, scientists have discovered potentially newer uses for both agonists and antagonists of the α1-AR. In this review, we highlight newer treatment potential for α1A-AR agonists (heart failure, ischemia, and Alzheimer's disease) and non-selective α1-AR antagonists (COVID-19/SARS, Parkinson's disease, and posttraumatic stress disorder). While the studies reviewed here are still preclinical in cell lines and rodent disease models or have undergone initial clinical trials, potential therapeutics discussed here should not be used for non-approved conditions.

Characterization of a novel positive allosteric modulator of the α1A-Adrenergic receptor.

α1-Adrenergic Receptors (ARs) are G-protein Coupled Receptors (GPCRs) that regulate the sympathetic nervous system via the binding and activation of norepinephrine (NE) and epinephrine (Epi). α1-ARs control various aspects of neurotransmission, cognition, cardiovascular functions as well as other organ systems. However, therapeutic drug development for these receptors, particularly agonists, has been stagnant due to unwanted effects on blood pressure regulation. We report the synthesis and characterization of the first positive allosteric modulator (PAM) for the α1-AR based upon the derivation of the α1A-AR selective imidazoline agonist, cirazoline. Compound 3 (Cmpd-3) binds the α1A-AR with high and low affinity sites (0.13pM; 54 â€‹nM) typical of GPCR agonists, and reverts to a single low affinity site of 100 â€‹nM upon the addition of GTP. Comparison of Cmpd-3 versus other orthosteric α1A-AR-selective imidazoline ligands reveal unique properties that are consistent with a type I PAM. Cmpd-3 is both conformationally and ligand-selective for the α1A-AR subtype. In competition binding studies, Cmpd-3 potentiates NE-binding at the α1A-AR only on the high affinity state of NE with no effect on the Epi-bound α1A-AR. Moreover, Cmpd-3 demonstrates signaling-bias and potentiates the NE-mediated cAMP response of the α1A-AR at nM concentrations with no effects on the NE-mediated inositol phosphate response. There are no effects of Cmpd-3 on the signaling at the α1B- or α1D-AR subtypes. Cmpd-3 displays characteristics of a pure PAM with no intrinsic agonist properties. Specific derivation of Cmpd-3 at the R1 ortho-position recapitulated PAM characteristics. Our results characterize the first PAM for the α1-AR and holds promise for a first-in-class therapeutic to treat various diseases without the side effect of increasing blood pressure intrinsic to classical orthosteric agonists.

Pharmacological characterization of the α2A-adrenergic receptor inhibiting rat hippocampal CA3 epileptiform activity: comparison of ligand efficacy and potency.

The mechanism underlying the antiepileptic actions of norepinephrine (NE) is unclear with conflicting results. Our objectives are to conclusively delineate the specific adrenergic receptor (AR) involved in attenuating hippocampal CA3 epileptiform activity and assess compounds for lead drug development. We utilized the picrotoxin model of seizure generation in rat brain slices using electrophysiological recordings. Epinephrine (EPI) reduced epileptiform burst frequency in a concentration-dependent manner. To identify the specific receptor involved in this response, the equilibrium dissociation constants were determined for a panel of ligands and compared with established binding values for α1, α2, and other receptor subtypes. Correlation and slope of unity were found for the α2A-AR, but not other receptors. Effects of different chemical classes of α-AR agonists at inhibiting epileptiform activity by potency (pEC50) and relative efficacy (RE) were determined. Compared with NE (pEC50, 6.20; RE, 100%), dexmedetomidine, an imidazoline (pEC50, 8.59; RE, 67.1%), and guanabenz, a guanidine (pEC50, 7.94; RE, 37.9%), exhibited the highest potency (pEC50). In contrast, the catecholamines, EPI (pEC50, 6.95; RE, 120%) and α-methyl-NE (pEC50, 6.38; RE, 116%) were the most efficacious. These findings confirm that CA3 epileptiform activity is mediated solely by α2A-ARs without activation of other receptor systems. These findings suggest a pharmacotherapeutic target for treating epilepsy and highlight the need for selective and efficacious α2A-AR agonists that can cross the blood-brain barrier.

The promise and problems of metabolic-based therapies for heart failure.

Despite standard therapies, heart failure patients have high rates of morbidity highlighting the need to develop alternative therapeutic approaches. Heart failure has been described as an energy-starved condition that is hypothesized to drive the pathological remodeling of the heart. Numerous studies have described the metabolic defects that occur when the heart fails and adaptive changes that take place to maintain the energy needed for the heart to function properly. In this review we will summarize the metabolic requirements of a normal heart and what happens during failure. We will also summarize the various metabolic therapeutic strategies that have been developed over the years to treat heart failure and their results from clinical trials.

Targeting Adrenergic Receptors in Metabolic Therapies for Heart Failure.

The heart has a reduced capacity to generate sufficient energy when failing, resulting in an energy-starved condition with diminished functions. Studies have identified numerous changes in metabolic pathways in the failing heart that result in reduced oxidation of both glucose and fatty acid substrates, defects in mitochondrial functions and oxidative phosphorylation, and inefficient substrate utilization for the ATP that is produced. Recent early-phase clinical studies indicate that inhibitors of fatty acid oxidation and antioxidants that target the mitochondria may improve heart function during failure by increasing compensatory glucose oxidation. Adrenergic receptors (α1 and ß) are a key sympathetic nervous system regulator that controls cardiac function. ß-AR blockers are an established treatment for heart failure and α1A-AR agonists have potential therapeutic benefit. Besides regulating inotropy and chronotropy, α1- and ß-adrenergic receptors also regulate metabolic functions in the heart that underlie many cardiac benefits. This review will highlight recent studies that describe how adrenergic receptor-mediated metabolic pathways may be able to restore cardiac energetics to non-failing levels that may offer promising therapeutic strategies.

Current Developments on the Role of α1-Adrenergic Receptors in Cognition, Cardioprotection, and Metabolism.

The α1-adrenergic receptors (ARs) are G-protein coupled receptors that bind the endogenous catecholamines, norepinephrine, and epinephrine. They play a key role in the regulation of the sympathetic nervous system along with ß and α2-AR family members. While all of the adrenergic receptors bind with similar affinity to the catecholamines, they can regulate different physiologies and pathophysiologies in the body because they couple to different G-proteins and signal transduction pathways, commonly in opposition to one another. While α1-AR subtypes (α1A, α1B, α1C) have long been known to be primary regulators of vascular smooth muscle contraction, blood pressure, and cardiac hypertrophy, their role in neurotransmission, improving cognition, protecting the heart during ischemia and failure, and regulating whole body and organ metabolism are not well known and are more recent developments. These advancements have been made possible through the development of transgenic and knockout mouse models and more selective ligands to advance their research. Here, we will review the recent literature to provide new insights into these physiological functions and possible use as a therapeutic target.

α1-Adrenergic receptors increase glucose oxidation under normal and ischemic conditions in adult mouse cardiomyocytes.

The role of catecholamine receptors in cardiac energy metabolism is unknown. α1-adrenergic receptors (α1-ARs) have been identified to play a role in whole body metabolism but its role in cardiac energy metabolism has not been explored. We used freshly prepared primary adult mouse cardiomyocytes and incubated with either 14C-palmitate or 14C-glucose tracers to measure oxidation rates in the presence or absence of phenylephrine, an α1-AR agonist (with ß and α2-AR blockers) under normal cell culture conditions. 14CO2 released was collected over a 10 min period in covered tissue culture plates using a 1 M hyamine hydroxide solution placed in well cups, counted by scintillation and converted into nmoles/hr. We found that phenylephrine stimulated glucose oxidation but not fatty acid oxidation in adult primary cardiomyocytes. α1-AR stimulated glucose oxidation was blocked by the AMPK inhibitor, dorsomorphin dihydrochloride, and the PKC inhibitor, rottlerin. Ischemic conditions were induced by lowering the glucose concentration from 22.5 mM to 1.375 mM. Under ischemic conditions, we found that phenylephrine also increased glucose oxidation. We report a direct role of α1-ARs in regulating glucose oxidation under normal and ischemic conditions that may lead to new therapeutic approaches in treating ischemia.

α1-Adrenergic Receptors in Neurotransmission, Synaptic Plasticity, and Cognition.

α1-adrenergic receptors are G-Protein Coupled Receptors that are involved in neurotransmission and regulate the sympathetic nervous system through binding and activating the neurotransmitter, norepinephrine, and the neurohormone, epinephrine. There are three α1-adrenergic receptor subtypes (α1A, α1B, α1D) that are known to play various roles in neurotransmission and cognition. They are related to two other adrenergic receptor families that also bind norepinephrine and epinephrine, the ß- and α2-, each with three subtypes (ß1, ß2, ß3, α2A, α2B, α2C). Previous studies assessing the roles of α1-adrenergic receptors in neurotransmission and cognition have been inconsistent. This was due to the use of poorly-selective ligands and many of these studies were published before the characterization of the cloned receptor subtypes and the subsequent development of animal models. With the availability of more-selective ligands and the development of animal models, a clearer picture of their role in cognition and neurotransmission can be assessed. In this review, we highlight the significant role that the α1-adrenergic receptor plays in regulating synaptic efficacy, both short and long-term synaptic plasticity, and its regulation of different types of memory. We will also present evidence that the α1-adrenergic receptors, and particularly the α1A-adrenergic receptor subtype, are a potentially good target to treat a wide variety of neurological conditions with diminished cognition.

A unique microRNA profile in end-stage heart failure indicates alterations in specific cardiovascular signaling networks.

It is well established that the gene expression patterns are substantially altered in cardiac hypertrophy and heart failure, however, less is known about the reasons behind such global differences. MicroRNAs (miRNAs) are short non-coding RNAs that can target multiple molecules to regulate wide array of proteins in diverse pathways. The goal of the study was to profile alterations in miRNA expression using end-stage human heart failure samples with an aim to build signaling network pathways using predicted targets for the altered miRNA and to determine nodal molecules regulating individual networks. Profiling of miRNAs using custom designed microarray and validation with an independent set of samples identified eight miRNAs that are altered in human heart failure including one novel miRNA yet to be implicated in cardiac pathology. To gain an unbiased perspective on global regulation by top eight altered miRNAs, functional relationship of predicted targets for these eight miRNAs were examined by network analysis. Ingenuity Pathways Analysis network algorithm was used to build global signaling networks based on the targets of altered miRNAs which allowed us to identify participating networks and nodal molecules that could contribute to cardiac pathophysiology. Majority of the nodal molecules identified in our analysis are targets of altered miRNAs and known regulators of cardiovascular signaling. Cardio-genomics heart failure gene expression public data base was used to analyze trends in expression pattern for target nodal molecules and indeed changes in expression of nodal molecules inversely correlated to miRNA alterations. We have used NF kappa B network as an example to show that targeting other molecules in the network could alter the nodal NF kappa B despite not being a miRNA target suggesting an integrated network response. Thus, using network analysis we show that altering key functional target proteins may regulate expression of the myriad signaling pathways underlying the cardiac pathology.

The role of α1-adrenergic receptors in regulating metabolism: increased glucose tolerance, leptin secretion and lipid oxidation.

The role of α1-adrenergic receptors (α1-ARs) and their subtypes in metabolism is not well known. Most previous studies were performed before the advent of transgenic mouse models and utilized transformed cell lines and poorly selective antagonists. We have now studied the metabolic regulation of the α1A- and α1B-AR subtypes in vivo using knock-out (KO) and transgenic mice that express a constitutively active mutant (CAM) form of the receptor, assessing subtype-selective functions. CAM mice increased glucose tolerance while KO mice display impaired glucose tolerance. CAM mice increased while KO decreased glucose uptake into white fat tissue and skeletal muscle with the CAM α1A-AR showing selective glucose uptake into the heart. Using indirect calorimetry, both CAM mice demonstrated increased whole body fatty acid oxidation, while KO mice preferentially oxidized carbohydrate. CAM α1A-AR mice displayed significantly decreased fasting plasma triglycerides and glucose levels while α1A-AR KO displayed increased levels of triglycerides and glucose. Both CAM mice displayed increased plasma levels of leptin while KO mice decreased leptin levels. Most metabolic effects were more efficacious with the α1A-AR subtype. Our results suggest that stimulation of α1-ARs results in a favorable metabolic profile of increased glucose tolerance, cardiac glucose uptake, leptin secretion and increased whole body lipid metabolism that may contribute to its previously recognized cardioprotective and neuroprotective benefits.

α1A-Adrenergic receptor prevents cardiac ischemic damage through PKCδ/GLUT1/4-mediated glucose uptake.

While α(1)-adrenergic receptors (ARs) have been previously shown to limit ischemic cardiac damage, the mechanisms remain unclear. Most previous studies utilized low oxygen conditions in addition to ischemic buffers with glucose deficiencies, but we discovered profound differences if the two conditions are separated. We assessed both mouse neonatal and adult myocytes and HL-1 cells in a series of assays assessing ischemic damage under hypoxic or low glucose conditions. We found that α(1)-AR stimulation protected against increased lactate dehydrogenase release or Annexin V(+) apoptosis under conditions that were due to low glucose concentration not to hypoxia. The α(1)-AR antagonist prazosin or nonselective protein kinase C (PKC) inhibitors blocked the protective effect. α(1)-AR stimulation increased (3)H-deoxyglucose uptake that was blocked with either an inhibitor to glucose transporter 1 or 4 (GLUT1 or GLUT4) or small interfering RNA (siRNA) against PKCδ. GLUT1/4 inhibition also blocked α(1)-AR-mediated protection from apoptosis. The PKC inhibitor rottlerin or siRNA against PKCδ blocked α(1)-AR stimulated GLUT1 or GLUT4 plasma membrane translocation. α(1)-AR stimulation increased plasma membrane concentration of either GLUT1 or GLUT4 in a time-dependent fashion. Transgenic mice overexpressing the α(1A)-AR but not α(1B)-AR mice displayed increased glucose uptake and increased GLUT1 and GLUT4 plasma membrane translocation in the adult heart while α(1A)-AR but not α(1B)-AR knockout mice displayed lowered glucose uptake and GLUT translocation. Our results suggest that α(1)-AR activation is anti-apoptotic and protective during cardiac ischemia due to glucose deprivation and not hypoxia by enhancing glucose uptake into the heart via PKCδ-mediated GLUT translocation that may be specific to the α(1A)-AR subtype.

Long-term α1B-adrenergic receptor activation shortens lifespan, while α1A-adrenergic receptor stimulation prolongs lifespan in association with decreased cancer incidence.

The α1-adrenergic receptor (α1AR) subtypes, α1AAR and α1BAR, have differential effects in the heart and central nervous system. Long-term stimulation of the α1AAR subtype prolongs lifespan and provides cardio- and neuro-protective effects. We examined the lifespan of constitutively active mutant (CAM)-α1BAR mice and the incidence of cancer in mice expressing the CAM form of either the α1AAR (CAM-α1AAR mice) or α1BAR. CAM-α1BAR mice have a significantly shortened lifespan when compared with wild-type (WT) animals; however, the effect was sex dependent. Female CAM-α1BAR mice lived significantly shorter lives, while the median lifespan of male CAM-α1BAR mice was not different when compared with that of WT animals. There was no difference in the incidence of cancer in either sex of CAM-α1BAR mice. The incidence of cancer was significantly decreased in CAM-α1AAR mice when compared with that in WT, and no sex-dependent effects were observed. Further study is warranted on cancer incidence after activation of each α1AR subtype and the effect of sex on lifespan following activation of the α1BAR. The implications of a decrease in cancer incidence following long-term α1AAR stimulation could lead to improved treatments for cancer.

Novel proteins associated with human dilated cardiomyopathy: selective reduction in α(1A)-adrenergic receptors and increased desensitization proteins.

Abstract Therapeutics to treat human heart failure (HF) and the identification of proteins associated with HF are still limited. We analyzed α(1)-adrenergic receptor (AR) subtypes in human HF and performed proteomic analysis on more uniform samples to identify novel proteins associated with human HF. Six failing hearts with end-stage dilated cardiomyopathy (DCM) and four non-failing heart controls were subjected to proteomic analysis. Out of 48 identified proteins, 26 proteins were redundant between samples. Ten of these 26 proteins were previously reported to be associated with HF. Of the newly identified proteins, we found several muscle proteins and mitochondrial/electron transport proteins, while novel were functionally similar to previous reports. However, we also found novel proteins involved in functional classes such as ß-oxidation and G-protein coupled receptor signaling and desensitization not previously associated with HF. We also performed radioligand-binding studies on the heart samples and not only confirmed a large loss of ß(1)-ARs in end-stage DCM, but also found a selective decrease in the α(1A)-AR subtype not previously reported. We have identified new proteins and functional categories associated with end-stage DCM. We also report that similar to the previously characterized loss of ß(1)-AR in HF, there is also a concomitant loss of α(1A)-ARs, which are considered cardioprotective proteins.

α1A-adrenergic receptors regulate cardiac hypertrophy in vivo through interleukin-6 secretion.

The role of α1-adrenergic receptors (ARs) in the regulation of cardiac hypertrophy is still unclear, because transgenic mice demonstrated hypertrophy or the lack of it despite high receptor overexpression. To further address the role of the α1-ARs in cardiac hypertrophy, we analyzed unique transgenic mice that overexpress constitutively active mutation (CAM) α1A-ARs or CAM α1B-ARs under the regulation of large fragments of their native promoters. These constitutively active receptors are expressed in all tissues that endogenously express their wild-type counterparts as opposed to only myocyte-targeted transgenic mice. In this study, we discovered that CAM α1A-AR mice in vivo have cardiac hypertrophy independent of changes in blood pressure, corroborating earlier studies, but in contrast to myocyte-targeted α1A-AR mice. We also found cardiac hypertrophy in CAM α1B-AR mice, in agreement with previous studies, but hypertrophy only developed in older mice. We also discovered unique α1-AR-mediated hypertrophic signaling that was AR subtype-specific with CAM α1A-AR mice secreting atrial naturietic factor and interleukin-6 (IL-6), whereas CAM α1B-AR mice expressed activated nuclear factor-κB (NF-κB). These particular hypertrophic signals were blocked when the other AR subtype was coactivated. We also discovered that crossbreeding the two CAM models (double CAM α1A/B-AR) inhibited the development of hypertrophy and was reversible with single receptor activation, suggesting that coactivation of the receptors can lead to novel antagonistic signal transduction. This was confirmed by demonstrating antagonistic signals that were even lower than normal controls in the double CAM α1A/B-AR mice for p38, NF-κB, and the IL-6/glycoprotein 130/signal transducer and activator of transcription 3 pathway. Because α1A/B double knockout mice fail to develop hypertrophy in response to IL-6, our results suggest that IL-6 is a major mediator of α1A-AR cardiac hypertrophy.

GPCRs in stem cell function.

Many tissues of the body cannot only repair themselves, but also self-renew, a property mainly due to stem cells and the various mechanisms that regulate their behavior. Stem cell biology is a relatively new field. While advances are slowly being realized, stem cells possess huge potential to ameliorate disease and counteract the aging process, causing its speculation as the next panacea. Amidst public pressure to advance rapidly to clinical trials, there is a need to understand the biology of stem cells and to support basic research programs. Without a proper comprehension of how cells and tissues are maintained during the adult life span, clinical trials are bound to fail. This review will cover the basic biology of stem cells, the various types of stem cells, their potential function, and the advantages and disadvantages to their use in medicine. We will next cover the role of G protein-coupled receptors in the regulation of stem cells and their potential in future clinical applications.

G-protein-coupled receptors in adult neurogenesis.

The importance of adult neurogenesis has only recently been accepted, resulting in a completely new field of investigation within stem cell biology. The regulation and functional significance of adult neurogenesis is currently an area of highly active research. G-protein-coupled receptors (GPCRs) have emerged as potential modulators of adult neurogenesis. GPCRs represent a class of proteins with significant clinical importance, because approximately 30% of all modern therapeutic treatments target these receptors. GPCRs bind to a large class of neurotransmitters and neuromodulators such as norepinephrine, dopamine, and serotonin. Besides their typical role in cellular communication, GPCRs are expressed on adult neural stem cells and their progenitors that relay specific signals to regulate the neurogenic process. This review summarizes the field of adult neurogenesis and its methods and specifies the roles of various GPCRs and their signal transduction pathways that are involved in the regulation of adult neural stem cells and their progenitors. Current evidence supporting adult neurogenesis as a model for self-repair in neuropathologic conditions, adult neural stem cell therapeutic strategies, and potential avenues for GPCR-based therapeutics are also discussed.

α(1A)-adrenergic receptor differentially regulates STAT3 phosphorylation through PKCϵ and PKCδ in myocytes.

Previous studies demonstrated α1-adrenergic receptors (ARs) increase STAT3 activation in transfected and non-cardiac primary cell lines. However, the mechanism used by α1-ARs resulting in STAT3 activation is unknown. While other G-protein-coupled receptors (GPCRs) can couple to STAT3, these mechanisms demonstrate coupling through SRC, TYK, Rac, or complex formation with Gq and used only transfected cell lines. Using normal and transgenic mice containing constitutively active mutations (CAM) of the α(1A)-AR subtype, neonatal mouse myocytes and whole hearts were analyzed for the mechanism to couple to STAT3 activation. α1-ARs stimulated time-dependent increases in p-SRC, p-JAK2, and p-STAT3 in normal neonatal myocytes. Using various kinase inhibitors and siRNA, we determined that the α(1A)-AR coupled to STAT3 through distinct and unique pathways in neonatal myocytes. We found that PKCϵ inhibition decreased p-ERK and p-Ser STAT3 levels without affecting p-Tyr STAT3. In contrast, we found that PKCδ inhibition affected p-SRC and p-JAK2 resulting in decreased p-Tyr and p-Ser STAT3 levels. We suggest a novel α(1A)-AR mediated PKCϵ/ERK pathway that regulates the phosphorylation status of STAT3 at Ser-727 while PKCδ couples to SRC/JAK2 to affect Tyr-705 phosphorylation. Furthermore, this pathway has not been previously described in a GPCR system that couples to STAT3. Given cell survival and protective cardiac effects induced by PKC, STAT3 and ERK signaling, our results could explain the neuroprotective and cardiac protective pathways that are enhanced with α(1A)-AR agonism.

Long-term α1A-adrenergic receptor stimulation improves synaptic plasticity, cognitive function, mood, and longevity.

The role of α(1)-adrenergic receptors (α(1)ARs) in cognition and mood is controversial, probably as a result of past use of nonselective agents. α(1A)AR activation was recently shown to increase neurogenesis, which is linked to cognition and mood. We studied the effects of long-term α(1A)AR stimulation using transgenic mice engineered to express a constitutively active mutant (CAM) form of the α(1A)AR. CAM-α(1A)AR mice showed enhancements in several behavioral models of learning and memory. In contrast, mice that have the α(1A)AR gene knocked out displayed poor cognitive function. Hippocampal brain slices from CAM-α(1A)AR mice demonstrated increased basal synaptic transmission, paired-pulse facilitation, and long-term potentiation compared with wild-type (WT) mice. WT mice treated with the α(1A)AR-selective agonist cirazoline also showed enhanced cognitive functions. In addition, CAM-α(1A)AR mice exhibited antidepressant and less anxious phenotypes in several behavioral tests compared with WT mice. Furthermore, the lifespan of CAM-α(1A)AR mice was 10% longer than that of WT mice. Our results suggest that long-term α(1A)AR stimulation improves synaptic plasticity, cognitive function, mood, and longevity. This may afford a potential therapeutic target for counteracting the decline in cognitive function and mood associated with aging and neurological disorders.