Chronic administration of cannabinoid agonists ACEA (CB1), AM1241 (CB2), and CP55,940 (mixed CB1/CB2) induce sex-specific differences in tolerance and sex hormone changes in a chemotherapy-induced peripheral neuropathy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of chemotherapy treatment, routinely manifesting as increased pain sensitivity (allodynia) in distal extremities. Despite its prevalence, effective treatment options are limited. Cannabinoids are increasingly being evaluated for their ability to treat chronic pain conditions, including CIPN. While previous studies have revealed sex differences in cannabinoid-mediated antinociception in acute and chronic pain models, there is a paucity of studies addressing potential sex differences in the response of CIPN to cannabinoid treatment. Therefore, we evaluated the long-term anti-allodynic efficacy of CB1-selective (ACEA), CB2-selective (AM1241), and CB1/CB2 mixed (CP55,940) agonists in the cisplatin CIPN model, using both male and female mice. CB1 selective agonism was observed to have sex differences in the development of tolerance to anti-allodynic effects, with females developing tolerance more rapidly than males, while the anti-allodynic effects of selective CB2 agonism lacked tolerance development. Compound-specific changes to the female estrous cycle and female plasma estradiol levels were noted, with CB1 selective agonism decreasing plasma estradiol while CB2 selective agonism increased plasma estradiol. Chronic administration of a mixed CB1/CB2 agonist resulted in increased mRNA expression of proinflammatory cytokines and endocannabinoid regulatory enzymes in female spinal cord tissue. Ovarian tissue was noted to have proinflammatory cytokine mRNA expression following administration of a CB2 acting compound while selective CB1 agonism resulted in decreased proinflammatory cytokines and endocannabinoid regulatory enzymes in testes. These results support the need for further investigation into the role of sex and sex hormones signaling in pain and cannabinoid-mediated antinociceptive effects. Significance Statement CIPN is a common side effect of chemotherapy. We have found that both CB1 and CB2 receptor agonism produce antinociceptive effects in a cisplatin CIPN model. We observed that tolerance to CB1-mediated antinociception developed faster in females and did not develop for CB¬2-mediated antinociception. Additionally, we found contrasting roles for CB1/CB¬2 receptors in the regulation of plasma estradiol in females, with CB1 agonism attenuating estradiol and CB¬2 agonism enhancing estradiol. These findings support the exploration of cannabinoid agonists for CIPN.

Social evaluative stress enhances central detail memory, reduces false memory, and results in intrusive memories that last for days.

Few studies have quantified what an individual remembers about a laboratory-controlled stressor. Here, we aimed to replicate previous work by using a modified version of the Trier Social Stress Test (TSST) to quantify participant memory for a stressful experience. We also aimed to extend this work by quantifying false and intrusive memories that ensued. One hundred and seven participants were exposed to the TSST (stress) or the friendly TSST (f-TSST; no stress). The TSST required participants to deliver a ten-minute speech in front of two laboratory panel members as part of a mock job interview; the f-TSST required participants to casually converse with the panel members about their interests. In both conditions, the panel members interacted with (central) or did not interact with (peripheral) several objects sitting on a desk in front of them. The next day, participants' memory for the objects was assessed with recall and recognition tests. We also quantified participants' intrusive memories on Days 2, 4, 6, and 8. Stressed participants recalled more central objects and exhibited greater recognition memory, particularly for central objects, than controls. Stress also led to less false recall and more intrusive memories on Days 2 and 4. Consistent with previous work, these findings suggest that participants exhibit enhanced memory for the central details of a stressful experience; they also extend prior work by showing that participants exposed to a stressor have less false memories and experience intrusive memories for several days following the event. The modified TSST paradigm used here may be useful for researchers studying not only what participants remember about a stressful event but also their susceptibility to intrusive memory formation.

Maternal use of methamphetamine alters cardiovascular function in the adult offspring.

Methamphetamine is one of the most commonly used illicit drugs during pregnancy. Most studies investigating the impact of maternal use of methamphetamine on children have focused on neurological outcomes. In contrast, cardiovascular outcomes in these children have not been characterized. Recent studies in rodents provide evidence that prenatal exposure to methamphetamine induces changes in cardiac gene expression, changes in the heart's susceptibility to ischemic injury, and changes in vascular function that may increase the risk of developing cardiovascular disorders later in life. Importantly, these changes are sex-dependent. This review summarizes our current understanding of how methamphetamine use during pregnancy impacts the cardiovascular function of adult offspring and highlights gaps in our knowledge of the potential cardiovascular risks associated with prenatal exposure to methamphetamine.

Role of Cannabinoid Signaling in Cardiovascular Function and Ischemic Injury.

Cardiovascular disease represents a leading cause of death, morbidity, and societal economic burden. The prevalence of cannabis use has significantly increased due to legalization and an increased societal acceptance of cannabis. Therefore, it is critically important that we gain a greater understanding of the effects and risks of cannabinoid use on cardiovascular diseases as well as the potential for cannabinoid-directed drugs to be used as therapeutics for the treatment of cardiovascular disease. This review summarizes our current understanding of the role of cannabinoid receptors in the pathophysiology of atherosclerosis and myocardial ischemia and explores their use as therapeutic targets in the treatment of ischemic heart disease. Endocannabinoids are elevated in patients with atherosclerosis, and activation of cannabinoid type 1 receptors (CB1Rs) generally leads to an enhancement of plaque formation and atherosclerosis. In contrast, selective activation of cannabinoid type 2 receptors (CB2Rs) appears to exert protective effects against atherosclerosis. Endocannabinoid signaling is also activated by myocardial ischemia. CB2R signaling appears to protect the heart from ischemic injury, whereas the role of CB1R in ischemic injury is less clear. This narrative review serves to summarize current research on the role of cannabinoid signaling in cardiovascular function with the goal of identifying critical knowledge gaps and future studies to address those gaps in a way that facilitates the development of new treatments and better cardiovascular health. SIGNIFICANCE STATEMENT: Cardiovascular diseases, including atherosclerosis and myocardial infarction, are a leading cause of death. Cannabinoid drugs have well known acute effects on cardiovascular function, including tachycardia and orthostatic hypotension. The recent legalization of marijuana and cannabinoids for both medical and recreational use has dramatically increased their prevalence of use. This narrative review on the role of cannabinoid signaling in cardiovascular disease contributes to a better understanding of this topic by integrating current knowledge and identifying critical gaps.

Methamphetamine-induced changes in myocardial gene transcription are sex-dependent.

BACKGROUND: Prior work demonstrated that female rats (but not their male littermates) exposed to methamphetamine become hypersensitive to myocardial ischemic injury. Importantly, this sex-dependent effect persists following 30 days of subsequent abstinence from the drug, suggesting that it may be mediated by long term changes in gene expression that are not rapidly reversed following discontinuation of methamphetamine use. The goal of the present study was to determine whether methamphetamine induces sex-dependent changes in myocardial gene expression and whether these changes persist following subsequent abstinence from methamphetamine. RESULTS: Methamphetamine induced changes in the myocardial transcriptome were significantly greater in female hearts than male hearts both in terms of the number of genes affected and the magnitude of the changes. The largest changes in female hearts involved genes that regulate the circadian clock (Dbp, Per3, Per2, BMal1, and Npas2) which are known to impact myocardial ischemic injury. These genes were unaffected by methamphetamine in male hearts. All changes in gene expression identified at day 11 returned to baseline by day 30. CONCLUSIONS: These data demonstrate that female rats are more sensitive than males to methamphetamine-induced changes in the myocardial transcriptome and that methamphetamine does not induce changes in myocardial transcription that persist long term after exposure to the drug has been discontinued.

Myocardial fibrosis, inflammation, and altered cardiac gene expression profiles in rats exposed to a predator-based model of posttraumatic stress disorder.

People who are exposed to life-threatening trauma are at risk of developing posttraumatic stress disorder (PTSD). In addition to psychological manifestations, PTSD is associated with an increased risk of myocardial infarction, arrhythmias, hypertension, and other cardiovascular problems. We previously reported that rats exposed to a predator-based model of PTSD develop myocardial hypersensitivity to ischemic injury. This study characterized cardiac changes in histology and gene expression in rats exposed this model. Male rats were subjected to two cat exposures (separated by a period of 10 d) and daily cage-mate changes for 31 d. Control rats were not exposed to the cat or cage-mate changes. Ventricular tissue was analyzed by RNA sequencing, western blotting, histology, and immunohistochemistry. Multifocal lesions characterized by necrosis, mononuclear cell infiltration, and collagen deposition were observed in hearts from all stressed rats but none of the control rats. Gene expression analysis identified clusters of upregulated genes associated with endothelial to mesenchymal transition, endothelial migration, mesenchyme differentiation, and extracellular matrix remodeling in hearts from stressed rats. Consistent with endothelial to mesenchymal transition, rats from stressed hearts exhibited increased expression of α-smooth muscle actin (a myofibroblast marker) and a decrease in the number of CD31 positive endothelial cells. These data provide evidence that predator-based stress induces myocardial lesions and reprograming of cardiac gene expression. These changes may underlie the myocardial hypersensitivity to ischemia observed in these animals. This rat model may provide a useful tool for investigating the cardiac impact of PTSD and other forms of chronic psychological stress.Lay summaryChronic predator stress induces the formation of myocardial lesions characterized by necrosis, collagen deposition, and mononuclear cell infiltration. This is accompanied by changes in gene expression and histology that are indicative of cardiac remodeling. These changes may underlie the increased risk of arrhythmias, myocardial infarction, and other cardiac pathologies in people who have PTSD or other forms of chronic stress.

A predator-based psychosocial stress animal model of PTSD in females: Influence of estrous phase and ovarian hormones.

Traumatized women are more likely than traumatized men to develop post-traumatic stress disorder (PTSD). Still, the inclusion of females in animal models of PTSD has largely been avoided, likely due to the variable hormone profile of female rodents. Because a valid animal model of PTSD that incorporates females is still needed, we examined the influence of estrous stage and ovarian hormones on the female rat response to a predator-based psychosocial stress model of PTSD. Female Sprague-Dawley rats were exposed to psychosocial stress or control conditions for 31 days. Stressed rats were given two cat exposures and daily social instability; control rats were handled daily. Beginning on Day 32, rats underwent physiological or behavioral testing. In Experiment 1, vaginal smears were collected on days of the first and second cat exposures and each day of behavioral testing to determine estrous stage. In Experiments 2 and 3, ovariectomized or sham control rats were exposed to stress or control conditions. Then, they were given behavioral testing (Exp 2), or their hearts were isolated and subjected to ischemia/reperfusion on a Langendorff isolated heart system (Exp 3). Chronic stress increased anxiety-like behavior, irrespective of estrous stage or ovariectomy condition. Ovariectomized females displayed greater startle responses and anxiety-like behavior than sham rats. Stress had no impact on myocardial sensitivity to ischemic injury; however, ovariectomized females exhibited greater ischemia-induced infarction than sham rats. These findings suggest that ovarian hormones may prevent anxiety-like behavior and be cardioprotective in non-stressed controls, but they do not interact with chronic stress to influence the development of PTSD-like sequelae in female rats.

Interactive influence of sex, stressor timing, and the BclI glucocorticoid receptor polymorphism on stress-induced alterations of long-term memory.

Certain susceptibility factors, such as genetic variants or specific physiological responses to stress, can dictate the effects of stress on learning and memory. Here, we examined the influence of the BclI polymorphism of the glucocorticoid receptor gene on the time-dependent effects of pre-learning stress on long-term memory. Healthy individuals were exposed to the socially evaluated cold pressor test or a control condition immediately or 30 min before word list learning. Participants' memory for the words was tested immediately and 24 h after learning, and saliva samples were collected to genotype participants for the BclI polymorphism and to assess cortisol responses to the stressor. Results revealed that stress immediately before learning enhanced memory, while stress 30 min before learning impaired memory; these effects were largely selective to males and non-arousing words. Additionally, stress, independent of when it was administered, enhanced memory in non-carriers of the BclI polymorphism, while impairing memory in carriers; these effects were largely selective to males and participants exhibiting a robust cortisol response to stress. These results provide further evidence for time-dependent effects of stress on long-term memory and suggest that carriers of the BclI polymorphism might be more sensitive to the negative effects of corticosteroids on learning.

Regulator of G protein signaling 2 differentially regulates nicotine-induced anxiolytic- and antidepressant-like effects in mice.

This study assessed the role of regulator of G protein signaling 2 (RGS2) in nicotine-induced anxiolytic- and antidepressant-like effects using RGS2 wildtype (WT) and RGS2 knockout (KO) mice. RGS2 negatively regulates monoaminergic neurotransmission, which is implicated in the pathology of anxiety and depression. We hypothesized that deletion of RGS2 would enhance nicotine-induced anxiolytic- and antidepressant-like effects, which were assessed using the elevated plus maze and tail suspension tests, respectively. Anxiolytic-like effects were observed in both RGS2 WT and KO mice after administration of low dose of nicotine (0.05 mg/kg, base) compared to respective saline controls. Additionally, administration of nicotine (0.1 mg/kg, base) compared to saline resulted in anxiolytic-like effects in RGS2 KO mice, but not RGS2 WT mice, suggesting genetic deletion of RGS2 facilitated anxiolytic-like effects of nicotine. Administration of nicotine (0.5 and 1 mg/kg, base) compared to saline resulted in antidepressant-like effects in RGS2 WT mice. Antidepressant-like effects were observed in RGS2 KO mice only at the highest tested dose of nicotine (1 mg/kg, base) compared to saline controls, suggesting that genetic deletion of RGS2 decreased sensitivity to antidepressant-like effects of nicotine. Together, the data suggest that RGS2 differentially regulated nicotine-induced affective behavioral responses. These data suggest that individuals with RGS2 polymorphisms may experience differential affective responses to tobacco smoking, which may make them vulnerable to developing nicotine addiction.

FKBP5 polymorphisms influence pre-learning stress-induced alterations of learning and memory.

FK506 binding protein 51 (FKBP5) is a co-chaperone of heat shock protein 90 and significantly influences glucocorticoid receptor sensitivity. Single nucleotide polymorphisms (SNPs) in the FKBP5 gene are associated with altered hypothalamus-pituitary-adrenal (HPA) axis function, changes in the structure and function of several cognitive brain areas, and increased susceptibility to post-traumatic stress disorder, major depression, bipolar disorder and suicidal events. The mechanisms underlying these associations are largely unknown, but it has been speculated that the influence of these SNPs on emotional memory systems may play a role. In the present study, 112 participants were exposed to the socially evaluated cold pressor test (stress) or control (no stress) conditions immediately prior to learning a list of 42 words. Participant memory was assessed immediately after learning (free recall) and 24 h later (free recall and recognition). Participants provided a saliva sample that enabled the genotyping of three FKBP5 polymorphisms: rs1360780, rs3800373 and rs9296158. Results showed that stress impaired immediate recall in risk allele carriers. More importantly, stress enhanced long-term recall and recognition memory in non-carriers of the risk alleles, effects that were completely absent in risk allele carriers. Follow-up analyses revealed that memory performance was correlated with salivary cortisol levels in non-carriers, but not in carriers. These findings suggest that FKBP5 risk allele carriers may possess a sensitized stress response system, perhaps specifically for stress-induced changes in corticosteroid levels, which might aid our understanding of how SNPs in the FKBP5 gene confer increased risk for stress-related psychological disorders and their related phenotypes.

Regulator of G Protein Signaling 6 Protects the Heart from Ischemic Injury.

Gαi-coupled receptors play important roles in protecting the heart from ischemic injury. Regulator of G protein signaling (RGS) proteins suppress Gαi signaling by accelerating the GTPase activity of Gαi subunits. However, the roles of individual RGS proteins in modulating ischemic injury are unknown. In this study, we investigated the effect of RGS6 deletion on myocardial sensitivity to ischemic injury. Hearts from RGS6 knockout (RGS6-/-) and RGS6 wild-type (RGS6+/+) mice were subjected to 30 minutes of ischemia and 2 hours of reperfusion on a Langendorff heart apparatus. Infarcts in RGS6-/- hearts were significantly larger than infarcts in RGS6+/+ hearts. RGS6-/- hearts also exhibited increased phosphorylation of ß2-adrenergic receptors and G protein-coupled receptor kinase 2 (GRK2). Mitochondrial GRK2 as well as caspase-3 cleavage were increased significantly in RGS6-/- hearts compared with RGS6+/+ hearts after ischemia. Chronic propranolol treatment of mice prevented the observed increases in ischemic injury and the GRK2 phosphorylation observed in RGS6-/- hearts. Our findings suggest that loss of RGS6 predisposes the ventricle to prodeath signaling through a ß2AR-GRK2-dependent signaling mechanism, and they provide evidence for a protective role of RGS6 in the ischemic heart. Individuals expressing genetic polymorphisms that suppress the activity of RGS6 may be at increased risk of cardiac ischemic injury. Furthermore, the development of agents that increase RGS6 expression or activity might provide a novel strategy for the treatment of ischemic heart disease.

ADRA2B deletion variant influences time-dependent effects of pre-learning stress on long-term memory.

Extensive work over the past few decades has shown that certain genetic variations interact with life events to confer increased susceptibility for the development of psychological disorders. The deletion variant of the ADRA2B gene, which has been associated with enhanced emotional memory and heightened amygdala responses to emotional stimuli, might confer increased susceptibility for the development of post-traumatic stress disorder (PTSD) or related phenotypes by increasing the likelihood of traumatic memory formation. Thus, we examined whether this genetic variant would predict stress effects on learning and memory in a non-clinical sample. Two hundred and thirty-five individuals were exposed to the socially evaluated cold pressor test or a control condition immediately or 30min prior to learning a list of words that varied in emotional valence and arousal level. Participants' memory for the words was tested immediately (recall) and 24h after learning (recall and recognition), and saliva samples were collected to genotype participants for the ADRA2B deletion variant. Results showed that stress administered immediately before learning selectively enhanced long-term recall in deletion carriers. Stress administered 30min before learning impaired recognition memory in male deletion carriers, while enhancing recognition memory in female deletion carriers. These findings provide additional evidence to support the idea that ADRA2B deletion variant carriers retain a sensitized stress response system, which results in amplified effects of stress on learning and memory. The accumulating evidence regarding this genetic variant implicates it as a susceptibility factor for traumatic memory formation and PTSD-related phenotypes.

Blunted cortisol response to acute pre-learning stress prevents misinformation effect in a forced confabulation paradigm.

Research examining the effects of stress on false memory formation has been equivocal, partly because of the complex nature of stress-memory interactions. A major factor influencing stress effects on learning is the timing of stress relative to encoding. Previous work has shown that brief stressors administered immediately before learning enhance long-term memory. Thus, we predicted that brief stress immediately before learning would decrease participants' susceptibility to subsequent misinformation and reduce false memory formation. Eighty-four male and female participants submerged their hand in ice cold (stress) or warm (no stress) water for 3min. Immediately afterwards, they viewed an 8-min excerpt from the Disney movie Looking for Miracles. The next day, participants were interviewed and asked several questions about the video, some of which forced them to confabulate responses. Three days and three weeks later, respectively, participants completed a recognition test in the lab and a free recall test via email. Our results revealed a robust misinformation effect, overall, as participants falsely recognized a significant amount of information that they had confabulated during the interview as having occurred in the original video. Stress, overall, did not significantly influence this misinformation effect. However, the misinformation effect was completely absent in stressed participants who exhibited a blunted cortisol response to the stress, for both recognition and recall tests. The complete absence of a misinformation effect in non-responders may lend insight into the interactive roles of autonomic arousal and corticosteroid levels in false memory development.

Prenatal methamphetamine differentially alters myocardial sensitivity to ischemic injury in male and female adult hearts.

Methamphetamine is one of the most common illicit drugs abused during pregnancy. The neurological effects of prenatal methamphetamine are well known. However, few studies have investigated the potential effects of prenatal methamphetamine on adult cardiovascular function. Previous work demonstrated that prenatal cocaine exposure increases sensitivity of the adult heart to ischemic injury. Methamphetamine and cocaine have different mechanisms of action, but both drugs exert their effects by increasing dopaminergic and adrenergic receptor stimulation. Thus the goal of this study was to determine whether prenatal methamphetamine also worsens ischemic injury in the adult heart. Pregnant rats were injected with methamphetamine (5 mg·kg(-1)·day(-1)) or saline throughout pregnancy. When pups reached 8 wk of age, their hearts were subjected to ischemia and reperfusion by means of a Langendorff isolated heart system. Prenatal methamphetamine had no significant effect on infarct size, preischemic contractile function, or postischemic recovery of contractile function in male hearts. However, methamphetamine-treated female hearts exhibited significantly larger infarcts and significantly elevated end-diastolic pressure during recovery from ischemia. Methamphetamine significantly reduced protein kinase Cε expression and Akt phosphorylation in female hearts but had no effect on these cardioprotective proteins in male hearts. These data indicate that prenatal methamphetamine differentially affects male and female sensitivity to myocardial ischemic injury and alters cardioprotective signaling proteins in the adult heart.

Sex-dependent effects of sleep deprivation on myocardial sensitivity to ischemic injury.

Sleep deprivation is associated with increased risk of myocardial infarction. However, it is unknown whether the effects of sleep deprivation are limited to increasing the likelihood of experiencing a myocardial infarction or if sleep deprivation also increases the extent of myocardial injury. In this study, rats were deprived of paradoxical sleep for 96 h using the platform-over-water method. Control rats were subjected to the same condition except the control platform was large enough for the rats to sleep. Hearts from sleep deprived and control rats were subjected to 20 min ischemia on a Langendorff isolated heart system. Infarct size and post ischemic recovery of contractile function were unaffected by sleep deprivation in male hearts. In contrast, hearts from sleep-deprived females exhibited significantly larger infarcts than hearts from control females. Post ischemic recovery of rate pressure product and + dP/dT were significantly attenuated by sleep deprivation in female hearts, and post ischemic recovery of end diastolic pressure was significantly elevated in hearts from sleep deprived females compared to control females, indicating that post ischemic recovery of both systolic and diastolic function were worsened by sleep deprivation. These data provide evidence that sleep deprivation increases the extent of ischemia-induced injury in a sex-dependent manner.

Sex-dependent effects of chronic psychosocial stress on myocardial sensitivity to ischemic injury.

Individuals with post-traumatic stress disorder (PTSD) experience many debilitating symptoms, including intrusive memories, persistent anxiety and avoidance of trauma-related cues. PTSD also results in numerous physiological complications, including increased risk for cardiovascular disease (CVD). However, characterization of PTSD-induced cardiovascular alterations is lacking, especially in preclinical models of the disorder. Thus, we examined the impact of a psychosocial predator-based animal model of PTSD on myocardial sensitivity to ischemic injury. Male and female Sprague-Dawley rats were exposed to psychosocial stress or control conditions for 31 days. Stressed rats were given two cat exposures, separated by a period of 10 days, and were subjected to daily social instability throughout the paradigm. Control rats were handled daily for the duration of the experiment. Rats were tested on the elevated plus maze (EPM) on day 32, and hearts were isolated on day 33 and subjected to 20 min ischemia and 2 h reperfusion on a Langendorff isolated heart system. Stressed male and female rats gained less body weight relative to controls, but only stressed males exhibited increased anxiety on the EPM. Male, but not female, rats exposed to psychosocial stress exhibited significantly larger infarcts and attenuated post-ischemic recovery of contractile function compared to controls. Our data demonstrate that predator stress combined with daily social instability sex-dependently increases myocardial sensitivity to ischemic injury. Thus, this manipulation may be useful for studying potential mechanisms underlying cardiovascular alterations in PTSD, as well as sex differences in the cardiovascular stress response.

Thymidine Phosphorylase Deficiency or Inhibition Preserves Cardiac Function in Mice With Acute Myocardial Infarction.

Background Ischemic cardiovascular disease is the leading cause of death worldwide. Current pharmacologic therapy has multiple limitations, and patients remain symptomatic despite maximal medical therapies. Deficiency or inhibition of thymidine phosphorylase (TYMP) in mice reduces thrombosis, suggesting that TYMP could be a novel therapeutic target for patients with acute myocardial infarction (AMI). Methods and Results A mouse AMI model was established by ligation of the left anterior descending coronary artery in C57BL/6J wild-type and TYMP-deficient (Tymp-/-) mice. Cardiac function was monitored by echocardiography or Langendorff assay. TYMP-deficient hearts had lower baseline contractility. However, cardiac function, systolic left ventricle anterior wall thickness, and diastolic wall strain were significantly greater 4 weeks after AMI compared with wild-type hearts. TYMP deficiency reduced microthrombus formation after AMI. TYMP deficiency did not affect angiogenesis in either normal or infarcted myocardium but increased arteriogenesis post-AMI. TYMP deficiency enhanced the mobilization of bone marrow stem cells and promoted mesenchymal stem cell (MSC) proliferation, migration, and resistance to inflammation and hypoxia. TYMP deficiency increased the number of larger MSCs and decreased matrix metalloproteinase-2 expression, resulting in a high homing capability. TYMP deficiency induced constitutive AKT phosphorylation in MSCs but reduced expression of genes associated with retinoid-interferon-induced mortality-19, a molecule that enhances cell death. Inhibition of TYMP with its selective inhibitor, tipiracil, phenocopied TYMP deficiency, improved post-AMI cardiac function and systolic left ventricle anterior wall thickness, attenuated diastolic stiffness, and reduced infarct size. Conclusions This study demonstrated that TYMP plays an adverse role after AMI. Targeting TYMP may be a novel therapy for patients with AMI.

Pre-Learning Stress That Is Temporally Removed from Acquisition Impairs Fear Learning.

Few studies have examined the time-dependent effects of stress on fear learning. Previously, we found that stress immediately before fear conditioning enhanced fear learning. Here, we aimed to extend these findings by assessing the effects of stress 30 min prior to fear conditioning on fear learning and fear generalization. Two hundred and twenty-one healthy adults underwent stress (socially evaluated cold pressor test) or a control manipulation 30 min before completing differential fear conditioning in a fear-potentiated startle paradigm. One visual stimulus (CS+), but not another (CS-), was associated with an aversive airblast to the throat (US) during acquisition. The next day, participants were tested for their fear responses to the CS+, CS-, and several generalization stimuli. Stress impaired the acquisition of fear on Day 1 but had no significant impact on fear generalization. The stress-induced impairment of fear learning was particularly evident in participants who exhibited a robust cortisol response to the stressor. These findings are consistent with the notion that stress administered 30 min before learning impairs memory formation via corticosteroid-related mechanisms and may help us understand how fear memories are altered in stress-related psychological disorders.

Prenatal Exposure to Methamphetamine Causes Vascular Dysfunction in Adult Male Rat Offspring.

Methamphetamine use during pregnancy can have negative consequences on the offspring. However, most studies investigating the impact of prenatal exposure to methamphetamine have focused on behavioral and neurological outcomes. Relatively little is known regarding the impact of prenatal methamphetamine on the adult cardiovascular system. This study investigated the impact of chronic fetal exposure to methamphetamine on vascular function in adult offspring. Pregnant female rats received daily saline or methamphetamine (5 mg/kg) injections starting on gestational day 1 and continuing until the pups were born. Vascular function was assessed in 5 month old offspring. Prenatal methamphetamine significantly decreased both the efficacy and potency of acetylcholine-induced relaxation in isolated male (but not female) aortas when perivascular adipose tissue (PVAT) remained intact. However, prenatal methamphetamine had no impact on acetylcholine-induced relaxation when PVAT was removed. Nitroprusside-induced relaxation of the aorta was unaffected by prenatal methamphetamine. Angiotensin II-induced contractile responses were significantly potentiated in male (but not female) aortas regardless of the presence of PVAT. This effect was reversed by L-nitro arginine methyl ester (L-NAME). Serotonin- and phenylephrine-induced contraction were unaffected by prenatal methamphetamine. Prenatal methamphetamine had no impact on acetylcholine-induced relaxation of third order mesenteric arteries and no effect on basal blood pressure. These data provide evidence that prenatal exposure to methamphetamine sex-dependently alters vasomotor function in the vasculature and may increase the risk of developing vascular disorders later in adult life.

Maternal use of methamphetamine induces sex-dependent changes in myocardial gene expression in adult offspring.

Methamphetamine is a commonly abused illicit stimulant that has prevalent use among women of child-bearing age. While there are extensive studies on the neurological effects of prenatal methamphetamine exposure, relatively little is known about the effect of prenatal methamphetamine on the adult cardiovascular system. Earlier work demonstrated that prenatal methamphetamine exposure sex dependently (females only) sensitizes the adult heart to ischemic injury. These data suggest that prenatal exposure to methamphetamine may induce sex-dependent changes in cardiac gene expression that persist in adult offspring. The goal of this study was to test the hypothesis that prenatal methamphetamine exposure induces changes in cardiac gene expression that persist in the adult heart. Hearts of prenatally exposed female offspring exhibited a greater number of changes in gene expression compared to male offspring (184 changes compared with 74 in male offspring and 89 changes common between both sexes). Dimethylarginine dimethylaminohydrolase 2 and 3-hydroxybutyrate dehydrogenase 1 (genes implicated in heart failure) were shown by Western Blot to be under expressed in adult females that were prenatally exposed to methamphetamine, while males were deficient in 3-Hydroxybutyrate Dehydrogenase 1 only. These data indicate that prenatal methamphetamine exposure induces changes in gene expression that persist into adulthood. This is consistent with previous findings that prenatal methamphetamine sex dependently sensitizes the adult heart to ischemic injury and may increase the risk of developing cardiac disorders during adulthood.