Physiological Mechanisms of Dietary Salt Sensing in the Brain, Kidney, and Gastrointestinal Tract.

Excess dietary salt (NaCl) intake is strongly correlated with cardiovascular disease and is a major contributing factor to the pathogenesis of hypertension. NaCl-sensitive hypertension is a multisystem disorder that involves renal dysfunction, vascular abnormalities, and neurogenically-mediated increases in peripheral resistance. Despite a major research focus on organ systems and these effector mechanisms causing NaCl-induced increases in arterial blood pressure, relatively less research has been directed at elucidating how NaCl is sensed by various tissues to elicit these downstream effects.

Nicotine Enhances Intravenous Self-administration of Cannabinoids in Adult Rats.

Introduction: Nicotine and cannabis are commonly used together, yet few studies have investigated the effects of concurrent administration. Nicotine exhibits reinforcement enhancing effects by promoting the reinforcing properties of stimuli including other drugs. As many studies of this effect used non-contingent nicotine, we implemented a dual-self-administration model where rats have simultaneous access to two drugs and choose which to self-administer throughout a session.

Elucidating the reinforcing effects of nicotine: a tribute to Nadia Chaudhri.

Nadia Chaudhri worked with us as a graduate student in the Center for Neuroscience at the University of Pittsburgh from 1999 until she earned her PhD in 2005, a time that coincided with the discovery in our lab of the dual reinforcing actions of nicotine, a concept that she played an important role in shaping. The research that was described in her doctoral thesis is among the foundational pillars of the now well-accepted notion that nicotine acts as both a primary reinforcer and an amplifier of other reinforcer stimuli. This reinforcement-enhancing action of nicotine is robust and likely to be a powerful driver of nicotine use.

Monoamine oxidase inhibition in cigarette smokers: From preclinical studies to tobacco product regulation.

Monoamine oxidase (MAO) activity is reduced in cigarette smokers and this may promote the reinforcing actions of nicotine, thereby enhancing the addictive properties of cigarettes. At present, it is unclear how cigarette smoking leads to MAO inhibition, but preclinical studies in rodents show that MAO inhibition increases nicotine self-administration, especially at low doses of nicotine. This effect of MAO inhibition develops slowly, likely due to plasticity of brain monoamine systems; studies relying on acute MAO inhibition are unlikely to replicate what happens with smoking.

Nicotine Administration Normalizes Behavioral and Neurophysiological Perturbations in the MAM Rodent Model of Schizophrenia.

Background: The present study utilized the methylazoxymethanol (MAM) neurodevelopmental rodent model of schizophrenia (SCZ) to evaluate the hypothesis that individuals with SCZ smoke in an attempt to "self-medicate" their symptoms through nicotine (NIC) intake.

Methods: To explore this question, we examined the effects of acute and chronic administration of NIC in 2 established behavioral tests known to be disrupted in the MAM model: prepulse inhibition of startle and novel object recognition. Additionally, we assessed the effects of acute and chronic NIC on 2 indices of the pathophysiology of SCZ modeled by MAM, elevated dopamine neuron population activity in the ventral tegmental area and neuronal activity in the ventral hippocampus, using in vivo electrophysiological recordings.

Centrally Projecting Edinger-Westphal Nucleus in the Control of Sympathetic Outflow and Energy Homeostasis.

The centrally projecting Edinger-Westphal nucleus (EWcp) is a midbrain neuronal group, adjacent but segregated from the preganglionic Edinger-Westphal nucleus that projects to the ciliary ganglion. The EWcp plays a crucial role in stress responses and in maintaining energy homeostasis under conditions that require an adjustment of energy expenditure, by virtue of modulating heart rate and blood pressure, thermogenesis, food intake, and fat and glucose metabolism. This modulation is ultimately mediated by changes in the sympathetic outflow to several effector organs, including the adrenal gland, heart, kidneys, brown and white adipose tissues and pancreas, in response to environmental conditions and the animal's energy state, providing for appropriate energy utilization.

Sympathetic Nervous System Contributions to Hypertension: Updates and Therapeutic Relevance.

The sympathetic nervous system plays a pivotal role in the long-term regulation of arterial blood pressure through the ability of the central nervous system to integrate neurohumoral signals and differentially regulate sympathetic neural input to specific end organs. Part 1 of this review will discuss neural mechanisms of salt-sensitive hypertension, obesity-induced hypertension, and the ability of prior experiences to sensitize autonomic networks. Part 2 of this review focuses on new therapeutic advances to treat resistant hypertension including renal denervation and carotid baroactivation.

Is the Brain an Early or Late Component of Essential Hypertension?

The brain's relationship to essential hypertension is primarily understood to be that of an end-organ, damaged late in life by stroke or dementia. Emerging evidence, however, shows that heightened blood pressure (BP) early in life and prior to traditionally defined hypertension, relates to altered brain structure, cerebrovascular function, and cognitive processing. Deficits in cognitive function, cerebral blood flow responsivity, volumes of brain areas, and white matter integrity all relate to increased but prehypertensive levels of BP.

Missing pieces of the Piezo1/Piezo2 baroreceptor hypothesis: an autonomic perspective.

Baroreceptors play a pivotal role in the regulation of blood pressure through moment to moment sensing of arterial blood pressure and providing information to the central nervous system to make autonomic adjustments to maintain appropriate tissue perfusion. A recent publication by Zeng and colleagues (Zeng WZ, Marshall KL, Min S, Daou I, Chapleau MW, Abboud FM, Liberles SD, 362: 464-467, 2018) suggests the mechanosensitive ion channels Piezo1 and Piezo2 represent the cellular mechanism by which baroreceptor nerve endings sense changes in arterial blood pressure. However, before Piezo1 and Piezo2 are accepted as the sensor of baroreceptors, the question must be asked of what criteria are necessary to establish this and how well the report of Zeng and colleagues (Zeng WZ, Marshall KL, Min S, Daou I, Chapleau MW, Abboud FM, Liberles SD, 362: 464-467, 2018) satisfies these criteria.

Renal sensory nerves increase sympathetic nerve activity and blood pressure in 2-kidney 1-clip hypertensive mice.

Renal denervation lowers arterial blood pressure (ABP) in multiple clinical trials and some experimental models of hypertension. These antihypertensive effects have been attributed to the removal of renal afferent nerves. The purpose of the present study was to define the function, anatomy, and contribution of mouse renal sensory neurons to a renal nerve-dependent model of hypertension.

Nicotine Self-administration Is Not Increased in the Methylazoxymethanol Acetate Rodent Model of Schizophrenia.

Introduction: Patients with schizophrenia (SCZ) smoke at a rate of 4-5 times higher than the general population, contributing to negative health consequences in this group. One possible explanation for this increased smoking is that individuals with SCZ find nicotine (NIC) more reinforcing. However, data supporting this possibility are limited.

Self-administered nicotine increases fat metabolism and suppresses weight gain in male rats.

Rationale: The ability of nicotine to suppress body weight is cited as a factor impacting smoking initiation and the failure to quit. Self-administered nicotine in male rats suppresses weight independent of food intake, suggesting that nicotine increases energy expenditure.

Objective: The current experiment evaluated the impact of self-administered nicotine on metabolism in rats using indirect calorimetry and body composition analysis.

Recent Advances in Neurogenic Hypertension: Dietary Salt, Obesity, and Inflammation.

Neurally-mediated hypertension results from a dysregulation of sympathetic and/or neuroendocrine mechanisms to increase ABP. Multiple factors may exert multiple central effects to alter neural circuits and produce unique sympathetic signatures and elevate ABP. In this brief review, we have discussed novel observations regarding three contributing factors: dietary salt intake, obesity, and inflammation.

Animal Research on Nicotine Reduction: Current Evidence and Research Gaps.

Unlabelled: A mandated reduction in the nicotine content of cigarettes may improve public health by reducing the prevalence of smoking. Animal self-administration research is an important complement to clinical research on nicotine reduction. It can fill research gaps that may be difficult to address with clinical research, guide clinical researchers about variables that are likely to be important in their own research, and provide policy makers with converging evidence between clinical and preclinical studies about the potential impact of a nicotine reduction policy.

Self-administered nicotine differentially impacts body weight gain in obesity-prone and obesity-resistant rats.

Obesity and tobacco smoking represent the largest challenges to public health, but the causal relationship between nicotine and obesity is poorly understood. Nicotine suppresses body weight gain, a factor impacting smoking initiation and the failure to quit, particularly among obese smokers. The impact of nicotine on body weight regulation in obesity-prone and obesity-resistant populations consuming densely caloric diets is unknown.

Reducing nicotine exposure results in weight gain in smokers randomised to very low nicotine content cigarettes.

Background: The Food and Drug Administration can reduce the nicotine content in cigarettes to very low levels. This potential regulatory action is hypothesised to improve public health by reducing smoking, but may have unintended consequences related to weight gain.

Methods: Weight gain was evaluated from a double-blind, parallel, randomised clinical trial of 839 participants assigned to smoke 1 of 6 investigational cigarettes with nicotine content ranging from 0.

Characterizing the relationship between increases in the cost of nicotine and decreases in nicotine content in adult male rats: implications for tobacco regulation.

Background: A large reduction in the nicotine content of cigarettes may benefit public health by reducing the rate and the prevalence of smoking. A behavioral economics framework suggests that a decrease in nicotine content may be considered an increase in the unit price of nicotine (unit price = reinforcer cost/reinforcer magnitude). Increasing the price of cigarettes (i.

Self-Administered Nicotine Suppresses Body Weight Gain Independent of Food Intake in Male Rats.

Introduction: The action of nicotine to suppress body weight is often cited as a factor impacting smoking initiation and the failure to quit. Despite the weight-suppressant effects of nicotine, smokers and nonsmokers report equal daily caloric intake. The weight-suppressive effects of nicotine in animal models of smoking are poorly understood.

Nicotine Enhances Footshock- and Lithium Chloride-Conditioned Place Avoidance in Male Rats.

Introduction: Numerous studies have shown that nicotine (NIC) can enhance the reinforcing effects of non-NIC stimuli through a nonassociative mechanism. To date, it is unclear whether NIC reinforcement enhancement serves to increase behaviors motivated by rewarding stimuli only, or whether NIC potentiates behavior motivated by all stimuli, regardless of valence.

Methods: The current study used a place conditioning procedure to examine whether acute NIC injection modulates avoidance of an environment previously associated with an aversive stimulus.

Effects of Monoamine Oxidase Inhibition on the Reinforcing Properties of Low-Dose Nicotine.

The Food and Drug Administration (FDA) has the authority to regulate cigarette smoke constituents, and a reduction in nicotine content might benefit public health by reducing the prevalence of smoking. Research suggests that cigarette smoke constituents that inhibit monoamine oxidase (MAO) may increase the reinforcing value of low doses of nicotine. The aim of the present experiments was to further characterize the impact of MAO inhibition on the primary reinforcing and reinforcement enhancing effects of nicotine in rats.

Adolescent Rats Self-Administer Less Nicotine Than Adults at Low Doses.

Introduction: Although nearly 90% of current smokers initiated tobacco use during adolescence, little is known about reinforcement by nicotine in adolescents. Researchers are currently investigating whether a potential public health policy setting a tobacco product standard with very low nicotine levels would improve public health, and it is essential to understand whether data generated in adults translates to adolescents, particularly as it relates to the threshold dose of nicotine required to support smoking. The present study compared self-administration of low doses of nicotine between adolescent and adult rats.

Obese Smokers as a Potential Subpopulation of Risk in Tobacco Reduction Policy.

Smoking and obesity represent the largest challenges to public health. There is an established inverse relationship between body mass index (BMI) and smoking, but this relationship becomes more complicated among obese smokers. Smokers with higher BMI consume more cigarettes per day and may be more nicotine-dependent than lean smokers.

Effects of MAO inhibition and a combination of minor alkaloids, β-carbolines, and acetaldehyde on nicotine self-administration in adult male rats.

Introduction: Although nicotine is the primary reinforcing constituent in cigarettes, there is evidence that other constituents in cigarette smoke may interact with nicotine to reinforce smoking behavior.

Methods: The present experiments investigated whether a novel combination of these cigarette smoke constituents would increase nicotine self-administration in adult male rats. The constituents included five minor alkaloids (anabasine, nornicotine, cotinine, myosmine, and anatabine), two β-carbolines (harman and norharman), and acetaldehyde.

Selective C1 Lesioning Slightly Decreases Angiotensin II Type I Receptor Expression in the Rat Rostral Ventrolateral Medulla (RVLM).

Cardiovascular homeostasis is regulated in large part by the rostral ventrolateral medulla (RVLM) in mammals. Projections from the RVLM to the intermediolateral column of the thoracolumbar spinal cord innervate preganglionic neurons of the sympathetic nervous system causing elevation of blood pressure and heart rate. A large proportion, but not all, of the neurons in the RVLM contain the enzymes necessary for the production of epinephrine and are identified as the C1 cell group.