An unprecedented rise in the availability of new synthetic drugs of abuse has been observed in the recent years. One of the most noted cases is that of a popularized designer drug mixture known as ‘bath salts’. Commonly obtained from various shops and on the internet, “bath salts” often contain the synthetic cathinones 3,4 methylenedioxypyrovalerone (MDPV), mephedrone, and methylone in diverse combinations. Individually, the synthetic cathinones are known to have similar pharmacology to controlled psychostimulants such as cocaine and the amphetamines, increasing the levels of dopamine (DA) in the synaptic cleft. DA is an important neurotransmitter that regulates a variety of behaviors and functions; neurons within the mesolimbic DA pathway (ventral tegmental area to nucleus accumbens) are involved in reward and motivation and are activated by these drugs of abuse. Additionally, psychostimulant-induced increases in DA in the nigrostriatal pathway (substantia nigra to corpus striatum) lead to increases in locomotor behavior. However, the majority of preclinical investigations have only assessed the effects of individual bath salt constituents and have provided little information regarding the possibility of significant drug interactions with the co-exposure of MDPV, mephedrone, and methylone. This study sought to evaluate and compare the effects of individual versus combined MDPV, mephedrone, and methylone on dopamine (DA) levels in discrete brain regions as well as motor stimulant responses in mice. Male adolescent Swiss-Webster mice received intraperitoneal injections of saline, MDPV, mephedrone, methylone (1.0 or 10.0 mg/kg), or the cathinone cocktail (MDPV + mephedrone + methylone at 1.0, 3.3, or 10 mg/kg). The effect of each treatment on DA and DA metabolite levels in mesolimbic and nigrostriatal brain tissue was quantified 15 min after a single exposure utilizing high pressure liquid chromatography with electrochemical detection (HPLC-ECD). Additionally, locomotor activity was recorded in mice after acute (day 1) and chronic intermittent (day 7) dosing. The results demonstrate that MDPV, mephedrone, and methylone produce dose-related increases in the mesolimbic and nigrostriatal DA levels that are significantly enhanced following their co-administration. Additionally, a decrease in locomotor activity on day 1 that was exacerbated by day 7 was noted in mice treated with the cathinone cocktail and was not observed with any of the single agents. The decrease in locomotor activity was accompanied by an increase in stereotypic-like behavior including excessive grooming and even self-mutilation. Our findings demonstrate a significantly enhanced effect of MDPV, mephedrone, and methylone on both DA and its metabolites resulting in significant alterations in locomotor activity. This work provides insight into the potential enhanced risk of the use of these combination synthetic cathinone products.

Metabolic syndrome is associated with pathologies that include type 2 diabetes, hypertension, and dyslipidemia, all of which increase the risks of heart disease. Glucagon-like peptide (GLP-1) is a hormone produced by intestinal enteroendocrine L‑cells. GLP-1 increases insulin sensitivity, augments glucose-dependent insulin secretion, and suppresses glucagon release. GLP-1 also works centrally to decrease appetite and increase metabolism. Evidence suggests that the beneficial effect is mediated by metabolically related sympathetic neurons within the hypothalamus. Although the hypothalamus contains neurons that control metabolism, there are also neurons that control cardiovascular activity. Considering that one main goal of obesity and diabetes treatments is to reduce cardiovascular-related comorbidities, any drug‑induced increase in blood pressure is unacceptable. Therefore, a better understanding of GLP-1 agonists on sympathetic activity and the role of the hypothalamus in central GLP‑1 activity is essential. In this study, we tested the hypothesis that the long‑acting FDA approved GLP-1 receptor agonist liraglutide activates both metabolic and cardiovascular‑related hypothalamic neurons and augments reflex cardiovascular sympathetic activity in rats. To test this hypothesis, we administered liraglutide (125 mg/kg, SC, n=10) or vehicle (saline, n=10) to rats for 15 days and measured food intake and body weight. Next, we recorded blood pressure and renal sympathetic nerve activity (RSNA) in the anesthetized rat before and after liraglutide treatment. Finally, to determine the activation of hypothalamic neurons we performed neuroanatomical tracing studies and turned metabolically-related (raphe‑projecting) neurons green, and cardiovascular-related (rostroventrolateral medulla, RVLM) neurons red. After treating rats with liraglutide, (75 mg/kg IV) we performed immunohistochemical (IHC) labeling to identify neurons expressing cFos, a marker of neuronal activation. Daily liraglutide significantly (p < 0.05) reduced both food intake and body weight from the pretreatment baseline. In vehicle-treated rats, the mean baseline food intake was 27.9 ± 0.5g. During vehicle treatment, the mean food intake was 28.6 ± 0.8 g and body weight was 110 ± 1.5% of its baseline. In liraglutide-treated rats, the mean baseline food intake was 29.9 ± 0.7g. During liraglutide treatment, the mean food intake was 22.7 ± 1.4g and body weight was 105 ± 1.1% of its baseline. At the end of liraglutide treatment, food intake and body weight returned to that of the vehicle-treated rats. In the anesthetized rat, liraglutide significantly (p < 0.05) increased basal RSNA and augmented baroreflex and chemoreflex activity. Lastly, our cFos data show that liraglutide activates metabolic, but not cardiovascular hypothalamic neurons. Collectively, these data suggest that although liraglutide elevates sympathetic activity, it is not by activation of pre-sympathetic hypothalamic neurons.

Obesity has risen 75% in the United States since 1980 and an estimated 80 million American adults are considered obese. Obesity activates the sympathetic nervous system and is associated with neurogenic hypertension. Leptin is an obesity-related neuropeptide released from fat cells which reduces appetite and increases metabolism. Leptin activates metabolic and cardiovascular responsive pre‑sympathetic neurons within the hypothalamus. Although leptin increases metabolism and curbs appetite, it also increases blood pressure. Considering that one main goal of obesity treatments is to diminish the cardiovascular-related co-morbidities this is an unacceptable side effect for potential treatments. Thus, a better understanding of the role hypothalamic sites involved in obesity-related hypertension is necessary for successful treatments. Our hypothesis is that leptin activates hypothalamic neurons that control metabolic (raphe pallidus) and cardiovascular activity (RVLM, rostroventrolateral medulla) within the brainstem. To test our hypothesis we created a line of transgenic mice using the cre-lox recombination system to express the reporter gene tdTomato under the control of the leptin (ObRb) receptor gene. First, we performed a behavioral study to verify the physiological effect and optimal dose of daily leptin treatment. To do this we implanted mini-osmotic pumps for continuous subcutaneous leptin (400 ng/hr) administration and measured food intake and body weight over 4 weeks. To determine if leptin activates pre‑sympathetic hypothalamic neurons we performed neuroanatomical tracer studies in these mice. At the end of the 4-week period, we injected fluorescent retrograde tracers into the raphe pallidus (green, metabolic center) and RVLM (magenta, cardiovascular). We then performed fluorescence immunohistochemical labelling to identify leptin-induced neuronal activation cFos a marker of neuronal activation of these neurons. Data from this behavioral, neurophysiological and neuroanatomical study will provide a better understanding of the role of the hypothalamus in controlling blood pressure and metabolism in obesity. Information from this study will provide groundwork for a better understanding of central autonomic mechanisms of cardiovascular risk as well as risk introduced by drugs intended to treat obesity.

Ventricular assist devices are used in patients with heart failure refractory to standard management. Though left ventricular assist devices are more often used, patients with severe right ventricular dysfunction may also be treated with mechanical support. This case presents a patient with mixed cardiogenic and septic shock requiring placement of a percutaneous right ventricular assist device. A 38-year-old obese male with a medical history of alcoholism presented to the hospital with a complaint of dyspnea. He was found to have volume overload and was given intravenous diuretics. However, he had progressive renal insufficiency, hypotension requiring vasopressor support, and worsening respiratory status requiring mechanical ventilation. An echocardiogram showed a severely enlarged right ventricle, reduced RV function, normal RV wall thickness, moderate to severe tricuspid regurgitation, a severely dilated right atrium, ventricular septal flattening, and mild pulmonary hypertension. Left ventricular ejection fraction was 65-70%, LV diastolic function was normal, and there were no other significant valvular abnormalities. Troponin levels, ECG, and CT pulmonary angiography were unrevealing. Right heart catheterization showed a right atrial pressure of 29 mmHg (2 – 6 mmHg), right ventricular pressures of 50/24 mmHg (15-25/0-8 mmHg), pulmonary artery pressures of 56/35/43 mmHg (15-25/8-15/10-20 mmHg), a pulmonary capillary wedge pressure of 22 mmHg (6-12 mmHg), and a Prognostic Impact of Pulmonary Artery Pulsatility Index (PAPi) score of 0.3 to 0.6 (>1). Cardiac chamber oxygen saturations did not demonstrate intracardiac shunting. A right-sided mechanical circulatory support device was placed. The hospital course was complicated by sepsis due to pneumonia and presumed central line-associated bloodstream infection requiring antibiotic therapy, anemia secondary to device-related hemolysis requiring blood transfusions, renal failure requiring renal replacement therapy, and candidemia requiring antifungal therapy. Due to concern for device-associated infection, his central lines were replaced. The mechanical circulatory support device was able to be removed after ten days. Subsequent cardiac imaging did not reveal any other structural abnormalities, and a definitive cause for the right heart failure was not determined. Etiologies of right-sided heart failure include left-sided heart failure, pulmonary hypertension, chronic pulmonary disease, myocardial infarction, pulmonary embolism, myocarditis, valvular dysfunction, and congenital anomalies. Mechanical circulatory support may be used to support cardiac function, to allow the ventricular function to improve. Potential complications of mechanical circulatory support include infection, hemolysis, bleeding, device migration, and malfunction. RVAD therapy should be considered for patients with isolated right ventricular failure refractory to less invasive therapy.