br Introduction Psychostimulant abuse and addiction

Introduction Psychostimulant abuse and addiction remain a societal problem in the United States. The latest statistics from the National Survey on Drug Use and Health indicate that slightly less than one million people over the age of 12 report having a cocaine use disorder (NSDUH, 2016). Additionally, about 11% of American children have been diagnosed with Attention Deficit Hyperactivity Disorder (ADHD), with over 70% being treated with stimulant medications (Visser et al., 2014). A problem that has arisen is the misuse of ADHD medications for nonmedical purposes, with recent surveys finding approximately 1.7 million individuals in the United States abusing stimulant drugs without a prescription (NSDUH, 2016). A goal in understanding the mechanisms behind dependency and abuse of psychostimulant drugs is to explore relevant underlying circuitry, receptors and neurochemistry in the brain.
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Introduction Aging is associated with a progressive decline in physiological processes. Cardiovascular disease, and TKI258 failure in particular, remains the leading cause of death among the elderly [1]. Therefore, it is indispensable to explore the molecular mechanisms underlying age-related cardiovascular disorders. Cardiac aging is characterized by several complex modifications including diastolic dysfunction, left ventricular hypertrophy, increased risk of atrial fibrillation, valvular degeneration, leading to a decreased maximal exercise capacity. Intriguingly, the sympathetic nervous system plays a key role in both aging and cardiovascular disease. Indeed, adrenergic receptors (ARs) are involved in a variety of pathophysiological processes and mounting evidence indicates their participation in aging and cardiovascular physiopathology (Fig. 1).
The sympathetic nervous system The aging process is accompanied by a series of changes in the autonomic control of the cardiovascular system, favoring heightened cardiac sympathetic tone with parasympathetic withdrawal and blunted cardiovagal baroreflex sensitivity. In a study of older males, the peripheral plasma norepinephrine concentration was approximately 66% higher than that observed in younger men. This finding is explained by the reduction in the rate of clearance of norepinephrine from plasma and 29% higher whole-body norepinephrine spillover to plasma The cardiac spillover of catecholamines is higher in older than in younger men [2], [3]. Different factors can play a role in determining the rate of spillover of norepinephrine from sympathetic nerve terminals to plasma including nerve traffic, pre-junctional modulation, and the rate of catecholamine reuptake, principally via neuronal uptake.
Adrenergic receptors and G protein-coupled receptor kinases Adrenergic receptors (ARs) belong to the guanine nucleotide-binding G protein-coupled receptor (GPCR) superfamily, and are membrane receptors that activate heterotrimeric G proteins. GPCRs consist of one extracellular N-terminal domain, seven membrane-spanning domains, three intra- and three extracellular loops, and one intracellular C-terminal tail. G proteins typically stimulate (Gs protein) or inhibit (Gi protein) the enzyme adenylyl-cyclase, or activate (Gq protein) phospholipase C (PLC). GPCR signaling is stopped by the family of G protein-coupled receptor kinases (GRKs). GRK-mediated phosphorylation leads to an increased affinity of GPCRs for the arrestin class of proteins, which then uncouples the phosphorylated receptor from G protein and targets the receptor for internalization [4]. Two classes of ARs have been identified: α and β. Phenylephrine is a selective agonist of αAR while isoproterenol is a non-selective agonist for βAR [5]. The subfamily of α1AR (Gq coupled receptors) consists of three highly homologous subtypes, including α1A-, α1B- and α1D-AR [6]. The α2AR subfamily (coupled to Gi) comprises three subtypes: α2A-, α2B- and α2C-AR [7]. Some species express a fourth α2D-AR [8]. In the βAR family there are three receptor subtypes: β1AR is highly expressed in the heart [9], β2AR is widely distributed throughout the body [10], and β3AR is found, although not exclusively, in the white and brown adipose tissue [11]. All βARs couple primarily to Gαs and subsequent cAMP-related pathways, however under certain conditions they can couple to Gαi[12].