Brain Receptors in Sympathetic Nervous System Regulation

Overview

The purpose of this study is to investigate the role of brain receptors called alpha2-adrenoreceptors in regulating the sympathetic nervous system, which maintains the supply of blood and fuel to the body's organs in times of stress, fear, anger, or exercise. Alpha(2)-adrenergic receptors (alpha(2)-AR) play a role in a variety of physiological functions. There are three subtypes of alpha(2)-ARs, and their differences are unknown. This study will examine the functional roles of these three subtypes by comparing the behavioral, biochemical, psychophysiological, and autonomic function effects of the alpha(2)-AR drugs clonidine and yohimbine. Participants in this study will undergo a physical examination, electrocardiogram (ECG), and blood, urine, and saliva tests. Women will have hormone tests to determine the time of their last period and the time of their next ovulation. Participants will undergo neuropsychological testing and other procedures.

Alpha(2)-adrenergic receptors (alpha(2)-AR) are cell surface receptors for catecholamines that bind to the G(i)/G(0) family of G proteins. Alpha(2)-ARs are widely distributed in the central and peripheral nervous system, and are known to play an important role in the regulation of catecholamine release. This mechanism and the broad distribution of these receptors explain their role in a wide variety of physiological functions. Alpha(2)-AR mediate central hypotensive, sedative, anesthetic, and analgesic responses to alpha(2)-AR agonists. However, cardiovascular and other responses to the alpha(2)-AR agonists are subject to interindividual variation in the human population. Such variability may be explained by genetic variation in the structure of the receptors themselves, the cognate G proteins, the transductional effectors, or the downstream intracellular targets. Molecular and pharmacological research has defined three alpha(2)-ARs subtypes designated alpha(2)(A), alpha(2)(B), and alpha(2)(C). All three alpha(2)-AR subtypes are involved in the regulation of blood pressure, and these receptors also modulate sedation, analgesia, regulation of insulin release, renal function, cognition and behavior. Biochemical research has identified three human genes that uniquely encode these alpha(2)-ARs. Recently, in preclinical studies polymorphisms of all three alpha(2)-AR subtypes have been described. The three polymorphisms are each relatively abundant, and two appear to be functional in vitro. However, in humans the in vivo physiological effect of these polymorphisms is unknown. This study will elucidate the potential functional role of the three alpha(2)-AR subtypes in humans by comparing the behavioral, biochemical, psychophysiological, and autonomic function effects of the well-established alpha(2)-AR agonists and antagonists, clonidine and yohimbine, respectively, in individuals selected for particular alpha(2)-AR genotypes. Based on preclinical studies the following hypotheses will be tested: 1) subjects homozygous or heterozygous for the alpha(2)(A)-AR Asn251Lys substitution will show a potentiation of clonidine-induced effects, relative to subjects who have the Asn251/Asn251 genotype, and a reduction of yohimbine-induced effects, 2) subjects homozygous or heterozygous for a alpha(2)(B)-AR three glutamic acid deletion (residues 301-303) will show reduced effects of the alpha(2)-AR agonist clonidine and possibly a potentiation of effects of yohimbine, and 3) we will evaluate whether altered responses in either direction occur in subjects homozygous and heterozygous for an in-frame deletion of a alpha(2)(C)-AR homologous repeat occurring at codons 322-325 relative to subjects without this deletion allele.