By H. Ugo. Lincoln University, San Francisco California.

ACTH and on proopiomelanocortin (POMC) gene ex- Because glucocorticoids inhibit the inflammatory re- pression (see Chapter 32) generic 850 mg glucophage otc. Their regulation of the production of PRODUCTS OF THE ADRENAL MEDULLA prostaglandins and leukotrienes is the best understood buy 850 mg glucophage with amex. These substances play a major role in mediating the in- The catecholamines, epinephrine and norepinephrine, are flammatory reaction. They are synthesized from the unsat- the two hormones synthesized by the chromaffin cells of urated fatty acid arachidonic acid, which is released from the adrenal medulla. The human adrenal medulla produces 620 PART IX ENDOCRINE PHYSIOLOGY and secretes about 4 times more epinephrine than norepi- found hypoglycemia can be tolerated depends on its sever- nephrine. Postganglionic sympathetic neurons also pro- ity and the individual’s sensitivity. The pathway for the synthe- ing to the fibers innervating the chromaffin cells. Sym- pathetic postganglionic nerve terminals also release norepinephrine. Trauma, Exercise, and Hypoglycemia Stimulate Catecholamines act on the liver to stimulate glucose the Medulla to Release Catecholamines production. They activate glycogen phosphorylase, result- Epinephrine and some NE are released from chromaffin ing in the hydrolysis of stored glycogen, and stimulate glu- cells by the fusion of secretory granules with the plasma coneogenesis from lactate and amino acids. The contents of the granules are extruded into cholamines also activate glycogen phosphorylase in the interstitial fluid. The catecholamines diffuse into capil- skeletal muscle and adipose cells by interacting with re- laries and are transported in the bloodstream. The elevated cAMP activates glycogen phos- fibers that innervate chromaffin cells triggers the secretion phorylase. Stimuli such as injury, anger, anxiety, cells is metabolized, although glucose is not released into pain, cold, strenuous exercise, and hypoglycemia generate the blood, since the cells lack glucose-6-phosphatase.

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Chaouloff buy glucophage 500mg cheap, F (1993) Physiopharmacological interactions between stress hormones and central serotonergic systems buy 500mg glucophage with visa. In Biological Psychiatry (Eds Bittar, EE and Bittar, N), JAI Press, Stanford, CT, pp. Chiu, TH, Dryden, DM and Rosenberg, HC (1982) Kinetics of [3H]-labelled flunitrazepam binding to membrane-bound benzodiazepine receptors. Costa, E and Guidotti, A (1991) Diazepam binding inhibitor (DBI): a peptide with multiple biological actions. Coupland, N, Glue, P and Nutt, DJ (1992) Challenge tests: assessment of the noradrenergic and GABA systems in depression and anxiety disorders. Dalley, JW, Mason, K and Stanford, SC (1996) Increased levels of extracellular noradrenaline in the frontal cortex of rats exposed to naturalistic environmental stimuli: modulation by acute systemic administration of diazepam or buspirone. Deakin, JFW, Graeff, FG and Guimaraes, FS (1992) 5-HT receptor subtypes and the modulation of aversion. In Central Serotonin Receptors and Psychotropic Drugs (Eds Marsden, CA and Heal, DJ), Blackwell Scientific Publications, Oxford, pp. De Robertis, E, Pena, C, Paladini, AC and Medina, JH (1988) New developments on the search for endogenous ligand(s) of central benzodiazepine receptors. Doble, A and Martin, IL (1996) The GABAA/Benzodiazepine Receptor as a Target for Psychoactive Drugs, RG Landes Co. Done, CJ and Sharp, T (1994) Biochemical evidence for the regulation of central noradrenergic activity by 5-HT1A and 5-HT2 receptors: Microdialysis studies in the awake and anaesthetised rat. Do Rego, JL, Mensah-Nyagan, AG, Feuilloley, M, Ferrara, P, Pelletier, G and Vaudry, H (1998) The endozepine triakontatetraneuropeptide diazepam-binding inhibitor [17±50] stimulates neurosteroid biosynthesis in the frog hypothalamus. Dorow, R, Horowski, R, Paschelke, G, Amin, M and Braestrup, C (1983) Severe anxiety induced by FG7142, a b-carboline ligand for benzodiazepine receptors. Dourish, CT, Hutson, PH and Curzon, G (1986) Putative anxiolytics 8-OHDPAT buspirone and TVXQ 7821 are agonists at 5-HT1A autoreceptors in the raphe nuclei. Duggan, MJ and Stephenson, FA (1988) Benzodiazepine binding site heterogeneity in the purified GABAA receptor.

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This is thought to be due to an interaction between the GABA recognition site on a b-subunit of the GABAA receptor and the benzodiazepine recognition site on an a-subunit (see Chapter 11 and Doble and Martin 1996) generic 850 mg glucophage mastercard. The overall effect of benzodiazepines is to augment the increase in Cl7 conductance caused by GABA and thereby potentiate its inhibitory actions; they achieve this by increasing the probability (and as a consequence order glucophage 850 mg free shipping, the frequency) of Cl7 channel opening. This action is thought to play a crucial role in the anti-anxiety effects of these drugs. The progressive increase in CNS depression, as drug dose is increased, is attributed to an increase in receptor occupancy, although the extent to which binding in different brain regions contributes to these different actions is not known. Barbiturates bind non-competitively to yet another, functionally distinct, domain on the receptor which is thought to be directly associated with the Cl7 channel itself. Although there is an allosteric interaction with GABA, as with the benzodiazepines, barbiturates also directly increase Cl7 conductance by increasing the duration of channel opening. Thus, by contrast with the benzodiazepines, the barbiturates activate this receptor even in the absence of GABA. This explains why antagonists of the GABA binding site, such as bicuculline, block the actions of benzodiazepines, but not those of the barbiturates, and probably accounts for the greater toxicity of the barbiturates in overdose. In recent years, the range of 404 NEUROTRANSMITTERS, DRUGS AND BRAIN FUNCTION Figure 19. This action of GABA is augmented (‡) by agonist benzodiazepines that bind to their own domain (BDZr) on the GABAA receptor and trigger an allosteric interaction with the GABA binding site. Some compounds, such as BDZr inverse agonists, have the opposite effect: i. BENZODIAZEPINE RECEPTOR SUBTYPES The discovery of the benzodiazepine receptor was quickly followed by their subdivision as evidenced by (see also Chapter 11): (1) The biphasic dissociation of [3H]flunitrazepam binding (Chiu, Dryden and Rosenberg 1982). In contrast, in the cerebellum, the curve was steep with a Hill coefficient of 1 (Duggan and Stephenson 1988). In this technique [3H]flunitrazepam binding is carried out under ultra-violet light which renders most of the ligand binding irreversible. The discovery of these receptor subtypes kindled the hope that it would be possible to develop subtype-selective drugs with specific clinical actions: i.