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In corticolimbic reward circuits are activated via different 1372 Neuropsychopharmacology: The Fifth Generation of Progress mechanisms by different classes of drugs buy kamagra super 160 mg otc. As noted purchase kamagra super 160 mg with mastercard, a shared property of addictive drugs is to promote dopamine release in multiple forebrain regions buy kamagra super 160mg with amex, including the NAc purchase kamagra super 160 mg, but also including the dorsal striatum kamagra super 160mg low price, amygdala, and hippocampus, in which dopamine release can act as a reinforcement signal, thus controlling learning processes (39,40). As drug use con- tinues, tolerance may occur, leading to dosage escalation. Depending on the drug, somatic dependence and/or emo- tional–motivational dependence my sustain drug seeking and drug use in attempts to avoid the aversive state of with- drawal. The emotional–motivational aspects of tolerance and dependence may largely occur within the mesocorticoli- mbic circuitry itself, but molecular adaptations occur in other circuits as well in a drug-specific manner reflecting the location of the target molecules for the given drug. Sen- sitization to some drug effects may occur, a phenomenon that is especially well documented for psychostimulants. Sensitization may act, inter alia, to increase the incentive salience of the drug, and thereby contribute to compulsive drug use (41). At the same time, multiple memory systems are affected by drugs of abuse (42)and, undoubtedly con- tribute to sustaining active drug use and late relapses (37). What follows are examples of different molecular processes that contribute to different aspects and stages of substance use disorders. These illustrations have been chosen based on the depth of available information, and likely relevance to the clinical situation in humans. Adaptations That Produce Tolerance and Somatic Dependence to Opiates FIGURE 96. Mechanism of opiate tolerance and dependence Opiates and ethanol produce somatic dependence and with- in the locus ceruleus: Acute administration of opiates increases drawal because their targets are expressed on cells and cir- outward K current, thereby hyperpolarizing locus ceruleus cells cuits that regulate bodily functions such as autonomic activ- (top). With chronic opiate use the cAMP signaling system is up- regulated, leading to PKA-dependent phosphorylation of the ity. Tolerance and dependence are generally thought to Na channel. In this state, the channel is more active, allowing represent homeostatic adaptations that compensate for Na ions to flow into the cell, increasingly the intrinsic excitability overstimulation by a drug or neurotransmitter. Up-regulation of the cAMP system also increases CREB Ser133 phosphorylation and CRE-dependent gene transcription. The molecular adaptations probably responsible for some aspects of tolerance and somatic dependence are best understood signaling mechanisms in opiate receptor-bearing cells (Fig. With repeat administration of mu agonist opiates such The locus ceruleus (LC), located in the dorsal pons, is as morphine or heroin, both tolerance and dependence the major noradrenergic nucleus of the brain and regulates emerge. There is a significant somatic component to heroin arousal, attention, and vigilance. It is involved in responses dependence as manifest by the classic heroin somatic with- to stress, and together with other noradrenergic cell groups drawal syndrome. It had initially been hypothesized that plays a role in regulation of the autonomic nervous system. Thus, despite continued op- turned out to be the case; rather opiate tolerance and depen- iate exposure, LC firing rates gradually return to their basal dence appear to be caused by adaptation in postreceptor levels. At this point, administration of an opioid receptor Chapter 96: Molecular and Cellular Biology of Addiction 1373 antagonist, such as naloxone or naltrexone, causes a dra- mice exhibited markedly reduced signs of withdrawal in- matic increase in LC firing rates. In animals, the period cluding complete absence of sniffing and ptosis (44,45). Opiate-induced syndrome, and drugs, such as the 2-adrenergic receptor up-regulation of PKA does not involve CREB and may be agonist clonidine, which inhibit LC firing, attenuate with- mediated posttranslationally. When the regulatory subunits are bound erance and dependence depend on the cyclic AMP (cAMP) by cAMP, the catalytic subunits are free to phosphor late pathway. In the LC, as in most other cell types, -opioid substrate proteins. However, free catalytic subunits of PKA receptor activation inhibits the cAMP pathway via Gi acti- are highly vulnerable to proteolysis, whereas inactive sub- vation and stimulates an inwardly rectifying K current by units bound to regulatory subunits are proteolysis-resistant. As the number of enzyme the actions of agonist opiates on these K and Na molecules increases, the kinase activity can be more readily channels expressed by LC neurons decrease the excitability activated by the low levels of cAMP. With long-term opiate administration, however, a homeostatic compensatory re- Adaptations That May Produce Tolerance sponse occurs: key components of the cAMP pathway be- and Somatic Dependence on Ethanol come up-regulated in LC neurons; thus, for example there Like opiates, ethanol produces somatic dependence and are increased concentrations of adenylyl cyclase and protein withdrawal, although the clinical syndrome is quite distinct, kinase A. This up-regulation increases the intrinsic excitabil- and potentially more dangerous. The molecular mecha- ity of LC neurons, by activating the cAMP-dependent Na nisms are less well understood than those underlying opiate current. The activation of this current may explain why LC tolerance and dependence, but the comparison is instruc- firing rates return to normal despite the continued presence tive.

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During correction of the water Replace half of the calculated water deficit over the first 12–24 hrs deficit buy kamagra super 160 mg overnight delivery, it is im portant to perform serial neurologic exam inations purchase 160mg kamagra super. Replace the remaining deficit over the next 24–36 hrs Perform serial neurologic examinations (prescribed rate of correction can be decreased as symptoms improve) Measure serum and urine electrolytes every 1–2 hrs *If UNa + U K is less than the concentration of PNa cheap 160 mg kamagra super overnight delivery, then water loss is ongoing and needs to be replaced discount kamagra super 160mg free shipping. Jacobson H R: Functional segm entation of the m am m alian nephron cheap 160 mg kamagra super mastercard. Berl T, Schrier RW : Disorders of water m etabolism. Berl T, Anderson RJ, M cDonald KM , Schreir RW : Clinical Disorders Publishing Co. Kokko J, Rector F: Countercurrent m ultiplication system without 18. Gullans SR, Verbalis JG: Control of brain volum e during hyperosm o- active transport in inner m edulla. Knepper M A, Roch-Ram el F: Pathways of urea transport in the m am - 19. Zarinetchi F, Berl T: Evaluation and m anagem ent of severe hypona- trem ia. Lauriat SM , Berl T: The H yponatrem ic Patient: Practical focus on 5. Zim m erm an E, Robertson AG: H ypothalam ic neurons secreting vaso- 21. Ayus JC, W heeler JM , Arieff AI: Postoperative hyponatrem ic pressin and neurophysin. Bichet DG: N ephrogenic and central diabetes insipidus. Laureno R, Karp BI: M yelinolysis after correction of hyponatrem ia. Bichet DG : Vasopressin receptors in health and disease. Kum ar S, Berl T: Disorders of serum sodium concentration. Dunn FL, Brennan TJ, N elson AE, Robertson GL: The role of blood 24. In Fluid & Electrolytes, osm olality and volum e in regulating vasopressin secretion in the rat. N ew York: m utations in the vasopressin-neurophysin II gene in 17 kindreds with M cGraw H ill, 1994. In Fluid & Electrolytes, Physiology and Pathophysiology. Edited by Jacobson H R, Striker GE, Appleton & Lange, 1991:98. H alterm an R, Berl T: Therapy of dysnatrem ic disorders. Barrett T, Bundey S: W olfram (DIDM O AD) syndrom e. H oltzm an EJ, Ausiello DA: N ephrogenic Diabetes insipidus: Causes 13. Veis JH , Berl T, H yponatrem ia: In The Principles and Practice of revealed. Bichet D, O ksche A, Rosenthal W : Congential N ephrogenic Diabetes St. Berl T, Schrier RW : Disorders of water m etabolism. Philadelphia: Lippincott-Raven, nephrogenic diabetes insipidus hom ozygous for m utations in the 1997:52. Verbalis JG: The syndrom e of ianappropriate diuretic horm one secre- 31.

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All these mechanisms aid in returning the serum Ca to normal levels kamagra super 160mg without prescription. Lack of parathyroid hormone (PTH) Increased calcium complexation After thyroidectomy or parathyroidectomy “Bone hunger” after parathyroidectomy Hereditary (congenital) hypoparathyroidism Rhabdomyolysis Pseudohypoparathyroidism (lack of Acute pancreatitis effective PTH) Tumor lysis syndrome Hypomagnesemia (blocks PTH secretion) (hyperphosphatemia) Malignancy (increased Lack of Vitamin D osteoblastic activity) Dietary deficiency or malabsorption (osteomalacia) Inadequate sunlight Defective metabolism Anticonvulsant therapy Liver disease Renal disease Vitamin D–resistant rickets Divalent Cation M etabolism: Calcium 5 purchase 160mg kamagra super fast delivery. The decrease in PTH and hypercalcem ia decrease the activity of the C-cells 1- -hydroxylase enzym e located in the Kidney – ↑CT proxim al tubular (PT) cells of the nephron generic kamagra super 160mg on line, which in turn discount 160 mg kamagra super otc, decreases the synthesis of – – + 1 generic kamagra super 160mg with amex,25-dihydroxy-vitam in D3 (1,25(O H )2D3). H ypercalcem ia stim ulates the C cells in the PTH↑ PTH Gastrointestinal thyroid gland to increase synthesis of calci- tract – – tonin (CT). Bone resorption by osteoclasts Parathyroid cell PT DCT Nucleus is blocked by the increased CT and decreased PTH. Decreased levels of PTH and 1,25(O H )2D3 inhibit Ca reabsorption in the distal convoluted tubules (DCT) of – the nephrons and overwhelm the effects of – CT, which augm ent Ca reabsorption in the m edullary thick ascending lim b leading to an increase in renal Ca excretion. The – Bone decrease in 1,25(O H ) D decreases gas- – 2 3 trointestinal (GI) tract absorption of dietary 1,25(OH)2D3↓ Ca. All of these effects tend to return serum Ca to norm al levels. Excess parathyroid hormone (PTH) production Increased intestinal absorption of calcium Primary hyperparathyroidism Vitamin D intoxication “Tertiary” hyperparathyroidism* Milk-alkali syndrome* Excess 1,25-dihydroxy-vitamin D3 (1,25(OH)2D3) Decreased renal excretion of calcium Vitamin D intoxication Familial hypocalciuric hypercalcemia Sarcoidosis and granulomatous diseases Thiazides Severe hypophosphatemia Impaired bone formation and incorporation of Neoplastic production of 1,25(OH)2D3 (lymphoma) calcium Increased bone resorption Aluminum intoxication* Metastatic (osteolytic) tumors (eg, breast, colon, prostate) Adynamic (“low-turnover”) bone disease* Humoral hypercalcemia Corticosteroids PTH-related protein (eg, squamous cell lung, renal cell cancer) Osteoclastic activating factor (myeloma) 1,25 (OH)2D3 (lymphoma) Prostaglandins Hyperthyroidism Immobilization Paget disease Vitamin A intoxication *Occurs in renal failure. Agent Mechanism of action Saline and loop diuretics Increase renal excretion of calcium Corticosteroids Block 1,25-dihydroxy-vitamin D3 synthesis and bone resorption Ketoconazole Blocks P450 system, decreases 1, 25-dihydroxy-vitamin D3 Oral or intravenous phosphate Complexes calcium Calcitonin Inhibits bone resorption Mithramycin Inhibits bone resorption Bisphosphonates Inhibit bone resorption *Always identify and treat the primary cause of hypercalcemia. Secondary Hyperparathyroidism FIGURE 5-22 Renal failure Pathogenesis of secondary hyperparathyroidism (H PT) in chronic renal failure (CRF). Decreased num bers of proxim al tubular (PT) cells, owing to loss of renal m ass, cause a quantitative decrease in ↓Number of nephrons synthesis of 1,25-dihydroxy-vitam in D (1,25(O H ) D ). Loss of 3 2 3 renal m ass also im pairs renal phosphate (P) and acid (H +) excretion. H ypocalcem ia and hyperphosphatem ia stim ulate PTH release and ↓H+ excretion synthesis and can recruit inactive parathyroid cells into activity and ↓P excretion PTH production. H ypocalcem ia also m ay decrease intracellular degradation of PTH. The lack of 1,25(O H )2D3, which would ordi- 1,25(OH)2D3↓ Hyperphosphatemia narily feed back to inhibit the transcription of prepro-PTH and exert an antiproliferative effect on parathyroid cells, allows the ↓Ca absorption Gastrointestinal increased PTH production to continue. In CRF there m ay be tract decreased expression of the Ca-sensing receptor (CaSR) in parathy- roid cells, m aking them less sensitive to levels of plasm a Ca. Patients with the b allele or the bb genotype vitam in D receptor (VDR) m ay be m ore susceptible to H PT, because the VDR- 1,25(O H )2D3 com plex is less effective at suppressing PTH produc- tion and cell proliferation. The deficiency of 1,25(O H )2D3 m ay also decrease VDR synthesis, m aking parathyroid cells less sensitive to Hypocalcemia ↓Activity 1,25(O H )2D3. Although the PTH receptor in bone cells is downreg- ↓Activity ulated in CRF (ie, for any level of PTH , bone cell activity is lower in CRF patients than in norm al persons), the increased plasm a levels of PTH m ay have harm ful effects on other system s (eg, cardiovascu- VDR CaSR lar system , nervous system , and integum ent) by way of alterations of intracellular Ca. Current therapeutic m ethods used to decrease Increased PTH release in CRF include correction of hyperphosphatem ia, transcription ↓Degradation m aintenance of norm al to high-norm al levels of plasm a Ca, adm in- of PTH istration of 1,25(O H )2D3 orally or intravenously, and adm inistra- Release tion of a Ca-ion sensing receptor (CaSR) agonist [14–16,19–22]. CALCIUM PREPARATIONS Calcium (Ca) salt Tablet size, mg Elemental Ca, mg, % Carbonate 1250 500 (40) Acetate 667 169 (25) Citrate 950 200 (21) Lactate 325 42 (13) Gluconate 500 4. VITAM IN D PREPARATIONS AVAILABLE IN THE UNITED STATES Ergocalciferol Calcifediol Calcitriol (Vitamin D2) (25-hydroxy-vitamin D3) Dihydrotachysterol (1,25-dihydroxy-vitamin D3) Commercial name Calciferol Calderol® (Organon, Inc, DHT Intensol® (Roxane Rocaltrol® (Roche Laboratories, W est Orange, NJ) Laboratories, Columbus, OH) Nutley, NJ) Calcijex® (Abbott Laboratories, Abbott Park, NJ) Oral preparations 50,000 IU tablets 20- and 50-µg capsules 0. Philbrick W M , W ysolm erski JJ, Galbraith S, et al. Louis: of parathyroid horm one-related protein in norm al physiology. Johnson JA, Kum ar R: Renal and intestinal calcium transport: roles of 14. Goodm an W G, Belin TR, Salusky IB: In vivo> assessm ents of vitam in D and vitam in D-dependent calcium binding proteins. Sem in calcium -regulated parathyroid horm one release in secondary N ephrol 1994, 14:119–128. H ebert SC, Brown EM , H arris H W : Role of the Ca2+-sensing receptor 50:1834–1844. Chattopadhyay N , M ithal A, Brown EM : The calcium -sensing 4. Hebert SC, Brown EM : The scent of an ion: calcium-sensing and its roles receptor: a window into the physiology and pathophysiology of in health and disease. Berridge M J: Elem entary and global aspects of calcium signalling. N em eth EF, Steffey M E, Fox J: The parathyroid calcium receptor: a novel therapeutic target for treating hyperparathyroidism.

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