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O nly 2 of 100 patients surviving kidney graft have no histologic changes on renal biopsy and norm al m ore than 10 years suffered graft loss from recurrent diabetic basement membrane thickness on electron microscopy of glomerular nephropathy order levitra with dapoxetine master card, occurring at 12 cheap 40/60mg levitra with dapoxetine with amex. Intensive insulin treatment with good glycemic control buy levitra with dapoxetine 40/60mg low price. The incidence of vascular com plications and the need for am pu- after transplantation also prevents the developm ent of recurrent tations, however, are substantially increased in patients with diabetes glom erular and arteriolar lesions. In most centers, overall graft survival rates are lower for recipients with diabetes than for those without diabetes. Prim ary hyperoxaluria H istologic slide of a patient who received an isolated renal allograft type I is an autosomal recessive inborn error of metabolism resulting for prim ary hyperoxaluria type I in which oxylate crystals are seen from a deficiency (or occasionally incorrect subcellular localization) clearly within the tubules and interstitium. The m ajor hazards for of hepatic peroxisom al alanine–glyoxylate am inotransferase. In m any patients, renal disease is m anifested by chronic renal Acute tubular obstruction by calcium oxalate crystals also can failure. O nce the glom erular filtration rate has decreased below 25 occur. Late nephrocalcinosis leads to progressive loss of renal function m L/m in the com bination of oxalate overproduction and reduced over several years. Rejection episodes are less com m on in patients urinary excretion leads to system ic oxalosis, with calcium oxalate receiving com bined liver and kidney grafts than in those receiving deposition in m any tissues. Renal transplantation alone has yielded kidney transplantation alone [3,19]. Acute rejection with renal poor results in the past, with 1-year graft survival rates of only dysfunction, however, causes additional episodes of acute calcium 26%. Com bined hepatorenal transplantation sim ultaneously oxalate deposition in the kidney. Recurrent oxalosis can be seen as replaces renal function and corrects the underlying m etabolic defect. The 1-year liver graft survival rate is 88% , with patient survival of 80% at 5 years. O f 24 renal grafts from the European experience of hepatorenal transplantation, 17 were still functioning at 3 months to 2 years after transplantation. FIGURE 17-14 PATIENT MANAGEMENT IN RENAL OR HEPATORENAL Daily hem odialysis for at least 1 week before transplantation TRANSPLANTATIONS FOR PRIMARY HYPEROXALURIA depletes the system ic oxalate pool to som e extent. Som e centers continue aggressive hem odialysis after transplantation, regardless of the renal function of the transplanted organ. In patients receiving Aggressive preoperative dialysis (and possibly continued postoperatively) com bined hepatorenal grafts, dietary m easures to reduce oxalate Maintenance of high urine output production are not as im portant as they are in patients receiving isolated kidney grafts. In these patients, excess production of Low oxalate, low ascorbic acid, diet low in vitamin D oxalate from glyoxylate still occurs. M agnesium and phosphate Phosphate supplements supplements are powerful inhibitors of calcium oxalate crystallization Magnesium glycerophosphate and should be used in all recipients, whereas thiazide diuretics m ay High-dose pyridoxine (500 mg/d) reduce urinary calcium excretion. Pyridoxine is a cofactor for alanine– Thiazide diuretics glyoxylate aminotransferase and can increase the activity of the enzyme in som e patients. Pyridoxine has no role in com bined hepatorenal transplantation. For m ost patients the ideal option is probably a com bined transplantation when their glom erular filtration rate decreases below 25 m L/m in [8,9]. H owever, increasing num bers of patients these grafts within 2 years of transplantation [20,21]. Patient survival with m yelom a and AL am yloid, or prim ary am yloidosis, are now is reduced, owing to infections and vascular complications, to 68% at receiving peripheral blood stem cell transplantations or bone m ar- 1 year and 51% at 2 years. Recurrence is characterized by proteinuria row allografts. Thus, these patients are surviving long enough to 11 m onths to 3 years after transplantation. Recurrent light chain consider renal transplantation. O ver 60 patients with renal failure deposition disease is found in half of patients receiving allografts, with resulting from system ic am yloid A (AA) am yloidosis have been graft loss in one third despite plasmapheresis and chemotherapy. Graft survival in these H eavy proteinuria is seen at the onset of recurrence. AL— prim ary patients is the sam e as that of a m atched population. FIGURE 17-16 M icroradioangiography com paring the vasculature of the kidney in a patient with no disease (panel A) and a patient with hom ozygous sickle cell disease (panel B). Despite the frequency of renal dam age in sickle cell disease, only 4% of patients progress to end-stage renal disease, and little experience exists with renal transplantation. Three patients have been reported with recurrent sickle cell nephropathy. In one case, a patient developed renal dysfunction 3. A second study reported recurrent sickle cell nephropathy leading to graft failure in two of eight patients receiving transplantation. Concentration defects were observed within 12 months of grafting. Patients also suffered an increased incidence of sickle cell crises after renal transplantation, possibly associated with the increase in A B hem atocrit. SLE accounts for approxim ately 1% after transplantation, with overall renal and extrarenal recurrence rates of up to 29% and of all patients receiving allografts, and less renal recurrences alone of up to 16%. Graft loss has been reported in up to 40% of than 1% of these will develop recurrent patients with renal recurrence. In the m ost recent data from the H am m ersm ith H ospital, renal disease. Tim e to recurrence has been however, renal recurrences were rare, with only 0. These patients have often been on long courses of im m unosuppres- tion [24,25]. Cyclosporine therapy does not sive therapy before receiving a graft. It is reasonable to can involve the ureter, causing stenosis and obstructive nephropathy. Serial m onitoring of ensure that serologic test results for SLE are antineutrophil cytoplasm ic antibodies after transplantation is im portant in all patients m inim ally abnorm al before transplantation with vasculitis because changes in titer m ay predict disease relapse [28,29]. Patients with lupus anticoagulant and anticardiolipin antibodies are at risk of throm boem bolic events, including renal graft vein or artery throm bosis. These patients m ay require anticoagulation therapy, or platelet inhibi- tion with aspirin.
Their the greatest decrease in -opioid-receptor–stimulated 35 finding that heroin alone failed to cause an increase in dopa- [ S]GTP S binding in the brainstem and the lowest altera- mine in the nucleus accumbens complemented several ear- tions in binding in the striatum and cortex (42) cheap 40/60 mg levitra with dapoxetine with amex. Because lier findings that heroin self-administration is not attenu- the changes of dopamine D1-receptor activation would act ated by administration of dopamine antagonists cheap levitra with dapoxetine 40/60mg online, as well as in one direction and dopamine D2-receptor activation even earlier studies showing that integrity of dopamine would act in the opposite direction on adenylyl cyclase activ- pathways in the nucleus accumbens is not essential for her- ity effective 40/60mg levitra with dapoxetine, the effects on these receptors could also influence the oin self-administration. These findings document further effects of -opioid-receptor activation, and the changes that the early hypothesis of the Kreek laboratory, and many oth- have been observed may result exclusively from the opioid ers, that the reinforcing properties of heroin are mediated effects acting at the -opioid receptors or also secondary primarily by dopamine-independent mechanisms and prob- indirect effects on dopamine receptors. This hypothesis has These and other findings suggest that opiates may act 1496 Neuropsychopharmacology: The Fifth Generation of Progress directly to alter dopaminergic systems both in the ventrome- that is, the neuroplasticity after chronic opiate administra- dial striatum, that is, the core and shell of the nucleus ac- tion that results in impairment of normal neural integrity. Clearly, there are abundant - regulatory events may alter neural growth, development, opioid receptors as well as -opioid receptors in those re- and synapse formation, signal transduction, and overall sys- gions (26,75–77). Work from the Kreek laboratory showed tem integrity (24,79). There have been no similar expression, as well as more direct effects of enhanced tran- findings with respect to increasing -opioid-receptor den- scription factors on dynorphin gene expression, may be sity after chronic opioid administration, however. It is not again important counterregulatory events, which also repre- really known to what extent reinforcement or reward result- sent examples of profound neuroplasticity of the brain. Such ing from heroin and morphine occurs because of activation findings have also been made during binge pattern cocaine directly in these areas, especially the nucleus accumbens and administration (80,81). Enhanced dynorphin peptides, in possibly also the amygdala, as contrasted to indirect effects turn, acting at -opioid receptors, may reduce dopaminergic on the ventral tegmental area. The effects on dopamine tone in many brain regions, including those involved in in each of these different locations and also the different reward and also locomotor activity, and they may also atten- mechanisms involved have not yet been fully elucidated uate opioid withdrawal in dependent animals or humans using a model of chronic, high-dose, intermittent but evenly (6,8,9–11,16). Again, these events must be considered to spaced opiate administration, mimicking the human pattern be a direct result of neuroplasticity and are counterregula- of heroin or morphine abuse and addiction, and also after tory, the attempt to attenuate, modulate, or even brake the withdrawal, as well as during reexposure after such opiate events caused by the rapid changes in dopaminergic tone administration. During chronic binge pattern cocaine ad- brought about especially by stimulants such as cocaine, but ministration, a pattern mimicking the human condition, also to a lesser extent also by opiates. Noble edly primarily the result of the effects of chronic opioid and Cox clearly defined a role of the dopaminergic system in administration. However, because there are also significant opioid-receptor desensitization in these brain regions during changes in dopaminergic tone with enhanced signaling chronic morphine administration (39). This is a rate-limiting enzyme in the biosyn- tion of the dopaminergic neurons, as stated earlier. They also found a reduction in mean D5-type dopaminergic receptors enhance adenylyl cyclase size of the ventral tegmental area dopaminergic neurons and activity, an effect similar to that occurring in the locus ceru- decreased axonal transport to the nucleus accumbens (24, leus after chronic, but not acute, morphine administration, 79). However, there were no changes in numbers of dopa- in most strains of rodents studied, and also in the nucleus minergic neurons and no changes in the size of nondopami- accumbens in some strains of some species. Within ventral tegmental area, infusion activation of the dopaminergic D2 receptors causes a reduc- of brain-derived neurotrophic factor prevented this mor- tion in adenylyl cyclase activity, such as observed during phine-induced reduction in size of dopaminergic neurons acute morphine administration in all brain regions of strains (79). Their group also found that chronic morphine admin- and species of rodents studied, as well as in all cell systems istration resulted in an increase of other components related studied, and an effect that continues to pertain in some to signal transduction, including the extracellular signal reg- specific regions of the brain and other parts of the body ulated kinases (ERKs), which are effectors for brain-derived during chronic opioid administration. Thus, the observa- neurotrophic factor in the ventral tegmental area (24). Crain There have been only limited studies of the time course and Shen hypothesized that, although most -opioid recep- of all these dopaminergic responses during investigator-ad- tors are coupled with inhibitory Gi/oprotein, a small propor- ministered morphine or heroin on an intermittent basis, tion may be coupled at the stimulatory Gs protein, which mimicking the human pattern of heroin abuse, or during can be suppressed with small amounts of opioid antagonists. It would be assumed These findings of enhanced morphine analgesia are, in part, that possibly, as with cocaine, one sees a progressive diminu- very similar to the findings of Bohn, Caron, Lefkowitz, and tion of the responsivity, with a resultant lowering of basal colleagues, in mice with deletion of -arrestin (60). These level and stimulant-induced rise of absolute levels of dopa- researchers also showed that -arrestin is important in sev- mine (78). Numerous human studies suggest this may in- eral distinct functions, including events leading to the inter- deed happen. It has been repeatedly shown in heroin addicts nalization of an agonist bound -opioid receptor, which, that the short acting -opioid agonist heroin will cause a after the phosphorylation of the bound form, binds to - prompt increase in serum prolactin levels, resulting directly arrestin, along with binding by G-protein–receptor kinases from an abrupt lowering of dopamine levels in the tuberoin- (60). This event of -arrestin binding has been described fundibular dopaminergic systems (85). In humans, and to a as potentially part of the process that desensitizes, that is, greater extent than in rodents, prolactin release is essentially leads to G-protein uncoupling of the -opioid receptors, solely under tonic inhibition by dopaminergic tone in the as well as being actually involved in the internalization of tuberoinfundibular dopaminergic system. However, it was endogenous and some exogenous agonist-bound -opioid found that during chronic methadone treatment, there is receptors (44–52,60). The role of internalization in the de- adaptation or tolerance to this phenomenon, an attenua- velopment of tolerance and the independent process of de- tion, but not a complete removal or ablation of this response pendence remain unclear because there are many conflicting caused by dopamine lowering and resulting in elevation of results, including the finding that most exogenous opioid serum prolactin levels (85). Even during long-term metha- ligands, including morphine, that do not induce prompt done maintenance treatment, as reported in 1978, it was internalization of -opioid receptors once bound, clearly found that peak plasma levels of the -opiate agonist metha- lead to the development of both tolerance and physical de- done are related temporally to the peak plasma levels of pendence (44–52). In sharp contrast, methadone and etor- prolactin (85). These findings suggest that the long-acting phine do lead to prompt internalization of -opioid recep- opioid methadone administered orally continues to have tors, just as do all the natural endogenous opioid peptides an impact at least on the tuberoinfundibular dopaminergic such as Met-enkephalin and -endorphin (44–52). Intrigu- system, with a lowering of dopaminergic tone, resulting in ingly, in the mice with deletion at the -arrestin-2 gene, a modest increase of prolactin levels, although not exceeding enhanced morphine analgesia was seen, and further studies upper levels of normal. However, that attenuation occurs revealed that tolerance does not develop to morphine effects, suggests that there may be either a lowering of dopaminergic and yet objective signs reflecting the development of physi- levels and tone in the turberoinfundibular dopaminergic cal dependence are present after chronic morphine adminis- system of that region or, alternatively, an attenuation of tration (60). These studies again dissociated the develop- responsivity of the -opiate-receptor system. It has been ment of tolerance from the development of physical shown that the -opiate-receptor system similarly plays a dependence. The studies of the group of Crain, as well as role in modulating prolactin levels in humans (86). In nor- the studies of the group of Caron and Lefkowitz, suggested mal healthy volunteers, dynorphin A causes a prompt rise that either deletion of -arrestin or suppression, by opioid in serum prolactin levels, resulting again presumably from antagonists in very small doses, of opioid receptor coupled a lowering of dopaminergic tone in the tuberoinfundibular to G , the stimulatory G-protein pathway, will enhance opi-s system (86). This is a , but also a -opioid-receptor effect, oid analgesia and also may attenuate or prevent develop- as documented by use of two different opioid antagonists ment of tolerance. It is not known whether blocking of the with different receptor selectivity (86). In preliminary stud- G coupling alters the development of physical dependence,s ies, the Kreek laboratory showed that there is altered respon- however. In possibly related studies, Jeziorski and White sivity both in former heroin addicts and in former cocaine showed that the NMDA antagonist, MK-801, prevents de- addicts, as well as those with combined heroin opioid and velopment of behavioral sensitization during chronic mor- cocaine dependency (87). Sensitization has been suggested to be ters; this group comprises fast-acting neurotransmitters in- related to drug reward or craving. Possibly in contrast, cluding excitatory amino acids such as glutamate and Churchill, Roques, and Kalivas found that dopamine deple- slower-acting neurotransmitters such as norepinephrine, tion, such as may happen during chronic opiate, as well as epinephrine, and serotonin, as well as dopamine, and a vari- 1498 Neuropsychopharmacology: The Fifth Generation of Progress ety of neuropeptides. Very few studies have been conducted to novelty or to risk and used different strains of rats, as well in models using chronic heroin or morphine administration, as mice. Similarly, more recent studies looked not simply at or self-administration, using long-term, high-dose, regularly the acute effects of drugs of abuse, but also at the subacute spaced intermittent administration or by long-access, high- and chronic effects of drugs of abuse and the impact of dose, self-administration, mimicking the human pattern of withdrawal from such drugs on components of the stress- heroin abuse. Further work will be central to detail the long- responsive axis. Even more recent studies went on to study term effects and, also of special interest, the effects of the levels of gene expression and the impact of exposure to drugs withdrawal and reexposure to mimic relapse. However, of abuse over a defined time course of exposure on gene qualitatively and quantitatively different changes have been expression, first on 'early gene response' and then, more found during chronic morphine or heroin administration recently, on changes of expression of many other specific by different patterns, dose, and routes of administration. The interactions of the dopaminergic system on the HPA Physiologic Systems and Behaviors axis as well as the effects of catecholamines on this axis have Primarily Altered been studied in both animal models and in humans. It is clear that opiates, like cocaine but to a much lesser extent, Stress Responsivity: Possible Implications for cause an elevation in dopaminergic tone, especially in the Opiate Addiction mesolimbic-mesocortical dopaminergic system.
Cannabinoid receptors in the agonist on adrenocorticotropic and diuretic function in man generic 40/60 mg levitra with dapoxetine free shipping. Abstinence symptoms conditioned place preference paradigm in rats purchase discount levitra with dapoxetine line. J Pharmacol Exp following smoked marijuana in humans buy generic levitra with dapoxetine 40/60mg on-line. Cannabinoid precipitated of cocaine: modulation by dynorphin and kappa-opioid receptor withdrawal by the selective cannabinoid receptor antagonist, SR agonists. Activation of receptor-regulated gene expression of striatonigral and striatopal- corticotropin-releasing factor in the limbic system during can- lidal neurons [see comments]. Addiction, dopamine, and the molecular norphin gene regulation in rat striatum. Basal ganglia—input, neural activity, and relation 79. AMPA receptors by the extracellular immediate- early gene prod- 62. D1 dopamine receptor activation uct Narp [see comments]. Regulation of immediate responsive element-binding protein. Proc Natl Acad Sci USA 1992;89: D, a RNA synthesis inhibitor, on long-term potentiation in rat 5764–5768. A macromolecular synthesis-dependent ine, and amphetamine. Proc Natl Acad Sci USA 1992;89: late phase of long-term potentiation requiring cAMP in the me- 4270–4274. AP-1 complex composed of altered Fos-like proteins in brain by 83. Synaptic tagging and long-term potentiation chronic cocaine and other chronic treatments. Blockade of morphine- and am- stage of LTP in hippocampal CA1 neurons. Science 1993;260: phetamine-induced conditioned place preference in the rat by 1661–1664. Influence of novel versus synthesis-dependent late potentiation in the CA1 region of the home environments on sensitization to the psychomotor stimu- hippocampus [see comments]. Proc Natl Acad Sci USA 1995;92: lant effects of cocaine and amphetamine. Sensitization to the behavioral effects nergic D1 receptor blockade during tetanization on the expres- of cocaine: modification by Pavlovian conditioning. Pharmacol sion of long-term potentiation in the rat CA1 region in vitro. Dopaminergic antagonists of sensitization induced by psychomotor stimulants. NIDARes prevent long-term maintenance of posttetanic LTP in the CA1 Monogr 1990 á:208–241. Dopamine D1-defi- tor stimulant effects of amphetamine: modulation by associative cient mutant mice do not express the late phase of hippocampal learning. Models of information processing North Ami 1986;9:413–425. In vivo activity-dependent plasticity diction and stages of change models. Dopamine reverses the putative 'effector' immediate early gene, by cocaine in rat brain. Nature 1989;340: plasticity in an in vitro slice preparation of the rat nucleus accum- 474–476. Requirement of a critical period factor and activity-regulated gene, encodes a novel cytoskeleton- of transcription for induction of a late phase of LTP. Science associated protein that is enriched in neuronal dendrites. Homer: a protein cleus accumbens and prefrontal cortex neurons produced by that selectively binds metabotropic glutamate receptors [see com- previous experience with amphetamine. KOOB DEFINITIONS AND VALIDATION OF butes of a drug (e. This chapter reviews animal models currently used to Definitions of Drug Addiction examine the neurobiological basis of drug addiction and the Drug addiction is defined as a compulsion to take a drug role of reinforcement processes in its initiation, mainte- with loss of control in limiting intake (33). Emphasis is place on more re- a chronic disorder because the risk of relapse remains high cently developed models, and where possible, the models even after completion of treatment and prolonged absti- are evaluated in terms of reliability and predictability to nence. In 1968, the term drug dependence replaced that of the human condition. Potential pitfalls to consider when addiction in the nomenclature of the World Health Organi- interpreting data also are discussed. Defined as a cluster of cognitive, behavioral, and physiologic symptoms ANIMAL MODELS OF THE POSITIVE indicative of an individual continuing substance use despite REINFORCING EFFECTS OF DRUGS significant substance related problems, this term has become the accepted diagnostic term for compulsive use of a psy- Drugs of abuse function as positive reinforcing stimuli; this choactive substance. When defined as described, it is analo- action has provided the framework for currently used animal gous to the term addiction. It is also clear that humans and experi- be confused with physical or psychic dependence, condi- mental animals will readily self-administer these agents in tions in which the cessation or reduction of drug usage the absence of a withdrawal state. Earlier models of drug results in a withdrawal syndrome. Withdrawal and tolerance reinforcement used operant paradigms in nonhuman pri- often are associated with compulsive drug use; however, mates; however, many of these same paradigms now are they are not required for drug addiction. The use of these rodent models, together als suffering from chronic pain may develop tolerance to with the development of modern neurobiological tech- the analgesic effects of an opiate and experience withdrawal niques, has provided important information regarding the symptoms, they do not exhibit signs of compulsive drug- neurobiology of addiction (11,15,36,45,51). The concept of reinforcement has provided the corner- Operant Intravenous Drug stone for current theories and animal models of drug addic- Self-Administration tion. A reinforcer is defined operationally as 'any event that increases the probability of a response' and often is used Drugs of abuse are readily self-administered intravenously interchangeably with 'reward. However, that not all drugs abused by humans are self-administered by experimental animals (e. Furthermore, there are species- and strain-related differences in the degree to which a drug is self-administered Toni S. Shippenberg: National Institutes of Health, National Institute (48,62). A detailed review of intravenous self-administra- on Drug Abuse, Bethesda, Maryland. Koob: Department of Neuropharmacology, The Scripps Re- tion was presented in the previous edition (46); therefore, search Institute, La Jolla, California. The number and pattern of responding required for each infusion is determined by the schedule of reinforcement Multiple Schedules imposed by the experimenter. Drug availability typically is signaled by an environmental stimulus. The dependent Clinical definitions of drug addiction and dependence typi- variables are the number of infusions obtained or the rate cally refer to the disruptive effects of addiction on of responding during a session.