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Is cue-elicited cocaine craving more 'druglike' or 'drug- Cocaine-induced craving was unrelated to DAT occupancy indomethacin 50mg overnight delivery arthritis pain in wrist. Do the multiple cues surrounding the cocaine However cheap indomethacin amex arthritis fingers popping, methylphenidate-induced cocaine craving was experience become linked predominantly to the brief cheap indomethacin 25 mg visa arthritis pain relief apr, in- correlated with right striatal and right orbitofrontal in- tense, orgasmic euphoria... These findings could support a postulated predictions for neuroimaging and pharmacotherapies. If DA dysfunction in the striatal–thalamic–orbitofrontal cir- craving to common external (paraphernalia, other users, cuit in cocaine addiction (33,67). One similarity between drug-buying locations, drug talk) or internal (e. As mesolimbic–mesocortical DA system activated by cocaine discussed in the final section, the orbitofrontal cortex is thus itself are also activated during cue-induced craving. In ani- far the only region linked to craving in all three paradigms: mals, cues for cocaine can indeed trigger mesolimbic DA (early) cessation, stimulant administration, and exposure to overflow in nucleus accumbens and amygdala (70) and can drug-related cues. Patients ministration, a role of transmitters other than DA in meth- often describe cocaine-like effects in response to cues, in- ylphenidate-induced effects (both high and craving) seems cluding heart pounding, ear ringing, head buzzing, stomach likely. Methylphenidate alone was insufficient to increase 'flipping,' mild euphoria, a 'taste' of cocaine in the back frontal metabolism, and in other studies by the Brookhaven of the throat, even the 'smell' of cocaine in the room... But what do the brains of methylphenidate did not always result in a subjective high in cocaine users say about the nature of cue-induced cocaine healthy controls (craving was not probed) (68). It tested whether video-induced cocaine IMAGING OF CRAVING DURING COCAINE craving might increase endogenous DA, as indexed by com- CUES 123I-iodobenzamide, in SPECT. After this initial effort, imaging studies ad- (5,6). According to this view, cocaine cues trigger cocaine- dressed the neuroanatomic rather than the neurochemical related subjective and physiologic responses, including crav- substrates of cue-induced craving. Drug-related conditioning can result cocaine cues since 1992. These studies cover a range of 15 18 in both responses similar to those produced by the drug imaging technologies (PET with O bolus, PET with F- itself ('druglike') and responses opposite to those of the fluorodeoxyglucose, fMRI) and include several variations drug ('drug-opposite') (69), likely reflecting a conditioned on the method of presenting drug cues to induce craving. Both kinds of The variations are useful because results obtained in only responses may be of motivational significance. Druglike re- one laboratory, or with one method of cue presentation, sponses to cues reminiscent of the drug ('Wow... Conversely, any replication and ing the user back to the drug. If drug-opposite responses convergence of findings across multiple laboratories and to the cues are uncomfortable (in opiate users, these include methods are very encouraging. BRAIN IMAGING OF CUE-INDUCED COCAINE CRAVING Imaging Cocaine Days of Laboratory Technology Population Cessation Cue Description Resultsa U. Nac/SCC +,^(–) each, same order) OFC 0 DLPFC 0 Cerebellum 0 Medical College of Wisconsin Garavan et al. When controls were studied, the summary reflects significant difference between groups for the drug cue vs. When no controls were studied, the effects are only for drug cue vs. Because of space constraints, results are summarized and “no difference” regions are presented only as relevant to discussion in the text. Please refer to the original articles for a complete listing of neuroanatomic regions studied. Abbreviations: SPECT, single-photon emission computed tomography; 123I-IBZM, iodobenzamide, a D2-receptor ligand; PET, positron emission tomography; ROI, region of interest analysis; OFC, orbitofrontal cortex; DLPFC, dorsolateral prefrontal cortax; VLPFC, ventrolateral prefrontal cortex; fMRI, functional magnetic resonance image; BOLD, blood oxygen level-dependent technique; SPM, statistical parametric mapping technique; FDG, 12F-fluorodeoxyglucose; NAc/SCC, nucleus accumbens/subcallosal cortex; l. In the first activated by cocaine itself (summarized above). Because of PET study of craving, predicted increases in amygdala rCBF the number of studies, the findings reviewed below are or- (measured with 15O-water as the perfusion tracer) were ganized according to the anatomic structures that have fre- found in cocaine patients viewing videos that induced crav- quently been activated during cue-induced craving. This effect was not evident in controls without a cocaine history. Inter- Limbic-Related Structures estingly, baseline rCBF in the amygdala of cocaine users Several of the structures activated during cue-induced crav- tended to be lower than in controls, such that increased ing are parts of an interconnected rostral limbic system, rCBF in response to the cocaine cues did not exceed the important in motivation and affective experience. Devinsky amygdala rCBF in control subjects under the same condi- et al.

In these paradigms and therefore it is important that the physician be aware of the behavior of drug taking can be more clearly approxi- the dangers of possible drug combinations generic 50mg indomethacin overnight delivery lyme arthritis definition, such as cocaine mated and a medication that might block the effects of and alcohol or heroin generic indomethacin 75 mg visa treating arthritis joint pain. This blocking effect would pre- Pharmacologic intervention may be necessary during sumably lead the subject to prefer the alternative reward stimulant-induced drug states purchase indomethacin from india king bio arthritis pain & joint relief. For instance, neuroleptics over the cocaine after the first test dose, when the medica- may be useful in controlling stimulant-induced psychosis tion is present, because the reinforcing effects of cocaine or delirium, and during withdrawal when depression may would be reduced (12). Although this model has theortical set in, antidepressants may be an appropriate choice for appeal and has shown the expected subject behaviors with treatment medication. Treatment medications can be given various doses of cocaine, it has yet to be tested with an on an inpatient or outpatient basis. However, if medications appropriate medication to judge its sensitivity for blocking are used for outpatient treatment, it is critical to warn the agents. For instance, high amphetamine interactions with potential pharmacothera- blood pressure could result from the release of epinephrine pies yields not only surrogate efficacy data, but also medical by cocaine combined with the reuptake blockade by the safety data. Cardiovascular measures in particular can be tricyclic (25), although later in the course of treatment tri- carefully monitored after both acute and subchronic dosing cyclics decrease the sensitivity of the postsynaptic adrenergic with potential medications. Finally monitoring of treatment is essential using treatment medications can be assessed in escalating dose urine toxicologies as well as self-reports. The frequency of regimes, and then dose–response evaluations using escalat- monitoring may be as infrequent as weekly, but three times ing doses of cocaine or amphetamine can be examined. There appears to be no advantage to jective responses may also be important to assess dysphoric quantitative over simple qualitative results based on typical interactions between the medication and the abused drugs. Overall, this is a powerful paradigm for medica- HUMAN TESTING PARADIGMS FOR NEW tion development because of its potential to inform the MEDICATIONS clinical trials process with information about how the outpa- tients in a trial are likely to respond to the newmedication, Human Laboratory when a study participant uses a stimulant. Its utility as a The human laboratory setting in which cocaine or amphet- rapid screening procedure for eliminating medications from amine is administered to volunteer subjects has been a criti- further outpatient testing has yet to be demonstrated, but 1464 Neuropsychopharmacology: The Fifth Generation of Progress this may be a future use of these highly controlled paradigms can be combined with self-reported use and compared to as we obtain gold standard agents with demonstrated effi- urine levels obtained prior to the urine in question to esti- cacy in outpatient trials. Although the goal of treatment is often com- potential medications is neuroimaging of either functional plete abstinence, the sensitivity of these urine tests can be activity or receptor and transporter occupancy (28). Thus, self-reported tional activity can involve either cerebral blood flow(CBF) decreases in stimulant use may be important as a treatment or metabolic activity using fluorodeoxyglucose (FDG). The outcome even when the goal may be abstinence initiation. In this study, selegiline reduced the available for intervention. Relapse that the cocaine-induced changes in metabolic activity were as defined by recurrent use or dependence after 'sustained blocked by the administration of selegiline (29). This surro- abstinence' first requires a definition of sustained absti- gate marker provided an interesting correlate of the attenua- nence, particularly among the binge users of stimulants. Because similar studies of subjective of the Diagnostic and Statistical Manual of Mental Disorders, effects alone have not had corresponding predictive validity fourth edition (DSM-IV) for stimulant dependence, the pe- for outpatient efficacy, these neuroimaging measures may riods of nonuse can manifest reasonable psychosocial func- have promise as a more rapid screening tool for medications. Simple definitions of sustained absti- roimaging focuses on the CBF defects that have been ob- nence can just be defined by a period of cocaine- or amphet- served in cocaine abusers and on the neuropsychological amine-free urines that lasts three, four, or perhaps ten times deficits that persist even during sustained abstinence (6,15, longer than the typical inter-binge interval. As reviewed below, these CBF defects may be respon- vestigations, an important prognostic stratification is evolv- sive to pharmacotherapy. The therapeutic implication is ing based on sustained abstinence; patients who are absti- that by resolving these CBF defects, cognitive functioning nent during the 2 to 5 weeks before entering a medication might improve, and the response to cognitive behavioral trial have better treatment outcomes than those who con- therapies also might be enhanced. Longer- term relapse prevention has also been an area where psycho- therapy may synergize with pharmacotherapy (32). For Outpatient Randomized Clinical Trials example, sustained abstinence with desipramine treatment Outpatient clinical trials remain the standard approach to for cocaine dependence was enhanced by relapse-prevention assessing efficacy of a medication. Although many principles cognitive behavioral therapy when examined at 6 and 12 of conducting randomized placebo-controlled clinical trials month follow-up. Relapse was significantly higher after at- in psychopharmacology apply to these studies, some specific taining abstinence with the medication alone than with both considerations are relevant to outcome measures that are not medication and the behavioral therapy. Urine toxicology is a most informative outcome that can be analyzed with both quantitative and qualitative approaches.

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This disorder having skeletal and renal m anifestations affects the glom eruli cheap 25mg indomethacin mastercard can arthritis in neck affect breathing, with accu- m ulation of banded collagen fibrils within the substance of the cap- illary basem ent m em brane order indomethacin 75mg with visa rheumatoid arthritis medication uk. This accum ulation appears as em pty lacunae when the usual stains with electron m icroscopy (lead cit- rate and uranyl acetate) are used order indomethacin without a prescription arthritis in knee food. H owever, as here, the fibrils easi- ly can be identified with the use of phosphotungstic acid stain in conjunction with or instead of typical stains. N ote that this disor- der differs structurally from collagen type III glom erulopathy in which the collagen fibrils are subendothelial and not intram em bra- nous in location. Patients with nail-patella syndrom e m ay develop proteinuria, som etim es in the nephrotic range, with variable pro- gression to end-stage renal failure. N o distinguishing abnorm alities are seen on light m icroscopy. The skeletal m anifestations of nail-patella syn- drom e are characteristic and consist of absent patella and absent and dystrophic nails. These photographs illustrate absent patella (A) and the characteristic nail changes (B) that occur in patients with the disorder. Lipid accum ula- m em branes are irregularly thickened. Som e capillary lum ina m ay tion occurs in this hereditary m etabolic disorder, especially in contain foam cells. Although quite rare, this autosom al recessive extracellular sites throughout glom erular basem ent m em branes disease has been described in m ost parts of the world; however, and the m esangial m atrix. A, O n electron m icroscopy the lipid it occurs m ost com m only in N orway. Patients exhibit proteinuria, appears as m ultiple sm all lacunae, often with sm all round dense often with m icroscopic hem aturia usually noted in childhood. Lipid-containing Renal insufficiency m ay develop in the fourth or fifth decade of m onocytes m ay be in the capillary lum ina. N onrenal m anifestations include regions are widened on light m icroscopy, usually with expansion corneal opacification, hem olytic anem ia, early atherosclerosis, of the m atrix that stains less intensely than norm al. Basem ent and sea-blue histocytes in the bone m arrow and spleen. A B FIGURE 3-9 (see Color Plate) Lipoprotein glom erulopathy. Patients with this rare disease, which m esangial hypercellularity or m esangiolysis m ay be present. W ith often is sporadic (although som e cases occur in the sam e fam ily), im m unostaining for -lipoprotein, apolipoproteins E and B are exhibit m assive proteinuria. Lipid profiles are characterized by identified in the lum inal m asses. B, Electron m icroscopic findings increased plasm a levels of cholesterol, triglycerides, and very low indicate the throm bi consist of finely granular m aterial with num er- density lipoproteins. M ost patients have heterozygosity for ous vacuoles (lipoprotein). Lipoprotein glom erulopathy m ay apolipoprotein E2/3 or E2/4. A, The glom eruli are the sites of m as- progress to renal insufficiency over a long period of tim e. In older children and young adults, have occasionally enlarged and multinucleated visceral epithelial cells compared with young children, patients with cystinosis commonly (arrow). As the disease progresses, segmental sclerosis becomes evident exhibit glomerular involvement rather than tubulointerstitial disease. B, Crystalline inclusions are identified on Proteinuria and renal insufficiency are the typical initial manifestations. The crystals of cysteine are usually dissolved in A, As the most constant abnormality on light microscopy, glomeruli processing, leaving an empty space as shown here by the arrows. A B FIGURE 3-11 (see Color Plate) Finnish type of congenital nephrotic syndrom e.

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Recent work has confirmed long-standing belief that the LCsystem is important in some of the proposed inputs order generic indomethacin canada arthritis x ray neck, showing direct contacts onto sleep–waking processes (28) and indicates that sleep disor- peri-LCdendrites from amygdala (9) and nucleus tractus ders may involve anomalies in this hypocretin projection to solitarius (NTS) (10) purchase indomethacin overnight delivery arthritis treatment kidney disease. These findings also offer a novel target for pharma- some of the other possible inputs to LCdistal dendrites order indomethacin with a visa arthritis hip pain relief exercises. Stimulation of the PGi strongly excites been found in LCafferents (see ref. The PGi has strong autonomic functions, sources of some of these inputs have been determined. These findings, in the PGi, -aminobutyric acid (GABA) inputs arise from together with the strong cortical projections of LCneurons, the PrH (13), and strong enkephalin projections to the LC suggest that the LCacts as a cognitive component of a global originate in both the PGi and the PrH (14). In contrast, strong inhibition is pro- fibers innervate the LC, presumably originating in the tub- duced by PrH stimulation (13); the functional significance eromammillary nucleus (15). A particularly dense innerva- of this input is unclear. That inhibitory adrenergic input tion by serotonin fibers also exists; the origin of this projec- also arises from the PGi is revealed when the strong gluta- tion has not been determined. Ultrastructural analyses have mate input is antagonized pharmacologically (30). Inputs shown that several of these inputs directly innervate LC to distal LCdendrites from the amygdala (9) or NTS (10) neurons (16–20). Our unpublished studies in monkey indicate that the tion presumably originates in the hypothalamus (the sole anterior cingulate cortex strongly innervates the LC(32). Finally, mammillary histamine cells, and cholinergic neurons of the our recent studies using transsynaptic retrograde tracing re- brainstem). Initial studies of this peptide suggested a role in veal that the suprachiasmatic nucleus is a prominent indirect feeding (24,25). However, more recent work has stimulated afferent to the LC(34–36). This is the first demonstration considerable interest in this neurotransmitter by closely of a circuit that links the circadian suprachiasmatic nucleus linking its function to sleep regulation. Specifically, muta- mechanism with the arousal/alerting LCsystem. Inasmuch tions of the gene that makes a hypocretin receptor (26), or as other studies have linked circadian disturbances with Chapter 4: Norepinephrine 49 depression (37), and the LCsystem is also associated with that alter cAMP (51). This is significant because electrotonic depression and other mood disorders (38), this pathway coupling allows rapid, powerful cell-to-cell communication may also be important for affective function. Once rele- gated to the domain of the esoteric but unimportant, elec- Topography of LC Efferents trotonic coupling is now being demonstrated in an increas- It is well-known that LCaxons are highly branched and ing number of central neurons. Of great interest is the fact have extensive efferents that ramify throughout the central that such coupling is readily modulated by other inputs to nervous system, providing NE innervation at all levels of coupled cells—for example, in the retina, coupling is the neuraxis (see ref. Previous studies have strongly attenuated by dopamine inputs in a cAMP/protein found topography among these efferent projections (39), kinase A manner. This line of work is very promising in but the degree of specificity for projections of different LC neuropsychopharmacology because it suggests a novel set neurons appears to be quite limited. Recent studies by of targets (receptors that regulate electrotonic coupling) that Simpson et al. They report that LCneurons selectively collateralize tion of systems important in mental function and dysfunc- to different nuclei of the somatosensory system, so that indi- tion (such as the LC). Our recent work (described below) vidual neurons are more likely to send branches to thalamic shows how modulation of such coupling can have profound and cortical areas within the somatosensory system than to, influences on behavior and cognitive performance (33). LC Activity, Electrotonic Coupling, and Cognitive Performance in Behaving A2 NE Neurons of the CaudalMedulla Monkeys Norepinephrine neurons in the A2 group (caudal NTS) A possible role for electrotonic coupling among LCneurons have recently been implicated in behavioral functions of in cognitive performance was revealed by combining our psychiatric importance. Previously relegated solely to auto- recordings of LCneurons in monkeys performing a signal nomic and visceral control (e. In these ascending projections of these NE cells to forebrain areas recordings, LCneurons exhibited two modes of activity dur- such as the hypothalamus (42), bed nucleus of the stria ing task performance: a phasic mode, in which LCcells terminalis (BNST) (43), nucleus accumbens (44), and responded phasically to target stimuli, and a tonic mode, amygdala (45,46) have now been shown also to be impor- in which the tonic baseline activity of LCneurons was high tant in affective and cognitive processes (43,47). Moreover, the pha- scribed below, these findings identify new circuits for under- sic mode corresponded closely to focused attention and standing affective and mnemonic functions. Task perfor- NEUROPHYSIOLOGY mance could be improved by systemic or local (intra-LC) injection of clonidine during poor performance, which indi- Several recent findings regarding the neurophysiology of LC cates a causal influence of these patterns of LCactivity on neurons have extended our understanding of this system. A neural network model was constructed to Notably, integration of studies at the cellular and behavioral investigate mechanisms involved in generating these modes levels indicates a potentially important role of coupling of LCactivity and the corresponding task performance.

If symptoms persist order indomethacin 75mg on-line best arthritis relief, sexually active women aged ≤25 years is recommended discount indomethacin 50 mg line treating arthritis with diet, as is women should be instructed to return for re-evaluation because screening of older women with risk factors (e order cheap indomethacin on line arthritis in the knee what to do. In June 2007, have a high rate of reinfection within 6 months after treatment. USPSTF reviewed and updated their chlamydia screening Terefore, repeat testing of all women with chlamydia or guidance and found that the epidemiology of chlamydial Vol. In issuing recommendations, USPSTF made detection of C. CDC has not changed its age cutof, and thus continues on rectal swab specimens for C. Recent evidence to recommend annual chlamydia screening of sexually active suggests that the liquid-based cytology specimens collected for women aged ≤25 years. Pap smears might be acceptable specimens for NAAT testing, Screening programs have been demonstrated to reduce although test sensitivity using these specimens might be lower both the prevalence of C. Although evidence is insufcient (282); regardless, certain NAATs have been FDA-cleared for to recommend routine screening for C. Persons who undergo ally active young men because of several factors (including testing and are diagnosed with chlamydia should be tested for feasibility, efcacy, and cost-efectiveness) (94), the screening other STDs. Among Treating infected patients prevents sexual transmission of women, the primary focus of chlamydia screening eforts the disease, and treating all sex partners of those testing positive should be to detect chlamydia and prevent complications, for chlamydia can prevent reinfection of the index patient and whereas targeted chlamydia screening in men should only be infection of other partners. Treating pregnant women usually considered when resources permit and do not hinder chlamydia prevents transmission of C. An appropriate sexual Chlamydia treatment should be provided promptly for all per- risk assessment should be conducted for all persons and might sons testing positive for infection; delays in receiving chlamydia indicate more frequent screening for some women or certain treatment have been associated with complications (e. Te following recommended treat- urethral infection in men can be made by testing a urethral ment regimens and alternative regimens cure infection and swab or urine specimen. NAATs, cell culture, direct immunofuorescence, EIA, and nucleic Azithromycin 1 g orally in a single dose acid hybridization tests are available for the detection of OR C. NAATs are the most sensitive tests for these specimens and are FDA-cleared for use with urine. Alternative Regimens Some NAATs are cleared for use with vaginal swab specimens, Erythromycin base 500 mg orally four times a day for 7 days which can be collected by a provider or self-collected by a OR patient. Self-collected vaginal swab specimens perform at Erythromycin ethylsuccinate 800 mg orally four times a day for 7 days least as well as with other approved specimens using NAATs OR (276,277), and women fnd this screening strategy highly Levofoxacin 500 mg orally once daily for 7 days acceptable. Most tests, including NAAT and nucleic acid hybridization tests, are not FDA-cleared for use with rectal or oropharyngeal swab A meta-analysis of 12 randomized clinical trials of specimens, and chlamydia culture is not widely available for azithromycin versus doxycycline for the treatment of genital this purpose. However, NAATs have demonstrated improved chlamydial infection demonstrated that the treatments were 46 MMWR December 17, 2010 equally efcacious, with microbial cure rates of 97% and 98%, infection during the preceding several months (251,267,286– respectively (284). Most post-treatment infections result from reinfection populations in which follow-up was encouraged, adherence to caused by failure of sex partners to receive treatment or the a 7-day regimen was efective, and culture or EIA (rather than initiation of sexual activity with a new infected partner. Repeat the more sensitive NAAT) was used for determining micro- infections confer an elevated risk for PID and other compli- biological outcome. Unlike the test-of-cure, which is not recommended, to treat patients for whom compliance with multiday dosing repeat C. Te clinical signifcance and transmissibility of men should be a priority for providers. If retesting at 3 months In patients who have erratic health-care–seeking behav- is not possible, clinicians should retest whenever persons next ior, poor treatment compliance, or unpredictable follow-up, present for medical care in the 12 months following initial azithromycin might be more cost-efective in treating chla- treatment. Erythromycin might be less efcacious than either azithromycin or doxycycline, mainly Patients should be instructed to refer their sex partners for because of the frequent occurrence of gastrointestinal side evaluation, testing, and treatment if they had sexual contact efects that can lead to noncompliance. Although the expensive and ofer no advantage in the dosage regimen. To minimize Among heterosexual patients, if concerns exist that sex disease transmission to sex partners, persons treated for chla- partners who are referred to evaluation and treatment will mydia should be instructed to abstain from sexual intercourse not seek these services (or if other management strategies are for 7 days after single-dose therapy or until completion of a impractical or unsuccessful), patient delivery of antibiotic 7-day regimen. To minimize the risk for reinfection, patients therapy to their partners can be considered (see Partner also should be instructed to abstain from sexual intercourse Management).

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