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However these costs do not take into account all overheads buy 5gm bactroban with amex. Furthermore bactroban 5gm visa, there are economies of scale if reagents are used in large quantities cheap bactroban 5gm amex. The values of several diagnostic parameters are summarised in Table 4 buy discount bactroban 5gm line. Bias was greater CG (43%) in across the People with for MDRD equation stage 5 CKD 5 stages of CKD GFR <60 ml/min/ (–6. The MDRD equation was less biased than the Cockcroft-Gault equation in patients with stage 3, 4, or 5 CKD. The MDRD equation was significantly less biased than the Cockcroft-Gault equation when patients were analysed by age (above or below 65 years) and gender (p<0. Two studies50,52 showed that both the MDRD and Cockcroft-Gault equations correlated highly with the measured GFR in people with CKD, often with no statistical difference between the correlation coefficients for the MDRD and Cockcroft-Gault equations. Both MDRD and Cockcroft-Gault equations correlated poorly with the gold standard test in renal donors. The Cockcroft-Gault equation often overestimated the GFR. The MDRD equation was also significantly less biased than the Cockcroft-Gault equation in the nondiabetic CKD (N=579) subgroup, the diabetic CKD (N=249) subgroup, and in people with a measured GFR <30 ml/min/1. The MDRD equation underestimated the measured GFR, while the Cockcroft-Gault equation significantly overestimated the GFR (–3. In the kidney donor control group (N=459), the Cockcroft-Gault equation was superior to the MDRD equation in terms of bias (1. The MDRD had higher sensitivity than the Cockcroft-Gault equation. Specificity was similar for the two predictive equations. Generally, the MDRD equation was more accurate than the Cockcroft-Gault equation. The MDRD equation had significantly higher diagnostic accuracy (AUC=0. However, in older people and in people with GFR greater than 60ml/min/ 1. The GDG noted that serum creatinine is correlated with muscle mass and therefore estimation of GFR using prediction equations in people with extremes of muscle mass is subject to inaccuracy. In those with increased muscle mass GFR will be under estimated and in those with reduced muscle mass GFR will be over estimated. Gold standard measures of GFR are time consuming and expensive to perform but where a highly accurate measurement of GFR is required, for example in assessment of kidney donors or for accurate calculation of dosing of potentially toxic chemotherapy, the evidence suggests that GFR estimated from prediction equations is insufficiently accurate. The GDG agreed that significant changes in GFR are equally important in those individuals with GFR greater than 60 ml/min/1. Where laboratories do not report levels of GFR greater than 60 ml/min/1. Although the original MDRD equation included a correction factor for the American black population, there are no correction factors for other populations and in routine use the derived GFR is not corrected for any ethnicity other than African-Caribbean. Although most laboratories would be capable of measuring cystatin C concentrations there is no evidence to suggest that it was more useful than using the MDRD, with the caveat that existing evidence comparing cystatin C and the MDRD failed to appropriately calibrate serum creatinine measurements to the method of the MDRD laboratory. Cystatin C measurement is also currently more expensive. Ideally use creatinine assays that are specific and zero-biased compared to IDMS (e. Jaffe assays), employ appropriate assay-specific adjustment factors to minimise between-laboratory variation (e. R3 Where indicated, apply a correction factor for ethnicity to reported GFR values (multiply eGFR by 1. R6 Where a highly accurate measure of GFR is required (e. R7 In cases where there are extremes of muscle mass (e. Biological variation includes random variation and predictable cyclical variation (daily, monthly, seasonal). Within-subject biological variation is the average random fluctuation around a homeostatic set point, expressed mathematically as a coefficient of variation (CV). Factors affecting measured serum creatinine concentration and estimated GFR from prediction equations include ingestion of cooked meat (where the cooking process converts meat creatine to creatinine, which is subsequently absorbed into the bloodstream after ingestion), individual patient fluid status, diurnal variation, and centrifugation of blood samples. Plasma creatinine measurements also vary depending on the method/analyser used and there is inter-laboratory variation which changes with creatinine concentration. There is no (single) standard method used across England. Method precision at higher levels of creatinine has less variability and thus has marginal impact on the interpretation of eGFR from prediction equations. However, in the critical diagnostic range there is concern that inter-method/laboratory variation may impact on the diagnostic utility of eGFR. This is probably at creatinine concentrations of less than 180 µmol/l. If creatinine levels are overestimated because of method bias/variability this will result in a reduced eGFR (false positives) and misclassification of CKD. This will lead to increased referral rates and inappropriate labelling of patients as having CKD. If creatinine levels are underestimated, the reverse will happen (false negatives). Since April 2006, creatinine assays in chemistry laboratories in England have been calibrated to the gold standard reference method of isotope dilution mass spectrophotometry (IDMS) through the National External Quality Assurance Scheme. This has enabled reporting of an IDMS-related MDRD derived eGFR to minimise interlaboratory variation in GFR results. This section addresses other sources of bias and variation in creatinine measurement. The effect of delayed centrifugation of blood samples on GFR estimation was determined. The average analytical variation for serum creatinine was 0. The average intra- individual biological variation of creatinine measurements was 1. The intra-individual biological variation of creatinine measurements was significantly higher in men with type 1 diabetes (N=16, CV=5. The creatinine concentration then decreased after 19:00 to 7:00 the next morning.

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These observations converge tion of estrogen receptor- and - mRNA in the rat central with in vitro and epidemiologic evidence for neuroprotec- nervous system cheap 5 gm bactroban otc. Cloning and (and adrenal androgens) may enter the neuropsychiatric characterization of human estrogen receptor isoforms purchase bactroban 5 gm on line. While not permitting an inference about the etiology of rat estrogen receptor with 18 amino acid insertion in the of reproductive endocrine-related mood disorders 5 gm bactroban with mastercard, the psy- ligand binding domain as a putative dominant negative regula- chotropic effects of hormones may help dissect neural path- tor of estrogen action generic bactroban 5gm online. Biochem Biophys Res Commun 1998;246: ways of relevance to the regulation of affect. Coup- define the mechanisms underlying both the psychotropic ling of dual signaling pathways: epidermal growth factor action effects of gonadal steroids and the differential response to involves the estrogen receptor. Proc Natl Acad Sci USA 1992; endogenous gonadal steroids should help advance our ef- 89:4658–4662. Chapter 80: Hormonal and Gender Influences on Mood Regulation 1173 19. Stimulation of estrogen re- of serotonin receptors (subtypes 1A and 2A) in rat brain: a ceptor-mediated transcription and alteration in the phosphory- possible role of testosterone. The structure of the rat cerebral cortex: effects of cyclic adenosine monophosphate, and insulin-like growth fac- gender and the environment. Estrogen actions in the central nervous mediating mating behavior in the female guinea pig. Mating behavior in male rats castrated at campal CA1 neurons. Hormonal factors controlling the differentiation, de- receptor. K channels (hSlo) by estradiol binding to the subunit. Morphological changes in the brains of adult male via the cAMP signaling pathway: stimulation of adenylate cy- rats after neonatal castration. Sexual dimorphism in vocal control Sci USA 1994;91:8517–8521. Sexual dimorphism in the preoptic area diol-17 inhibit gonadotropin-releasing hormone, stimulation of the rat. Sexual dimorphism in the neuropil of anterior pituitary lobe. Acta Endocrinol (Copenh) 1992;126: the preoptic area of the rat and its dependence on neonatal 345–349. Evidence for a mor- calcium currents in rat neostriatal neurons via a membrane re- phological sex difference within the medial preoptic area of the rat brain. Activation of the brain oestrogen and progestin receptors. Nature 1982;300: Src/p21ras/Erk pathway by progesterone receptor via cross-talk 648–649. Sexual differentiation of the endocrine brain and 31. New York: brane effects of steroids in neuroblastoma cells: effects of estro- Raven Press, 1991:71–104. Developmental regulation of sex dif- c-fos immediate early gene transcription. Endocrinology 1997; ferences in the brain: can the role of gonadal steroids be rede- 138:4030–4033. Effects of discrete lesions of the diated effects of estrogen. Neuroprotection against preoptic regions on the sexual behavior of male rats. Brain Res oxidative stress by estrogens: structure–activity relationship. Behavioral correlates of sexual differentiation in 1996;212:13–16. Garcia-Segura LM, Cardona-Gomez P, Naftolin F, et al. Effects of early diol upregulates Bcl-2 expression in adult brain neurons. Neu- postnatal gonadal steroids on extinction of a continuously food- roendocrinology 1998;9:593–597. Proc Natl and differentiation in a vocal control nucleus of the adult female Acad SciUSA2000;97:1202–1205. Androgen effects on the development with the neurotrophins and their receptors. Sexual differentiation of monoaminergic Cambridge, UK: Cambridge University Press, 1994:391–411. Sex differences in unipolar depression: evi- model for sexual development. Testosterone triggers growth of brain vocal sion in the National Comorbidity Survey II: cohort effects. Sexual differentiation: do males differ from females depressive symptoms over naturalistic follow-up. Am J Psychiatry in behavioral sensitivity to gonadal hormones? New York: The Free Press, Res Commun Ment Health 1985;5:45–74. Twelve-month outcome rates of depression: cross-national perspectives. J Affect Disord of patients with major depression and comorbid psychiatric or 1993;29:77–84. Diagnostic and statistical man- the lifetime prevalence of depression: does varying the diagnostic ual of mental disorders, fourth ed. Washington, DC: American criteria reduce the female/male ratio? J Affect Disord 1990;18: Psychiatric Association, 1994. Do the diagnostic criteria determine miology of depression. Major psychiatric disorders: overviews and selected readings. Collaborative Depression Study, I: depressed probands—adver- 73. Women with bipolar illness: clinical and research 97. The influence of genetic in preadolescent children: prevalence in a large sample from the factors and life stress on depression among adolescent girls. J Am Acad Child Adolesc Psychiatry 1992; and distribution of major depression in a national community 31:50–59.

The second hypothetical pathogenic mechanism to ac- The strategies for making animal models that recapitulate count for brain degeneration in FTDP-17 owing to other tauopathies are summarized in the following and include: tau gene mutations suggests that these mutations directly cause deficits in the abilities of tau to bind to MTs and 1 purchase bactroban 5 gm online. Selection of DNA constructs to be expressed in the CNS promote assembly and stability of MTs 5 gm bactroban fast delivery. This disease mecha- of the model order bactroban 5gm line, and the use of cDNA or genomic DNA nism has been linked to several tau gene missense mutations tau constructs is a straightforward strategy to induce ac- including: G272V trusted 5gm bactroban, K280, P301L, P301S, V337M cumulations of tau in the CNS of experimental animals. On Indeed, tau cDNAs or minigenes have been used to over- the other hand, the mutations that increase E10 splicing express specific tau isoform(s), and cause an imbalance do not have similar effects on the functions of tau (111, of the tau isoform profile similar to that seen in human 159). Nonetheless, a loss of the binding ability of tau to tauopathies. Further, animal models engineered to ex- MTs may produce an increase in the levels of free tau pro- press human genomic tau DNA using bacterial artificial teins in the neuronal cytoplasm, and this could promote chromosome (BAC) or a P1-derived artificial chromo- their fibrillogenesis. Mutant tau proteins are also likely to some (PAC) containing the entire tau gene may be in- accelerate the accumulation of insoluble tau filaments formative for elucidating the biochemistry (including within neurons. This notion has been supported by several E10 splicing) and neuropathology (including emergence studies of the in vitro assembly of tau filaments, which also of tau deposits) in animals with and without a tau gene demonstrated that tau filament formation is enhanced by mutation. Other possible strategies to generate animal heparin using recombinant G272, P301L, V337M, and models of tauopathies are to express proteins that regu- R406W tau mutant proteins compared to wild-type tau late the phosphorylation of tau proteins, or to express protein (172,173). Moreover, mutations in exons other APP, PS-1, and PS-2 in tau transgenic (Tg) animals to than those in E10 (i. Overexpression of tau without mutation to assess the nary data to account for the differential effects of these mu- effects of excess tau proteins in the cytoplasm of neurons tations, additional studies are needed to fully elucidate how and glia on the formation of tau aggregates. Further, the generation of tau DNA with mutations that The discovery of tau gene mutations pathogenic for FTDP- alter the splicing of E10 to produce animal models would 17 indicates that genetic abnormalities directly influence be informative using the entire gene or minigene of the levels or functions of tau proteins, thereby resulting human tau. However, the phenotypes of these mutant in the aggregation of insoluble tau and neurodegeneration. Use of neuron-specific promoters including the Thy-1, in FTDP-17 syndromes that vary from patient to patient 3-hydroxy-3-methylglutaryl coenzyme A reductase by analyzing human cases because of the following reasons: (HMG-CoA) and prion protein (PrP) promoters to gen- (a) limited sample size of kindreds with each mutation; (b) erate tau pathology in neurons, whereas animals showing the difficulty of conducting biochemical and pathologic glial tau pathology can be developed by using glia-spe- studies in early stages of the disease; and (c) the possibility cific promoters including glial fibrillary acid protein that several additional but as yet unknown environmental (GFAP) promoter for astrocytes and 2′,3′-cyclin-nucleo- and/or genetic factors might modify the biochemical and tide phosphodiesterase (CNP) and myelin basic protein clinicopathologic phenotype of FTDP-17. Accordingly, an- (MBP) promoters for oligodendrocytes. Tg animals with imal models that reproduce tauopathies are required for genomic DNA are generally driven by endogenous pro- better understanding of the central roles played by tau ab- moters. Hence, this Tg mouse Thy-1 promoter was reported in 1995 (174), followed by is thought to be a good model for age-related neurodegener- a study of tau Tg mice expressing the shortest tau isoform ation in tauopathies, and it is useful for studying the time (T44 or fetal tau, 3R0N tau) driven by the HMG-CoA course of CNS degeneration in a human tauopathy. In these studies, somatodendritic spheroidal tau inclusions in these tau Tg mice have also overexpression of human tau was observed using anti-phos- been shown to contain neurofilaments (NFs) and tubulin. However, these Tg mice did not show This colocalization of tau and NFs is found in the inclusions tau aggregates in any of the CNS regions nor other tauopa- of ALS/PDC spinal cord. Further studies using these tau thy-like phenotypic changes, probably owing to the low Tg mice crossed with NF-knockout mice could be informa- expression level of the transgene product. Filamentous tau tive by determining whether or not NFs promote the forma- aggregates have been observed in the spinal cord and brain- tion of tau aggregates, and whether or not tau can form stem of tau Tg mice generated by using a transgene consist- aggregates in the absence of NFs. Tau Tg mice with the T40 transgene combined with the This Tg mouse showed approximately ninefold more tau Thy-1 promoter have been developed recently (177,178). The tau aggregates in the colocalization of tau and NFs has also observed in these this Tg mouse are spheroidal inclusions in proximal axons, inclusions. Axonal degeneration and corresponding pheno- and they showed an increase in number with aging, consis- typic changes were found in these Tg mice, and thus they tent with an age-dependent increase in the extent of tau may be regarded as models of neurodegenerative tauopathies phosphorylation and an age-dependent decrease in the solu- with increased 4R tau. In addition, these 4R tau Tg mice bility of overexpressed human tau. In addition, this tau Tg showed somatodendritic tau expression to a greater extent than 3R tau Tg mice. This suggests that the difference in affected brain areas between 4R tau and 3R tau Tg mice as well as the effect of predominant tau isoforms on the distribution of pathology should be analyzed by using tau Tg mice with the same promoter and a similar expression level of human tau. To date, only a few genomic tau Tg mice using PAC and BAC have been generated, and they have shown a so- matodendritic pattern of phosphorylated tau expression (179). Although all of the mentioned tau Tg mice have shown a somatodendritic tau expression that resembles the 'pretangles' in AD, none of them have developed NFTs containing a -pleated sheet structure that can be recog- nized by thioflavin-S and Congo red. In fact, overexpressed tau in the cytoplasm and processes of neurons is rather dif- fuse and does not show a filamentous structure by EM (179). One possible method to generate NFTs in tau Tg mice would be to use a mutant tau gene construct to de- crease the ability of tau to regulate MTs. Another method would be to follow tau Tg mice showing an age-related FIGURE 94. Spheroidal tau deposits in the spinal cord of tau increase of tau pathology to vary advanced ages. Tg mice over-expressing the shortest human tau isoform. A: Low power field of the spinal cord section of a 6-month-old Tg mouse One of the major goals in developing animal models is stained with anti-tau antibody T14. Spheroidal deposits (arrows) to generate a model for AD, which is the most common are observed in axons, and somatodendritic tau stain (arrowhead) neurodegenerative tauopathy. It seems feasible to develop is found in the neuron. B: Higher magnification of the spheroidal tau deposit indicated with asterisk in (A). C: Higher magnification mice with human APP, PS-1, PS-2, and ApoE transgenes of the somatodendritic tau stain shown in (A). D,E,F: Triple-la- to elucidate the mechanism of biochemical and clinicopath- beled indirect immunofluorescence of the spinal cord deposit ologic changes caused by genetic abnormalities in AD. Blue, anti-tau antibody T14 and AMCA (D); red, anti-low-molecular-mass-neurofilament (NFL) an- mice overexpressing APP with FAD mutations have shown tibody and Text Red (E); and green, anti-high-molecular-mass- diffuse and neuritic A plaques in the brain, but they have neurofilament (NFH) antibody and FITC (F). Note that tau is colo- calized with neurofilaments in the spheroid deposits. Scale bar, lacked tau-positive NFTs and neuron loss (180–182). Thus, the generation of double Tg mouse overexpressing 9. Ann Neurol 1991;30:156– mouse models recapitulating AD pathology. Identification of normal and pathologic aging in prospectively studied nondemented elderly humans. Neurobiol Aging 1992;13:179- Genetic, biochemical, and pathologic analyses have indi- 189. Transgenic experiments have also shown that overexpres- 14.

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Certain 1370 Neuropsychopharmacology: The Fifth Generation of Progress ligand-gated and voltage-gated channels may be preferen- Serotonin also appears to be involved in ethanol con- tially affected by ethanol because discount 5 gm bactroban, as complex multimeric sumption and reinforcement; ethanol consumption is gen- proteins generic 5gm bactroban with visa, they may be particularly vulnerable to ethanol- erally curbed by experimental manipulations that increase mediated changes in their lipid environment 5 gm bactroban visa. The alterna- serotonergic function purchase bactroban 5gm with visa, and experiments with rats selectively tive hypothesis is that ethanol interacts with specific hydro- bred for ethanol preference suggest that strong ethanol pref- phobic regions of these proteins to produce allosteric erence is associated with reduced serotonergic function. Mice lacking 5-HT1B serotonin recep- more specifically, in interaction with particular regions of tors consume higher levels of ethanol yet demonstrate less proteins, ethanol has been shown to allosterically regulate ataxia (21). A The anxiolytic and sedative effects of ethanol, like those of Nicotine barbiturates and benzodiazepines, are believed to result from Nicotine is the main psychoactive ingredient of tobacco and facilitation of the GABAA receptor, although the precise is responsible for the stimulant effects, reinforcement, and mechanism differs for each drug. For example, distinct dependence that result from tobacco use. Cigarette smoking binding sites on the receptor have been identified for barbi- rapidly delivers nicotine into the bloodstream. The convergence of actions fers from cocaine and opiates in that it is powerfully rein- of ethanol, barbiturates, and benzodiazepines on a single forcing in the absence of subjective euphoria. In addition, these agents nicotinic acetylcholine receptors (nAChRs). Nicotinic all produce cross-tolerance, thus permitting the use of ben- AChRs are ligand-gated cation channels located both pre- zodiazepines in ethanol detoxification protocols. Presynaptic nAChRs fa- Not all GABAA receptors are ethanol sensitive. The reinforcing effects of receptor complexes are heteropentamers comprised of com- nicotine depend on an intact mesolimbic dopamine system; binations of the various members of five distinct subunit nicotine-induced increases in locomotor behavior are also families. The subunit combinations vary in different cell blocked by destruction of mesolimbic dopamine nerve ter- types, leading to differences in the sensitivity of GABAA minals or cell bodies (22). Moreover, nicotine increases do- receptors to ethanol in different brain regions. Other actions of ethanol that are possibly relevant be involved in both nicotine-induced dopamine release and to its psychotropic effects include potentiation of the action reinforcement and in nicotine-induced locomotor activa- of serotonin at 5-HT3 receptors, which, like NMDA recep- tion (24,25). Systemic nicotine self-administration is dis- tors, are excitatory, cation-selective ion channels. Nicotine may also have some ability to stimu- effects of ethanol are partly explained by its ability to activate late dopamine release in the NAc, however, mediated by mesocorticolimbic dopamine circuitry (15), with enhanced presynaptic nAChRs located on dopamine terminals within release of dopamine in the NAc. Nicotinic AChRs on VTA dopamine neurons are this effect is mediated by disinhibition of dopamine neurons normally activated by cholinergic innervation from the at the level of the VTA or whether it occurs at the level of laterodorsal tegmental nucleus or the pedunculopontine nu- the NAc, nor is it known whether it is caused primarily by cleus. Finally, it is not know to what degree opioid, peptide system. Not only dopamine antagonists, but also serotonin, and other systems play a role in ethanol-mediated opiate antagonists, block nicotine-induced behaviors and reinforcement. Thus, for example, not only GABA recep- self-administration (26,27). These findings suggest a role A for endogenous opioid systems in the reinforcing effects of tor antagonists but also opiate antagonists, decrease ethanol nicotine, and raise the possibility that such antagonists may self-administration and ethanol-related behavioral effects in be of use in the treatment of nicotine addiction. The opiate antagonist naltrexone reduces ethanol self-administration in animals; moreover, naltrex- Cannabinoids one and other opioid receptor antagonists reduce ethanol consumption, relapse to active drinking, and craving clini- -9-Tetrahydrocannabinol (THC)is the major psychoac- cally (19,20). THC produces ef- Chapter 96: Molecular and Cellular Biology of Addiction 1371 fects in humans that range from mild relaxation, euphoria, contrast, hallucinogens, such as LSD, act at 5-HT2 seroto- analgesia, and hunger to panic attacks. THC MECHANISMS OF LONG-LIVED DRUG increases mesolimbic dopamine transmission in the NAc EFFECTS shell, probably via a -opioid receptor-mediated mecha- Homeostasis Versus Associative Learning nism because -receptor antagonists prevent the THC- induced dopamine increases in the brain mesolimbic area Diverse behaviors, symptoms, and signs of substance use (30). Cannabinoids have also been reported to inhibit exci- disorders coexist clinically, but depending on the drug and tatory glutamatergic neurotransmission in the substantia on the stage of the disorder, these may involve multiple nigra pars reticulata (31). THC binds to two cannabinoid receptors denoted CB1 Heuristically, the types of molecular mechanisms involved and CB2. Of the two, only the CB1 receptor is expressed in the long-lived effects of addictive drugs may be divided in the central nervous system, with high levels in the basal into two major classes: homeostatic adaptations and associa- ganglia and limbic system (32). These adaptations tend to dampen drug effects, thus receptor. The Despite ongoing debates about the addictiveness of can- adapted state of neurons or neural systems may be un- nabinoids in humans, there appear to be many compulsive masked on drug cessation, leading to the production of marijuana users. Withdrawal symptoms typically are not withdrawal symptoms, as illustrated in the following. Ho- reported with termination of long-term marijuana use, but meostatic adaptations typically occur within reversible withdrawal symptoms have been demonstrated in a labora- bounds, and with removal of the drug, tend to dissipate tory setting after four days of marijuana smoking (33). Relapse often occurs on re-exposure to cues with THC, a selective cannabinoid receptor antagonist pro- associated with drug use, consistent with an important role duced withdrawal symptoms that included head shakes, fa- for associative learning (36). Although homeostatic mecha- cial tremors, tongue rolling, biting, wet dog shakes, and nisms are thought to represent reversible global alterations ptosis (34). Neurobiologically, withdrawal effects include in the sensitivity of neurons or circuits to neurotransmitters increases in c-fos expression in the basal ganglia systems and or drugs, associative learning is thought to represent long- CRF release in the amygdala (35). The clear separation between homeostasis and associative learning Phencyclidine-Like Drugs that has been implied, however, is an oversimplification. For Phencyclidine (PCP or angel dust)and ketamine are related example, there is recent evidence that associative learning drugs classified as dissociative anesthetics. These drugs ex- mechanisms and compensatory adaptations may interact. Moreover, molecular adaptations that occur The reinforcing properties of PCP and ketamine are me- as a homeostatic response to drug bombardment may alter diated by the binding to specific sites in the channel of the the threshold for associative learning involving affected cells. NMDA glutamate receptor, where they act as noncompeti- tive NMDA antagonists. PCP is self-administered directly Recruitment of Different Molecular into the NAc, where its reinforcing effects are believed to Mechanisms Over Time result from the blockade of excitatory glutamatergic input to the same medium spiny NAc neurons inhibited by During the earliest periods of drug experimentation, meso- opioids, and also by increases in extracellular dopamine. In corticolimbic reward circuits are activated via different 1372 Neuropsychopharmacology: The Fifth Generation of Progress mechanisms by different classes of drugs. As noted, a shared property of addictive drugs is to promote dopamine release in multiple forebrain regions, including the NAc, but also including the dorsal striatum, 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).