By U. Wenzel. Western New Mexico University.
Subjects had to complete three individual learning sessions to avoid the confounding effect of time generic 30 mg vytorin with amex. Processing of object identity is mainly a property of the ventral visual pathway generic vytorin 20mg with amex, whereas object location is a property of the dorsal stream discount vytorin 20mg with mastercard. We focused on the interstream connec- tions (mainly posterior parietal cortex to posterior inferotemporal cortex) based on the hypothesis that learning the association of object identity and spatial location leads to an increase in effective connectivity between the ventral and dorsal streams purchase vytorin 20 mg on-line. The predictive value of changes in effective connectivity for human learning. To establish unequivocally a relationship between prises fewer scans relative to LATE) (Fig. In other neurophysiologically mediated changes in connectivity and words, the temporal pattern of changes in effective connec- behavioral learning, we examined the relationship between tivity strongly predicted learning or acquisition. We estimated Example: Attention the differences in effective connectivity for seven EARLY and LATE partitions by successively shifting the cutoff. The Electrophysiologic and neuroimaging studies have shown cutoff time at which the connectivity change peaked was that attention to visual motion can increase the responsive- used as a temporal index of changes in effective connectivity ness of the motion-selective cortical area (V5) (23,24) and (i. The significant regression of k, a measure the PP (25). Increased or decreased activation in a cortical of learning speed*, on this plasticity index indicated that area is often attributed to attentional modulation of the for sessions showing fast learning (i. This leads to the notion maximum difference in path coefficients between PP and that attention is associated with changes in connectivity. Here we present fMRI data from an individual subject, scanned under identical visual motion stimulus conditions while only the attentional component of the tasks employed * All individual behavioral learning curves were well approximated by the function 1 e kx, where 0 k. First, we identify regions that show differential of k indicate slower learning. In the second stage, 388 Neuropsychopharmacology: The Fifth Generation of Progress paring attention with no attention and comparing no atten- tion with fixation. As predicted, given a stimulus consisting of radially moving dots, we found activation of the lateral geniculate nucleus, primary visual cortex (V1), motion-sen- sitive area (V5), and posterior parietal complex. For the subsequent analysis of effective connectivity, we defined re- gions of interest with a diameter of 8 mm centered around the most significant voxel as revealed by the categoric com- parison. A single time series, representative of this region, was defined by the first eigenvector of all the voxels in the region of interest (15). Our model of the dorsal visual stream included the lateral FIGURE 29. This graph shows the correlation between the temporal index of geniculate nucleus, V1, V5, and the PP. Although connec- changes in effective connectivity and learning. The temporal tions between regions are generally reciprocal, for simplicity index is defined as the time of a maximum increase in effective we modeled only unidirectional paths. For example, a temporal index of 3 indicates To assess effective connectivity in a condition-specific that the maximum increase in effective connectivity occurred be- fashion, we used time series that comprised observations tween the third and fourth blocks. The numbers denote the sub- during the condition in question. Path coefficients for both ject from which this temporal index of effective connectivity was obtained. Each subject was scanned during three independent conditions (attention and no attention) were estimated by learning sessions; therefore, each number appears three times. To test for the im- A negative slope means that the maximum increase in effective pact of changes in effective connectivity between attention connectivity occurs earlier in fast learning. The predictive value of changes in effective connec- and no attention, we defined a free model (allowing different tivity for human learning. Science 1999;283:1538–1541, with per- path coefficients between V1 and V5 for attention and no mission. The connectivity be- tween V1 and V5 increases significantly during attention. The specific hypothesis we addressed was that parietal cortex could modulate the inputs from V1 to V5. The experiment was performed on a 2-T MRI system equipped with a head volume coil. The subject was scanned during four dif- ferent conditions: fixation, attention, no attention, and sta- tionary. Each condition lasted 32 seconds to give 10 volumes per condition. During all conditions, the subjects looked at a fixation point in the middle of a screen. In this section, we are interested only in the two conditions with visual motion (attention and no attention), in which 250 small white dots moved radially from the fixation point, in random directions, toward the border of the screen at a constant speed of 4. The difference between attention and no attention lay in the explicit command given to the subject shortly before the condition: just look indicated no attention, and FIGURE 29. Structural equation model of the dorsal visual pathway, comparing attention and no attention. Connectivity be- detect changes indicated the attention condition. Both visual tween right primary visual cortex (V1) and motion-sensitive area motion conditions were interleaved with fixation. No re- (V5) is increased during attention relative to no attention. Effective connectivity¨ Regions of interest were defined by categoric compari- in functional brain imaging. Neural Networks 2000;13:871–882, sons with use of an output statistical image (SPM Z ) com- with permission. This can be tested by splitting the observations into two sets, one containing observations in which the PP activity is high and another one in which the PP activity is low. It is now possible to perform separate regressions of V5 on V1 by using both sets. If the hypothesis of positive modula- tion is true, the slope of the regression of V5 on V1 should be steeper under high values of PP. Variable Parameter Regression As demonstrated in the previous sections, the basic linear model can be seen as a linear regression. Structural equation model of the dorsal visual coefficient is then interpreted as a measure of the connectiv- pathway incorporating the interaction effect of right posterior parietal cortex on the connection from right primary visual cortex ity between areas. This interpretation of course implies that (V1) to motion-sensitive area (V5). Neural Net- effective strength equal to the regression coefficient. This is unsuitable for the assessment tion revealed increased effective connectivity in the dorsal of effective connectivity in functional imaging because the visual pathway in relation to attention. The question that goal in some experiments is to demonstrate changes in effec- arises is, which part of the brain is capable of modulating tive connectivity—for instance, as a function of different this pathway? Based on lesion studies (26) and the system conditions (e. In the framework of regression analysis, there are three sized to play such a modulatory role. Firstly, one can split the data in We extended our model accordingly to allow for nonlin- different groups according to the experimental condition ear interactions, testing the hypothesis that the PP acts as (e. However, we may not ing a nonlinear modulation of this connection, we con- know a priori the time course of the changes that allow us structed a new variable, V1PP, in our analysis. A second, more general solution mediating the interaction, is simply the time series from is to expand the explanatory variable in terms of a set of region V1 multiplied (element by element) by the time series basis functions to account for changes in connectivity. Because our nonlinear model could accommodate changes in connectivity between attention and no attention, the entire Mathematical Background time series was analyzed (i. As in the linear model, we tested for the significance of y x u the interaction effect by comparing a restricted and a free model.
In an attempt to develop a more physiologic solution generic vytorin 20mg fast delivery, various mmol/L buy vytorin 20mg mastercard. Emphasis is now being placed on individually adjusting new osmotic agents are now under investigation discount 30 mg vytorin with visa. Some of these the dialysate bicarbonate concentration so as to maintain the may prove useful as alternatives to the standard glucose solutions discount vytorin 30 mg on-line. Those that contain amino acids have received the most attention. Increasing evidence suggests that correction of chronic acidosis The sodium concentration in the ultrafiltrate during peri- is of clinical benefit in terms of bone metabolism and nutrition. Commercially available peritoneal dialysates have a disease. Excess potassium is removed by using a dialysate with a sodium concentration of 132 mEq/L to compensate for this ten- lower potassium concentration, so that a gradient is achieved dency toward dehydration. The effect is more pronounced with that favors movement of potassium. In general, one can expect increasing frequency of exchanges and with increasing dialysate only up to 70 to 90 mEq of potassium to be removed during a glucose concentrations. Use of the more hypertonic solutions typical dialysis session. As a result, one should not overestimate and frequent cycling can result in significant dehydration and the effectiveness of dialysis in the treatment of severe hyper- hypernatremia. As a result of stimulated thirst, water intake and kalemia. The total amount removed varies considerably and is weight may increase, resulting in a vicious cycle. W ith chronic ambulatory peritoneal dialysis and The concentration of calcium in the dialysate has implications 10 L of drainage per day, approximately 35 to 46 mEq of potas- for metabolic bone disease and hemodynamic stability. Daily potassium intake is usually other constituents of the dialysate, the calcium concentration greater than this, yet significant hyperkalemia is uncommon in should be tailored to the individual patient. Presumably potassium balance is maintained by that lowering the dialysate calcium concentration would exac- increased colonic secretion of potassium and by some residual Dialysate Composition in Hemodialysis and Peritoneal Dialysis 2. Given these considerations, potassium is not absorption. The pH of commercially available peritoneal dialysis routinely added to the dialysate. Once instilled, the pH of the solution rises to values function, lactate is rapidly converted to bicarbonate, so that greater than 7. There is some evidence that the acidic pH of each mM of lactate absorbed generates one mM of bicarbonate. The rapid To avoid negative calcium balance— and possibly to suppress m etabolism of lactate to bicarbonate m aintains the high circulating parathyroid hormone— commercially available peri- dialysate-plasm a lactate gradient necessary for continued toneal dialysis solutions evolved to have a calcium concentration 150 Baseline Low-sodium dialysate High-sodium dialysate Step Linear Interstitial Exponential space BUN H O BUN H2O Cell Cell 2 Intravascular Decreased Stable osmolality space osmolality BUN H O 145 2 BUN Na H2O • Less vascular refilling •↓Peripheral vasoconstriction •Exacerbated autonomic insufficiency -inhibits afferent sensing -↓ CNS efferent outflow •Venous pooling secondary to↑ PGE2 140 Hypotension 1 2 3 4 Time, h of 3. This concentration is equal to or slightly greater than the ionized concentration in the serum of most patients. As a result, there is net calcium absorption in of administered calcium, contributing to the development of most patients treated with a conventional chronic ambulatory hypercalcemia. As a result, there has been increased interest in peritoneal dialysis regimen. As the use of calcium-containing using a strategy similar to that employed in hemodialysis, phosphate binders has increased, hypercalcemia has become a namely, lowering the calcium content of the dialysate. This complication has been particularly common in binders and more liberal use of 1,25-dihydroxyvitamin D to patients treated with peritoneal dialysis, since they have a much effect decreases in the circulating level of parathyroid hormone. In fact, the continual positive calcium balance Dialysate Na in Hemodialysis associated with the 3. The low bone turnover state typical of this disorder impairs accrual 2. The drop in serum osm olality as urea is rem oved leads to a shift of water into the intracellular com partm ent that prevents adequate Indications refilling of the intravascular space. This intracellular m ovem ent of Intradialysis hypotension Cramping Initiation of hemodialysis in setting of severe azotemia Hemodynamic instability (eg, intensive care setting) Contraindications Intradialysis development of hypertension Large interdialysis weight gain induced by high-sodium dialysate Hypernatremia Dialysate Buffer in Hemodialysis water, com bined with rem oval of water by ultrafiltration, leads to contraction of the Acid concentrate intravascular space and contributes to the developm ent of hypotension. H igh-sodium NaCl dialysate helps to m inim ize the developm ent of hypo-osm olality. As a result, fluid can be CaCl m obilized from the intracellular and interstitial com partm ents to refill the intravascular KCL M gCl space during volum e rem oval. O ther potential m echanism s whereby low-sodium dialysate Acetic acid contributes to hypotension are indicated. N a— sodium ; BUN — blood urea nitrogen; Dextrose PGE2— prostaglandin E2. Final dialysate FIGURE 2-2 NaHCO3 Na 137 mEq/L There has been interest in varying the concentration of sodium (Na) in the dialysate during concentrate Cl 105 mEq/L the dialysis procedure so as to minimize the potential complications of a high-sodium solution NaHCO Ca 3. The concentration of sodi- um can be reduced in a linear, exponential, or step pattern. This M ECHANISM S BY W HICH ACETATE BUFFER method of sodium control allows for a diffusive sodium influx early CONTRIBUTES TO HEM ODYNAM IC INSTABILITY in the session to prevent a rapid decline in plasm a osm olality sec- ondary to efflux of urea and other sm all-m olecular weight solutes. During the rem ainder of the procedure, when the reduction in Directly decreases peripheral vascular resistance in approximately 10% of patients osm olality accom panying urea rem oval is less abrupt, the dialysate Stimulates release of the vasodilator compound interleukin 1 is sodium level is set lower, thus m inim izing the developm ent of Induces metabolic acidosis via bicarbonate loss through the dialyzer Produces arterial hypoxemia and increased oxygen consumption? Decreased myocardial contractility Dialysate Composition in Hemodialysis and Peritoneal Dialysis 2. In som e but not all studies, sodi- um m odeling has been shown to be effective in treating intradialysis hypotension and cram ps [5-11]. Use of a sodium modeling program is not indi- cated in all patients. As a result the physician needs to be aware of the benefits as well as the dangers of sodium remodeling. The generation of car- -adrenergic receptor agonists bon dioxide causes the pH of the final solution to fall to approxi- m ately 7. The acidic pH and the lower concentrations in the final m ixture allow the calcium and m agnesium to rem ain in solu- tion. The final concentration of bicarbonate in the dialysate is FIGURE 2-4 approxim ately 33–38 m m ol/L. The current utilization of a bicarbonate dialysate requires a special- ly designed system that m ixes a bicarbonate and an acid concen- trate with purified water. The acid concentrate contains a sm all am ount of lactic or acetic acid and all the calcium and m agnesium. The exclusion of these cations from the bicarbonate concentrate prevents the precipitation of m agnesium and calcium carbonate that would otherwise occur in the setting of a high bicarbonate concentration. During the m ixing procedure the acid in the acid 2. Although bicarbonate is the standard buffer in use phosphate serum calcium secondary today, hem odynam ically stable patients can be dialyzed safely using hyperparathyroidism as acetate-containing dialysis solution. Since m uscle is the prim ary Low-phosphate diet If calcium is still low (800–1000 mg/d) after control of Treat with 1,25(OH) site of m etabolism of acetate, patients with reduced m uscle m ass 2 Phophate binders phosphate, treat with vitamin D tend to be acetate intolerant. Such patients include m alnourished 1,25-(OH)2 vitamin D and elderly patients and wom en. Use calcium-containing phosphate binders Dialysate Potassium in 1. Risk of adynamic bone disease Dialysate Composition in Hemodialysis and Peritoneal Dialysis 2. Since potassium is freely perm eable across the dialysis m em brane, m ovem ent of potassium from the intracellular space to the extracellular space appears to be the limiting factor that accounts for the sm aller fractional decline in potassium concentration at lower plasma potassium concentrations. Presumably, the m ovem ent of potassium out of cells and into the extracellular space is slower than the removal of potassium from the extracellular space into the dialysate, so a COM POSITION OF A disequilibrium is created. The rate of potassium removal is largely a function of its predialysis COM M ERCIALLY AVAILABLE concentration. The higher the initial plasma concentration, the greater is the plasma-dialysate PERITONEAL DIALYSATE gradient and, thus, the m ore potassium is rem oved.
Animal research on stereotypic self-injurious behavior has Daphne Simeon: Mt cheap 30 mg vytorin amex. This view is consistent with a view of striatal func- teractions with one another buy cheap vytorin 20mg line. Nevertheless purchase 20 mg vytorin, for the sake of tion that emphasizes the development generic vytorin 30 mg with visa, maintenance, and simplicity, we list studies on each system in turn. Early work with rodents demonstrated that ampheta- Different terms given to allude to this group of functions mines act to produce an increase in stereotypic behavior have included habit system, response set, and procedural (5), including automutilation (6), and such findings have mobilization (19). These responses are prevented by 6-hydroxy- dopamine–induced lesions or by dopamine antagonists (7, VETERINARY BEHAVIORAL DISORDERS 8), perhaps particularly by D1 antagonists (9,10). Further- Phenomenology more, early destruction of dopaminergic neurons may lead to hypersensitivity of D1 receptors, with increased self-bit- In addition to animal laboratory studies, there is an interest- ing behavior in response to later administration of dopa- ing literature on veterinary behavioral disorders character- mine agonists (11). Acral lick dermatitis, for example, is a Traditional serotonin models include the administration condition characterized by excessive paw licking and of a monoamine oxidase inhibitor with L-tryptophan to in- scratching in dogs. This results in the characteristic derma- duce a hyperactivity syndrome in rats, and the use of 5- titis; in severe cases sequelae include osteomyelitis. The dis- hydroxytryptophan to induce the head-twitch syndrome in order is seen in certain breeds of large dog, and within breeds mice and the wet dog shake in rats. Reviewing this literature, may be more common in particular families. Jacobs and Fornal (12) conclude that serotonin facilitates Different species may manifest a range of different kinds gross motor output and inhibits sensory information pro- of SIB (20). Psychogenic alopecia is found in cats, with cessing. Certainly, isolation may be associated with de- excessive depilation leading to bare patches. Furthermore, in confining in birds is seen in a range of avian species, and can be or depriving environments, the animal may activate dorsal complicated by severe hemorrhage. Although stereotypies raphe neurons by performance of stereotypies (12). Indeed, it has been suggested that excessive opioid activity is responsible for SIB (15). However, an alternative Neurochemistry hypothesis emphasizes that pain associated with SIB results in the release of brain endorphins and draws a parallel be- The pharmacotherapeutic profile of acral lick dermatitis tween such endogenous release of endorphins and addiction overlaps remarkably neatly with that of obsessive-compul- to an exogenous substance (16). Thus, the disorder responds to From an integrated brain-mind perspective, interactions selective serotonin reuptake inhibitors (SSRIs), but fails to and overlaps between environmental and pharmacologic in- respond to desipramine or fenfluramine. However, the dis- ducers of stereotypy would be predicted. Indeed, compared order may also respond to opioid agents. Although not well to normally reared rodents, isolation-reared subjects show studied pharmacologically, there are a number of reports increased stereotypic responses after administration of am- indicating that psychogenic alopecia responds to treatment phetamine (17) or tail-pinch (18). In addition, administration of a dopamine blocker has been noted to lead to a decrease in symptoms. Similarly, feather-picking in birds and SIB in horses may Neuroanatomy respond to treatment with SSRIs (20). There is evidence that corticostriatal circuits are important We noted earlier the cross-sensitization between pharma- in mediating stereotypic behavior (3). First, infusion of the cologic and environmental inducers of stereotypies (22). Conversely, infusion of do- duced SIB may respond to psychopharmacologic interven- pamine blockers into the same areas reduces amphetamine- tion. For example, in a placebo-controlled study of fluoxe- induced stereotypy. Second, frontal lesions and dopamine tine in isolation-reared primates, this SSRI was effective in agonists produce similar behavioral and cognitive effects, reducing such symptoms (23). Furthermore, striatal lesions may also lead to stereotypic Neuroanatomy behavior. Reviewing this literature and his own work, Ridley (3) concludes that loss of inhibition induced by frontal le- In the previous section, the possible involvement of fronto- sions results in a release of previously stored response se- striatal circuits in animal stereotypic behavior was noted. Chapter 121: Compulsive and Impulsive Aspects of Self-Injurious Behavior 1745 With regard to stereotypic SIB in higher mammals, a partic- disability and symptoms in patients with OCD (28). Fur- ularly interesting finding is that socially isolated primates thermore, as noted earlier, in patients with developmental develop striatal cellular disorganization together with stereo- disability, there are significant positive associations between typic and self-injurious behaviors (24). The neuroanatomy the occurrence of self-injury, stereotypy, and compulsions of early social isolation and other developmental stressors (27). Nevertheless, relatively few studies have directly ex- would seem to be a promising area for further investigation, plored the role of serotonin in mediating SIB in such pa- one that may have direct relevance to some of the clinical tients. There is, however, some evidence of the value of SSRIs in the treatment of SIB in developmental disabled patients. SMD IN DEVELOPMENTAL DISABILITY Aretrospective review suggested that response of SIB in such patients was higher for SSRIs and was not predicted Phenomenology by comorbid depressive symptoms (30). Indeed, both open SIB in patients with developmental disabilities may fall and controlled (31) studies have confirmed the efficacy of within the diagnostic category of SMD. This disorder is SSRIs in the treatment of SIB in developmental disabilities. Examples include body rocking, in the mediation of SIB in mental retardation, questions hand waving, head banging, and skin picking. The DSM- remain about whether the effects of these agents are not IV provides a subtype 'with self-injurious behavior,' to be 'downstream' of their primary actions and about their used when bodily damage requires medical treatment. Several methodologies are available for delineat- have reviewed this disorder elsewhere (25,26), and draw ing different aspects of serotonin dysfunction in psychiatric extensively on those reviews here. It must 'markedly interfere with been useful in showing that serotonin plays a specific role normal activities' or result in 'bodily injury that requires in several disorders characterized by unwanted repetitive medical treatment. Asimilarly designed ity the behavior must be sufficiently severe to be a focus of study in mental retardation patients with SIB would be of treatment, and the behavior must persist for at least 4 weeks. The DSM-IV also states that stereotypic behaviors in SMD It may be noted here that other agents with serotoniner- should not be better accounted for by the compulsions of gic effects have also been studied for the treatment of SIB obsessive-compulsive disorder, the stereotypies of pervasive in developmental disability (28,34). Buspirone (15 to 45 mg/day), a 5-HT1A agonist, always meet the rather strict DSM-IV criteria for SMD. Eltoprazine, a selective rious, and compulsive behaviors appear to be correlated in 5-HT1A and 5-HT1B agonist, has yielded conflicting evi- such patients (27). Certainly, the relatively large body of dence of efficacy. Although early studies in this area suffered Reports of the incidence of SIB in patients with develop- from methodologic flaws, lithium has long been used with mental disability range from 3% to 46% (27,28). Head some apparent success in the treatment of SIB and aggressive banging, head and body hitting, eye gouging, biting, and behaviors in patients with mental retardation (28,34). Pro- scratching are the most common of these behaviors (29). Also, in a controlled study, pindolol (40 mg/ head banging or hitting may lead to cuts, bleeding, infec- day) was significantly more effective than placebo in 14 tion, retinal detachment, and blindness. Incidence of SIB patients with developmental disability and SIB (35). Dopamine blockers, however, are often successfully and institutionalization status (28). Preliminary evidence suggests that the atypical neuroleptics, which have Neurochemistry both dopaminergic and serotoninergic effects, may also be It has been argued that there is phenomenologic evidence useful in SIB and other target symptoms in this patient of similarities between SIB in patients with developmental population (36,37). Given their apparently favorable side- 1746 Neuropsychopharmacology: The Fifth Generation of Progress effect profile, controlled trials with such agents are war- ing behavior (hand licking and hair stroking) and SIB in- ranted. Increased plasma enkephalin levels in patients with devel- Prader-Willi syndrome (PWS) is a congenital disorder opmental disability compared with normal controls have that affects approximately 1 in 10,000 newborns and is one been reported (38). Although this may support the excessive of the five commonest abnormalities seen in birth defect opioid hypothesis, it is also possible that decreased endoge- clinics (53a,53b). PWS is associated with marked hyper- nous brain opioid levels ultimately lead to compensatory phagia, and the disorder is the most common dysmorphic overproduction (39). It has also been argued, however, that form of obesity. In addition, PWS is characterized by behav- opioid effects on self-injury may be primarily mediated via ioral disturbances, mental retardation, sleep disturbances, the dopamine or serotonin system (28).
One example of this is in the development results suggest that a 20-mg dose may be administered once of drugs for cocaine abuse buy vytorin 30mg on line. Unlike neuroleptics and antide- daily vytorin 20 mg free shipping, whereas a 10-mg dose requires administration twice pressants purchase vytorin 30mg, drugs developed to inhibit the action of cocaine a day generic 20mg vytorin overnight delivery. Thus, occupancy studies constitute surrogate markers have failed clinical trials. Although cocaine has been shown for the outcome variable and frequency of drug administra- to affect multiple neurotransmitter systems, current research tion. Another use of occupancy studies is the correlation of efforts to develop effective treatment for cocaine depen- D R occupancy with plasma levels of neuroleptics. Cocaine is hypothe- 2 approach has been successfully applied to estimate D R oc- sized to produce euphoria by increasing the intrasynaptic 2 cupancy by haloperidol in patients with low doses of halo- concentration of dopamine. These preliminary results can be refined in the dopamine transporter (DAT); therefore, contemporary future research with larger sample sizes. One example of po- These imaging methods also have a role to determine in tential treatments for cocaine dependence is the develop- vivo occupancy of new neuroleptics with multiple sites for ment of GBR12909 (GBR), a potent DAT inhibitor. The studies probably have their pharmaceutical, originally developed in Europe as an anti- greatest role in giving approximate dosage estimates for fu- depressant, has found a potential new application as a proto- ture clinical trials. Prior studies have shown that IV infusion of GBR to Rhesus monkeys selectively reduced (1 mg/kg) and eliminated (3 mg/kg) cocaine self- Other Roles for Neuroreceptor Imaging administration (119). Villemagne and colleagues (120) in Drug Development tested the hypothesis that doses of GBR, which reduce self- Four major areas in which neuroreceptor imaging can assist administration, also produce significant occupation of in drug development are listed in Table 34. Doses of 1, 3, and 10 mg/kg demonstrated occupancy of 26%, 53%, and 72%, respectively, in Papio anubis ba- boons (Figs. These data suggest that doses that suppress cocaine administration also provide high occu- pancy of the DAT. COMPONENTS OF THE DRUG DEVELOPMENT PROCESS ACCOMPLISHED BY esis that elevations of mesolimbic DA mediate the addictive NEURORECEPTOR IMAGING and reinforcing effects of methamphetamine and amphet- amine. In vivo rodent microdialysis has demonstrated that Rational drug dosing GBR attenuates cocaine and amphetamine induced in- Biodistribution of drug bound to radiolabels 11C and 18F for PET creases in mesolimbic DA. Utilizing PET scans of a continu- 123 99m 11 I and Tc for SPECT ous infusion of [ C]raclopride in baboons, Villemagne and Therapeutic rationale for drug utilization colleagues (120a) also showed that GBR attenuates amphet- Mechanism of drug action amine induced striatal DA release by 74% (Figs. Thus, GBR is a potentially effective agent to treat computed tomography. This experi- 466 Neuropsychopharmacology: The Fifth Generation of Progress 1 mg/kg Saline 3 mg/kg GBR 12909 1 mg/kg 10 mg/kg FIGURE 34. These images illustrate the binding of [11C]raclo- FIGURE 34. Reductions in dopamine transporter occupancy pride to the basal ganglia of Papio anubis baboons treated with are shown in transaxial [11C]WIN35,428 images in Papio anubis saline (top row) and GBR (1 mg/kg) (bottom row) after the admin- baboons before (left) and after (right) administration of three istration of saline (3 mL/kg) (PRE AMP) (left column) or amphet- different doses of GBR. Each dose is given 90 minutes before amine (1 mg/kg) (POST AMP) (right column). The illustrations represent average PET tion of saline (3 mg/kg) (top row) there is prominent binding of [11C]raclopride to the basal ganglia at baseline (PRE AMP) (upper images at midstriatal level between 70 and 90 minutes after the injection of the radiotracer normalized to the injected radioactiv- left) and significant reduction after the administration of am- ity. Modified from Villemagne V, Rothman RB, Yokoi F, et al. After the admin- Doses of GBR12909 that suppress cocaine self-administration in istration of GBR (1 mg/kg) (bottom row) there is reduced binding of [11C]raclopride to the basal ganglia at baseline (PRE AMP) non-human primates substantially occupy dopamine transporters as measured by [11C]WIN35, 428 PET scans. Synapse 1999;32: (lower left) and minimal reduction after the administration of 44–50. Villemagne VL, Wong DF, Yokoi F, Stephane M, Rice KC, Matecka D, Clough DJ, Dannals RF, Rothman RB. GBR12909 attenuates am- phetamine-induced striatal dopamine release as measured by continuous infusion PET scans. The fourth method in which neuroreceptor imaging can assist in drug development is the empirical evaluation of theories of disease, such as the DA hypothesis for schizo- phrenia. For example, Grace (1991) (121) proposed that schizophrenia is characterized by intrasynaptic concentra- tions of DA that are abnormally low in the basal tonic state and abnormally high in the simulated phasic state. This has been supported by numerous findings of elevated dopa GBR 12909 (mg/kg) 18 decarboxylase measurements using [ F]fluorodopa (122), FIGURE 34. This histogram illustrates the percentage dopa- elevated amphetamine induced dopamine release mine transporter (DAT) occupancy by GBR 12909 (GBR) as mea- suredby positronemissiontomographyimaging with[11C]WIN35, (123–125), and elevated D2Rs (97,126). DAT occupancy is represented as the percentage mean potential evidence that elevated intrasynaptic dopamine re- standard error of the mean differences between binding poten- lease is also found at baseline (126–128). In this example tials at baseline and after GBR administration. Percentage occu- pancy is calculated by the formula as follows: [(Baseline binding of the DA system, the combined strength of measuring pre- potential GBR binding potential)/Baseline binding potential] synaptic, postsynaptic, and intrasynaptic DA, for example, 100. Inset: Relation between DAT occupancy and GBR dose provides converging evidence to test this hypothesis. Modified from Villemagne V, Rothman RB, Yokoi F, Rice KC, Matecka D, Dannals RF, Wong DF. Doses of GBR12909 that opment of additional ligands such as those for glutamate, suppress cocaine self-administration in nonhuman primates sub- glycine, and second messengers, will further expand the po- stantially occupy dopamine transporters as measured by [11C]WIN35, 428 PET scans. Copyright tential to evaluate the complex pathophysiology of schizo- 1999, Wiley-Liss, Inc. Chapter 34: Proof of Concept 467 half-lives (131), although the sensitivity allows only micro- molar measures in contrast to the nanomolar measures at- tained with PET. These methods have also been employed in animal models using [19F]nuclear magnetic resonance (NMR) chemical shift imaging to study the cerebral distri- bution of general anesthetics in vivo (132). MAGNETIC RESONANCE IMAGING Magnetic resonance imaging (MRI) provides surrogate markers for disease progression to facilitate drug develop- A ment. For example, T2-weighted cerebral MRI functions as a surrogate marker in early stages of demyelinating disease to predict disease progression and disability over the subse- quent 10 years (132a–132e). Another example of the use of MRI as a surrogate marker for drug development is in the diagnosis and treatment of subjects with AD. Atrophy of the hippocampal formation has been correlated with memory and cognitive impair- ments. Reductions in the volume of the hippocampus have been predictive for the individuals who later develop mem- ory impairments consistent with AD (133). Another marker of the vulnerability to develop AD is the measure of the B apolipoprotein E (APOE) genotype. These histograms contrast the release of DA after AD is increased for people with the gene (134). The APOE administration of amphetamine (AMP) in Papio anubis baboons gene is associated with loss of hippocampal volume (135). For each histo- Cross-sectional studies in 116 healthy volunteers, 59 to 85 gram, the abscissa indicates the intravenous administration of saline (3 mL/kg) (PRE AMP) or amphetamine (1 mg/kg) (POST years old, demonstrated significantly larger ventricular vol- AMP) and the ordinate is the average volume of distribution (Vh) umes and smaller gray and white matter volumes in older and the standard error of the mean. The left histogram illustrates compared to younger individuals and in men compared to a significant reduction in Vh consistent with the release of DA induced by amphetamine. The right histogram demonstrates a women over a period of only 1 year. An increase of over 1,500 mm3 in ventricular volume was demonstrated during reduced baseline (PRE AMP) Vh after administration of GBR con- sistent with an increase in baseline extracellular intrasynaptic DA this time but no detectable change in the total or regional concentration (PRE AMP) and the absence of a significant change in V after the administration of amphetamine (POST AMP). This suggests that determination of the pat- h ified from Villemagne VL, Wong DF, Yokoi F, Stephane M, Rice tern and rate of these changes longitudinally could be a KC, Matecka D, Clough DJ, Dannals RF, Rothman RB. GBR12909 future predictor of cognitive declines and dementia (136). Syn- Functional MRI (fMRI), a technique in which subjects apse1999;33:268–273. For example, the rCBF of cocaine- dependent subjects administered intravenous cocaine exhib- ited increases in the nucleus accumbens, subcallosal cortex, MAGNETIC RESONANCE SPECTROSCOPY and hippocampus and decreases in rCBF in the amygdala, temporal pole, and medial frontal cortex (137). Future stud- Magnetic resonance spectroscopy (MRS) provides surrogate ies utilizing this paradigm could additionally assess whether markers to determine clinical endpoints to evaluate new another compound administered before cocaine can antago- therapeutic interventions for specific diseases. Additionally, [19F]MRS has been explicitly employed to examine the pharmacokinetics of BIOMARKERS OF ALCOHOL ABUSE psychotropic medications containing a fluorine group such as fluvoxamine (130). This allows direct comparison of The synergistic combination of carbohydrate-deficient brain and plasma concentrations, and brain elimination transferrin (CDT), gamma-glutamyl transferase (GGT), 468 Neuropsychopharmacology: The Fifth Generation of Progress and mean red cell volume (MCV) functions as a possible the CNS could be administered as therapeutic agents to biomarker for alcohol abuse (138). CSF from treated patients and bioluminescent compounds responsive to the presence of the enzyme that should be NEWER MARKERS FOR DRUG absent could then be injected into experimental animals. DEVELOPMENT Detection of the bioluminescence in the experimental ani- mal would then indicate failure of the new drug to prevent Several techniques recently have been developed to provide the growth of the tumor or infection. Thus, this technique the means to assess the efficacy of newly developed potential offers the potential of surrogate markers to monitor the drugs.