By I. Hernando. Rockhurst University.

Moreover cheap finax 1mg overnight delivery, application of cholinergic ago- because these responses are absent in M2 knockout mice nists to the basal forebrain produces behavioral activation (15) finax 1 mg sale. M4 receptors are also involved in locomotion; these and EEG desynchrony (33). Although the brainstem cholin- knockout animals exhibit increased basal locomotor activity ergic projections to the thalamus undoubtedly also contrib- and a potentiated locomotor response to D1-selective dopa- ute to EEG regulation (36), these findings suggest that cho- minergic agonists (16). In behavioral experiments, the 2 projections largely formed connections with noncholinergic nicotinic subunit mediates the ability of nicotine to improve neurons within the basal forebrain (37). This finding is avoidance learning and may also be involved in the circuitry critical because it could explain why stimulation of the hori- underlying this form of associative learning in wild-type zontal diagonal band, preoptic area, and substantia innomi- mice (11). In addition, this subunit appears to be necessary nata, but not of the septal nucleus and nucleus basalis, pro- for the mouse to experience the reinforcing properties of duces sleep in the cat (33). The ratio of cholinergic to nicotine because animals without the 2 subunit will not noncholinergic neurons in the horizontal diagonal band, self-administer nicotine (31). Extensions of these experi- preoptic area, and substantia innominata is significantly ments to mice lacking other subunits of the nicotinic recep- lower than in the septum and nucleus basalis. This observa- tor should allow identification of the receptor subtypes that tion has led to the hypothesis that activation of primarily are activated by smoking in humans and result in tobacco noncholinergic neurons is responsible for producing sleep addiction. An interesting effect of ACh on neuronal survival after basal forebrain stimulation (33). These noncholinergic was demonstrated in mice lacking the 2 nAChR subunit neurons are believed to be GABAergic and achieve their (32). Mice that lack this cholinergic-receptor subtype show effects through inhibition of cholinergic basal forebrain progressive neuronal loss with age in cortical and hippocam- neurons and neurons within the brainstem reticular forma- pal brain areas, which appears to lead to age-related impair- tion. In contrast, stimulation of the nucleus basalis or septal ments in spatial learning. These experiments demonstrate nucleus produces behavioral activation and cortical ACh that the effects of ACh on cognition, antinociception, loco- release, and this is consistent with the notion that basal motion, and overall neuronal activity are differentially me- forebrain cholinergic neurons are involved in behavioral diated through the various subtypes of muscarinic and nico- arousal (activation), whereas noncholinergic basal forebrain tinic receptors, and that the various roles of ACh may be neurons are involved in regulating the sleep state. These separated pharmacologically, suggesting new targets for ra- two effects are related (sleep vs. ROLE FOR CHOLINERGIC NEURONS IN AROUSAL AND SLEEP ROLE FOR CHOLINERGIC NEURONS IN MOTIVATION AND REWARD Traditionally, the basal forebrain complex, the primary source of cholinergic innervation to the telencephalon (Fig. Cholinergic neurons have also been implicated in motiva- 1. Either lesions or electric stimulation of subregions of that nAChRs are involved in motivation and reward is that the basal forebrain can facilitate sleep and synchronize the nicotine is abused by humans and is reinforcing in animals EEG, and cholinergic drugs regulate EEG synchrony (33). The effects of nicotine on tests Moreover, a correlation between cortical ACh release and of reinforcement and behavioral sensitization are primarily the state of behavioral activation or sleep has been observed mediated through the mesolimbic dopamine system (39). Thus, it was hypothesized that cholinergic input Indeed, the ventral tegmental area (VTA) may be sufficient to the neocortex from the basal forebrain is critical for regu- to mediate the reinforcing properties of nicotine, as local lating arousal (see ref. These neurons largely do not inner- preference (41). Chapter 1: Acetylcholine 7 Basal forebrain cholinergic neurons may also be involved lesions increased sucrose consumption, similar lesions did in modulating cortical processing of stimuli with condi- not affect discrimination or contrast effects (57). Neverthe- tioned or unconditioned rewarding properties because these less, the hypothesis of Winn (58) is that lesions of the PPT neurons are more responsive to stimuli with a high incentive affect responding for rewarding stimuli similarly to lesions value. Novel stimuli that typically elicit orienting responses of the frontal cortex, so that the role of the PPT, like that of and attention in animals increase cortical ACh release, but the basal forebrain, is expanded into higher-order cognitive this effect is diminished with repeated exposure if the stimu- processes. In contrast, if the stimulus is repeatedly paired with an incentive stimulus (e. Pontomesencephalic cholinergic neurons are also The hypothesis of cholinergic involvement in learning and involved in motivation and reward, although these effects memory processes arose from several findings. Both destruc- are likely mediated, in part, by projections to the dopamine tion of the basal forebrain complex and the administration neurons within the VTA (44,45). While a significant proportion of the The original finding that lesions of the basal forebrain PPT neurons that project to the tegmental dopamine neu- could produce deficits in a variety of cognitive tasks sug- rons are noncholinergic (44), the cholinergic input per se gested a role for ACh in cognitive function. Electrolytic, appears to stimulate dopamine neurons (47). Thus, ascend- radiofrequency, or nonspecific excitotoxic lesions of cholin- ing projections from the PPT to the dopamine cells may ergic subnuclei within the basal forebrain (particularly the regulate the ability of mesostriatal dopamine neurons to medial septum/diagonal band) profoundly impair perfor- affect incentive/motivational processes. These deficits appeared modulate the rewarding qualities of addictive drugs. Lesions to be reversed following regeneration of cholinergic projec- of the PPT reduce the self-administration of nicotine (48) tions across a bridging graft (61) or after grafting of ACh- and opiates (49). Moreover, conditioned place preference producing cells in the hippocampus (62). These findings for food, opiates (50), morphine (51), and amphetamine have been interpreted as support for the hypothesis of cho- (52) is blocked or reduced by PPT lesions, whereas cocaine- linergic involvement in cognitive functions; however (as induced reward is unaffected (53).

GABA levels are also found of 1 order finax 1mg free shipping,998 mg/day buy finax 1mg without a prescription, with two 333-mg tablets given three times to be reduced in the brain and CSF of recently detoxified per day (six tablets per day). Moreover, drugs that modulate GABA receptor behavioral interventions was not specified and typically was A function such as benzodiazepines, barbiturates, and anticon­ that used by a particular site. The primary outcome mea­ vulsants have been shown to suppress the symptoms of sures included retention in treatment and measures of absti­ ethanol withdrawal. Given the above evidence, there has nence, such as rate of abstinence preceding study visits, con­ been increased interest in examining the effects of agents tinuous abstinence (i. Information Acamprosate (calcium acetyl-homotaurine), a homotau­ about the actual quantity of alcohol consumed on a nonab­ rine derivative is a structural analogue of GABA and an stinent day was rarely reported. It displays high binding capac­ Summarizing across the studies in Table 101. Studies cebo on measures of total abstinence, time to first drink, suggest it also inhibits NMDA receptors and reduces gluta­ and/or cumulative abstinence duration (71–74,77–81). For mate concentrations, particularly in the nucleus accumbens example, in an early 12-week trial, Lhuintre et al. A number of preclinical studies have shown that that abstinence rates for patients treated with acamprosate acamprosate produces dose-dependent decreases in alcohol were nearly double (61%) that of patients treated with pla­ consumption, with complete suppression of drinking seen cebo (32%). It has also been shown that acampro­ of acamprosate on measures of abstinence were dose depen­ sate diminishes reinstatement of alcohol drinking in the dent. Specifically, point prevalence measures of abstinence alcohol-dependent rat. Similar dose effects were found on retention in treatment. Pharmacodynamics, Pharmacokinetics, and In a study of 272 severely dependent alcoholics who had Safety been abstinent 14 to 28 days prior to acamprosate treat­ ment, 43% of the acamprosate-treated patients were contin­ Acamprosate has low bioavailability (10%), is not metabo­ uously abstinent compared to 21% of those who received lized by the liver, and is primarily excreted through the placebo over the course of 48 weeks (75). Although overall kidney, with an excretion half-life of 18 hours (69,70). The most com­ dependent alcoholics with only 5 days of abstinence pre- mon adverse effect distinguishing acamprosate from placebo treatment (76), differences in abstinence rates were found is diarrhea; other reported side effects that may be associated favoring acamprosate over placebo during the 360-day treat­ with acamprosate are rash and changes in libido. The advantage of acamprosate over placebo action studies indicate that acamprosate does not interact continued once acamprosate was discontinued after 6 and with a variety of medications prescribed to individuals with 12 months of active treatment. Although the duration of treatment has varied across studies (e. Given Acamprosate is approved for use as a treatment for alcohol that differences between acamprosate and placebo appear dependence in most European countries and in many Latin to emerge after 2 to 3 months of treatment and generally American countries as well as in Australia, South Africa, persist after treatment is discontinued, studies addressing and Hong Kong. The efficacy of acamprosate has been eval­ the potential value of short- versus long-term treatment are uated in over ten published placebo-controlled trials ranging warranted to guide clinical practice. DOUBLE-BLIND, PLACEBO-CONTROLLED TRIALS OF ACAMPROSATE FOR THE TREATMENT OF ALCOHOL DEPENDENCE Results No. Minus sign means a significant difference in favor of the placebo group. A plus/minus sign is a trend in favor of the medication group or a significant difference in a subsample. A 21-site, 6-month, double-blind, placebo- drawal and withdrawal-related craving (83–85), ratings on controlled trial has recently been conducted to determine analogue scales of craving have not distinguished acampro­ safety and efficacy of acamprosate in 601U. This study tested the efficacy of a In addition, the potential effect of acamprosate on alcohol 2-g daily dose against placebo and includes an exploratory reward and drinking following a lapse in abstinence is not 3-g dose, given the absence of rate-limiting side effects. In understood at this time, because the majority of studies contrast to European studies in which patients were ran­ collected information on abstinence only, and there are no domized into study treatments following inpatient detoxifi­ laboratory studies examining the interactions of acampro­ cation, the U. The results of this study are not may provide additional information because daily reports published as of this time. Serotoninergic Medications Summary Background The evidence suggests that acamprosate can have a positive effect on measures of abstinence from alcohol following in- The use of medications that affect the serotonin (5-HT) patient detoxification. These effects appear to be dose de- system was initially anticipated by clinical observations re­ pendent, favoring the higher doses of acamprosate that have garding similarities between alcoholism and mood, anxiety, been tested. Although it is hypothesized that the efficacy of impulse control, and antisocial personality disorders. Given Chapter 101: Alcoholism Pharmacotherapy 1451 the presumed relationship between these various disorders (SSRIs) available today: fluoxetine (Prozac), fluvoxamine and a dysfunction in the serotonin system, this clinical ob­ (Luvox), paroxetine (Paxil), sertraline (Zoloft), and citalo­ servation led to speculation that alcohol dependence was pram (Celexa). SSRIs have in common the ability to block also related to some serotonin dysfunction. Several lines of the reuptake of serotonin, and this functionally enhances preclinical research in animals and social drinkers support serotoninergic activity. Fluoxetine is characterized by a long the notion that alcohol drinking compensates for some defi­ plasma half-life with a range of 1to 4 days and its active ciency in serotoninergic activity.

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For example order 1mg finax overnight delivery, the answer to buy discount finax 1 mg on line, “What is your date of birth” rarely reveals thought disorder. When FTD is suspected, the examiner may ask open ended questions which require the patient to structure answers and stay on track. Thought processes can be tested by purposefully asking abstract questions. Such questions do not have standard, structured answers and there is a greater chance of loss of logical connections. Religious or philosophical questions are useful, and should be tailored to suit the patient. If a patient has talked about having faith, it is reasonable to ask, “Why do you believe in God? It is important, of course, to give consideration to the intelligence, education and cultural background of people when assessing their response to abstract questions. An example of an “abstract” question is given by Solovay et al (1986): Interviewer, “Why should we pay taxes? Thus, the mention of treason suggests the patient may have delusional content. While dramatic or humorous FTD may be remembered for a few minutes, the more common and less remarkable examples, which carry the same diagnostic power, are very difficult to remember (probably because we store memories in logical sequences). It is recommended the interviewer writes down verbatim examples as the patient speaks, either directly into the file, or on other paper, from which they can be copied into the file later. Classification of FTD The following definitions are taken from authoritative texts, and are widely accepted. At the end of the chapter an idiosyncratic attempt is made to simplify. Derailment Derailment occurs when a train jumps off the track. Andreasen (1979) defines derailment as “A pattern of...... Here he is complaining that his hospital notes state he did not “stick to the answer”. He states that he knows that he digresses when speaking, and that this is “a normal bad habit of mine”. He then (next sentence, same paragraph) slips onto the topic of his weight, and that it has “always been about 11 stone”. Thus, he is explaining that he has always had the habit of digressing, and immediately slips onto the track of what his weight has always been. This patient is complaining about rules which prohibit smoking on a psychiatric ward. He is about to say that this is unfair, and against the Australian law or constitution. However, he slips from these official rights based institutions onto, “the Australian national anthem”. Yes, this may simply be a slip of the tongue (pen), and nothing should be made of a single slip, but notice that the letter is addressed to Tony (Weare, Chief Nurse), but continues, “To whom it may concern…”. The term derailment was introduced to replace the earlier term, “loosening of associations” (which had been introduced by Eugene Bleuler in 1911 - who believed that looseness of associations represented the fundamental disturbance in schizophrenia). It was said that this term had been used indiscriminately, lost meaning, and needed to be replaced. Either term can be used, but derailment is now more common. However, it is a basic type and at least some of the other types can be considered as elaborations of derailment. Tangentiality (which once meant something else) was redefined by Andreasen (1979) to apply only to answers and not events occurring in spontaneous speech. The term is applied when a question is asked and the patient gives an answer which is “off the track”. An example of tangentiality: Interviewer, “How old are you? After all, in this era of anti- discrimination, people are encouraged to assert that they are “35 (or any number) years young” rather than “35 years old”. However, this answer came early in an interview, at the time when the demographic data of the patient was being collected. That is, in a part of the interview where there is structure and the conventional response is to provide factual rather than philosophical responses. In this setting, such a response suggests (but does not prove) FTD. A touch of rebellion – the current writer recommends that, to simplify matters, the academic distinction between derailment and tangentiality be ignored, and the term derailment be used for both.

Recently x-ray diffraction has 22: G-Protein–Coupled Receptors 281 been used to solve the structure of three dimensional crystals chemical probe buy 1 mg finax with amex. Approaches of this type have been applied of rhodopsin to a resolution of 2 order finax 1mg with amex. This accomplishment˚ to several GPCRs, and have begun to yield interesting new is truly a major milestone in the field, revealing for the information about the dynamic effects of clinically relevant first time the atomic structure of any GPCR and providing drugs on GPCR structure (29). A precedent for such an approach is the membrane structure are relevant to other GPCRs. It remains to be determined cation of existing drugs. However, an important goal is to the degree to which specific features of diverse GPCRs are design completely new drugs de novo based on the struc- actually conserved at the level of atomic resolution. A clue that this may be based on well established differences in the pharmacology of possible comes from recent studies of mutant GPCRs, in individual GPCRs, one might expect there to be significant which histidine residues have been introduced at defined limitations of such homology-based predictive methods, at positions in the receptor structure that can be coordinated least with respect to structural features involved in drug by certain metal ions. Nevertheless, the available experimental data leave receptor, by coordinating histidine residues introduced little doubt that this approach is an important starting point within specific transmembrane helices, influences the recep- for mechanistic studies and for rational drug development tor conformation to either activate or inactivate the receptor (34). While it is unlikely that this strategy will directly yield clinically Biophysical Studies of Conformational useful drugs, these exciting studies serve as a proof of the Dynamics Involved in GPCR Activation principle motivating further studies of GPCR structure and While crystallographic methods have the potential to pro- conformational change. Thus REGULATION OF RECEPTOR SIGNALING additional methods are required to examine dynamic con- Methods to Examine Regulation of formational transitions that mediate ligand-dependent sig- Receptors byPosttranslational nal transduction via GPCRs. Several biophysical approaches Modification: GPCR Phosphorylation have been utilized for this purpose. Classic studies of rho- dopsin measured the optical absorbance properties of this Many different types of posttranslational modification have photoprotein that are highly sensitive to changes in protein been implicated in the regulation in of GPCR function, conformation. Sophisticated studies using optical spectros- localization or stability. A detailed discussion of this large copy indicate that rhodopsin cycles rapidly through a series area of research is beyond the scope of this chapter. Instead, of distinct conformational states following photon-induced we illustrate the use of specific methods by discussing some activation. Many other types of biophysical techniques have aspects of protein phosphorylation, the most extensively been applied to examine specific features of light-induced characterized type of posttranslational modification that conformational changes of rhodopsin, as well as to examine regulates GPCRs. Specific residues in the receptor protein can be labeled 1950s demonstrated that enzyme-catalyzed protein phos- with a chemical probe, typically using a combination of phorylation and dephosphorylation reactions were involved site-directed mutagenesis and organic chemistry techniques. Phosphorylation of mammalian proteins in relative size and charge. Proteins resolved by gel electrophoresis can be transferred Serine/threonine phosphorylation is widely recognized to to a membrane composed of nitrocellulose or polyvinyl di- regulate GPCRs. Tyrosine phosphorylation, a more recently fluoride (PVDF). This allows many manipulations to be discovered modification that is well established to mediate performed, such as detection of a specific protein from a signaling via non-GPCR growth factor receptors (39), may complex mixture by the ability of the protein to be bound also play a role in regulating certain GPCRs (40). Other kinases, such as the GPCRs resolved by gel electrophoresis can also be ana- 3′,5′-cyclic adenosine monophosphate (cAMP)-dependent lyzed by chemical sequencing, typically by a process called protein kinase (PKA) and protein kinase C can also regulate Edman degradation, which sequentially cleaves residues GPCRs by phosphorylating distinct cytoplasmic serine/ from the amino-terminal end of the protein. A very powerful method for phorylated by other kinases, such as GRKs, are more diffi- determining amino acid sequence and detecting posttransla- cult to predict because they do not conform to a rigidly tional modifications of proteins is via mass spectrometric defined consensus sequence. For example, with tandem mass spectrometry it is enzymes with relatively well-understood substrate specificity possible to measure the mass of specific protein fragments in vitro, there are major limitations to the use of sequence with an accuracy of one part in 10,000 up to 12,000 daltons analysis for predicting phosphorylation sites in vivo. The impressive dues conforming to a specific consensus sequence are not accuracy of this method makes it possible to detect phos- always phosphorylated under physiologic conditions, and, phorylation as well as many other posttranslational modifi- conversely, in some cases residues that do not conform to cations, even those that cause subtle changes in the protein a well-defined consensus sequence can be phosphorylated size or charge. Thus it is important to determine the Chromatography, which refers to any separation based phosphorylation of GPCRs when expressed in the appropri- on differential behavior of a molecule between a stationary ate mammalian cells. High-performance liquid chroma- tography (HPLC) using reverse-phase (e. By compar- There are many ways of detecting phosphorylated proteins. Subsequently, these fragments can be isolated and fur- PAGE, proteins dissolved in SDS are loaded onto one end ther analyzed by methods such as Edman degradation or of a porous gel and exposed to an electric field, which causes mass spectrometry. By using Methods to Examine Regulation of appropriate radiolabeled compounds (such as inorganic Receptors byLocalization and Trafficking phosphate added to the culture medium), it is possible to apply the technique of autoradiography to specifically detect It has been appreciated for many years that a critical parame- radioactive, phosphorylated proteins resolved by SDS- ter that can regulate the strength of functional signal trans- PAGE. It is also possible to use gel electrophoresis to sepa- duction via GPCRs is the actual number of receptors present rate proteins according to relative charge, a property that in target tissues and, in particular, the number of receptors is modified predictably by certain modifications such as present in the plasma membrane of individual cells. These types of separation can be com- disturbances in the regulation of receptor number and/or bined in the use of two-dimensional gel electrophoresis, distribution may be of primary importance in the patho- 22: G-Protein–Coupled Receptors 283 physiology of certain neuropsychiatric disorders. For exam- which antibodies recognizing the native receptor are not ple, long-term administration of dopamine receptor antago- available. In either case the general scheme is as follows: nists can induce upregulation of specific receptors, which Cells or tissues expressing the receptor of interest are fixed may contribute to the apparent supersensitivity of dopamine using standard histologic methods. The fixed cells or tissue receptors associated with tardive dyskinesia (46). This phenomenon is termed bodies recognizing the receptor of interest. Studies using ra- tive epitopes in the specimen (typically several hours), the dioligand binding and subcellular fractionation techniques specimens are washed extensively to remove nonspecifically provided early evidence that multiple mechanisms are capa- associated antibodies.

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Activation of the amygdala in this study was initially 'the amygdala and septum order finax 1mg fast delivery, and orbitofrontal generic 1mg finax with mastercard, anterior in- documented by a region-of-interest (ROI) analysis and has sula, and anterior cingulate cortices, the ventral striatum in- recently been confirmed by statistical parametric mapping cluding the nucleus accumbens, and several brainstem motor (SPM) of the group data (Fig. The amygdala is critical in signal surrounding the ventral amygdala, in response to cocaine learning for biologically significant (pleasant or unpleasant) versus nature video. The PET camera used in the recent events (76,77) and has been activated by cue-induced crav- 18F-fluorodeoxyglucose study by Wang et al. Anterior Cingulate The anterior cingulate is located in the dorsomedial prefron- tal cortex and is interconnected with other rostral limbic structures, including the amygdala and nucleus accumbens. Multiple roles of the anterior cingulate include selective at- tention and emotional reactivity to significant stimuli (75, 87). In parallel with the amygdala findings, the anterior cingulate was differentially activated during video-induced cocaine craving in our initial PET study with 15O bolus (by ROI analysis and later confirmation by SPM analysis of the group data) (Fig. As with the amyg- dala effect, the cue-induced rCBF increase in anterior cingu- late was from a resting baseline that was hypoactive relative to the baseline of controls. These studies used fMRI (84,86) and PET with 15O bolus (82), FIGURE110. Amygdala andanterior cingulateactivations dur- imaging techniques that provide good temporal resolution. They both used PET with F-fluorodeoxyglucose; because of its low temporal resolution, this technique may be insensitive to a relatively brief or nonhomogeneous acti- vation of the anterior cingulate. Functional magnetic resonance imag- ing of cocaine versus nature video. Individual differ- encemapsshowamygdala andanteriorcingulateacti- vationinthreepilotcocaine patients. One interpretation that inte- ventral part of the striatum. It is a prominent terminal re- grates the earlier observations with those in the explicit cue gion for DA cells projecting from the ventral tegmental area, paradigms is that orbitofrontal cortex hyperactivity is associ- and much animal research points to this mesolim- ated with enhanced responsivity to cues, whether naturally bic–nucleus accumbens pathway as a critical substrate for occurring or presented by a laboratory experiment. Orbito- the reinforcing effects of natural rewards (88), cocaine, and frontal cortex hypoactivity, on the other hand, clearly does other drugs of abuse (89). In humans, the size of the nucleus not prevent cue-induced craving and may represent a differ- accumbens is about 5 mm. Thus, the nucleus accumbens ent vulnerability (see summary below). The The insular cortex is located interior to the lateral sulcus. Subjects given a (double-blinded) infusion of saline orbitofrontal cortex; it also reflects input from the viscera solution in the fMRI magnet showed clear activation of (autonomic nervous system) and sensory systems. Three lab- the nucleus accumbens if they had previously received an oratories have reported activation of the insula in response infusion of cocaine in this novel environment. The nucleus to cocaine-related cues, but the effects vary. This striking finding suggests that a (64) reported activation of the right insula in response to druglike response to cocaine cues can be established with a the cocaine infusion environment; no correlation with crav- single trial. Given the disparate findings, additional was an unpredicted decrease in rCBF, but the larger dorsal studies will be needed to sort out the nature and direction striatum (which receives primary projections from the sub- of cue effects in the insula. It was not differentially activated but did not report on nucleus accumbens. Orbitofrontal Cortex This is in contrast to the common finding of amygdala The orbitofrontal cortex is located in the ventromedial re- activation across several cue studies. The orbitofrontal cortex is richly the hippocampus and interconnected to it, the amygdala is interconnected with DA-related regions involved in reward not activated by explicit memory demands; rather, it sup- and stimulus–reward learning (90). Three studies (64,83, ports functions of implicit, emotional memory (92). The remaining two studies, in Other Structures which fMRI was used, did not report on the orbitofrontal cortex response (84,86) (ventral orbital regions are often Dorsolateral Prefrontal Cortex difficult to image with fMRI because of artifact introduced The dorsolateral prefrontal cortex, best known for its role by air in the sinus cavities). In the three studies finding an in working memory, was not differentially activated by the orbitofrontal cortex response to cues, the subjects were in uninterrupted, narrative cocaine videos in our PET study early cessation (ranging from 18 hours to 7 days); in the (47), although craving was robust. Similarly, it was not acti- two studies finding no orbitofrontal cortex activation to vated by the paradigm of Kilts et al. These alternating conditions may preliminary conclusions about the substrates of the state have engaged working memory in the cocaine subjects be- and, importantly, for generating new hypotheses that will cause the same cocaine users reappeared in an ongoing drug help to refine the emerging picture. Despite the variability scenario that was interrupted by the nondrug video seg- in imaging techniques, analysis techniques, the abstinence/ ments. Controls are generally less engaged by cocaine stim- treatment status of the subjects, and the varied methods uli and therefore would also be expected to show less engage- used to induce cocaine desire, several convergent findings ment of working memory. A similar explanation may for regions of activation have been obtained. The most com- account for activation of the dorsolateral prefrontal cortex monly activated regions during cocaine cues, across the lab- in the paradigm of Grant et al.

AFFINITY OF ANTIPSYCHOTIC DRUGS FOR HUMAN NEUROTRANSMITTER RECEPTORS (Ki generic 1mg finax overnight delivery, nM)a Receptor Clozapine Risperidone Olanzapine Quetiapine Ziprasidone Aripiprazole Iloperidone Haloperidol D 290 580 52 1 generic 1mg finax with visa,300 130 410c 320 120 1 D 130 2. Mechanisms of typical and atypical antipsychotic drug action in relation to dopamine and NMDA receptor hypofunction hypotheses of schizophrenia. Interactions of the novel antipsychotic aripiprazole (OPC-14597) with dopamine and serotonin receptor subtypes. Iloperidone binding to human and rat dopamine and 5-HT receptors. However, as well as H1 and 1-adrenergic receptors (55) (Table 56. Aripiprazole is distinct from the other atypical useful for treating cognitive deficits of the disease (50). Olanzapine is more potent at 5-HT2A than D2 drugs (56,57). Clozapine, however, does not exhibit high receptors (Table 56. The low occupancy of striatal D2 receptors by but there are also some notable distinctions between the clozapine could account for its low EPS liability (20,58, two drugs. For example, clozapine has substantially higher 59). Although 5-HT2A receptor an- for 5-HT2A than for D2 receptors, but also some affinity tagonism is likely to be associated with the low EPS liability for 1-adrenergic and H1 receptors (53) (Table 56. Inter- of risperidone and olanzapine, the role of this molecular estingly, quetiapine produces only transiently high striatal action in the superior therapeutic responses to clozapine is D2 occupancy in schizophrenic patients, although the study unclear (13). Ziprasidone has potent 5-HT2A and D2 affinities, and like clozapine, it Efficacy shows 5-HT1A agonist properties that could potentially act as protective effects on the development of EPS. Ziprasi- Although the proportion of patients who improve and the done also has significant affinity for 5-HT1D and 5-HT2C, magnitude of therapeutic effects vary greatly, atypical anti- Chapter 56: Therapeutics of Schizophrenia 779 psychotics are at least as effective for psychotic symptoms and clozapine in treatment-resistant patients. Well-controlled double-blind was found to be more effective than haloperidol (74,76), studies of atypical antipsychotics suggest that clozapine, but not chlorpromazine (77), in treatment-refractory pa- risperidone, and olanzapine may be superior to haloperidol tients. In a recent randomized double-blind study of treat- for controlling psychotic symptoms (61). At selected doses, ment-resistant schizophrenia, olanzapine and clozapine had risperidone appears to be more effective than haloperidol similar antipsychotic efficacy (74). Additional studies are in treating positive and negative symptoms (53). Olanza- needed to reach definitive conclusions regarding efficacy pine has been demonstrated to be effective for positive, neg- of the newer atypical antipsychotics in treatment-resistant ative, and depressive symptoms (62), and in some studies schizophrenia. Results of studies investigating the effects the drug was superior to haloperidol and risperidone in of atypical antipsychotics in treatment-resistant patients are terms of negative symptoms and long-term efficacy (63,64). However, in a recent large double-blind study (that has The efficacy of atypical antipsychotics in treating primary only been preliminarily reported), risperidone demonstrated negative symptoms has not been clearly demonstrated (61). Quetiapine inantly negative symptoms is less clear (8). In addition, the appears to be comparable to chlorpromazine and haloperi- effects of atypical antipsychotics on cognitive impairment dol in treating both positive and secondary negative symp- have not yet been clearly proved. Similarly, ziprasidone appears to be as effective ies (only three of which were double-blind) of atypical anti- as haloperidol in alleviating positive and negative signs in psychotics and cognitive impairment in patients with schiz- an acute treatment study (66), whereas a 52-week placebo- ophrenia suggests that they may improve attention and controlled maintenance study found primary and secondary executive function (37). Available results, however, are rela- negative symptom efficacy for ziprasidone (67). Furthermore, To date, clozapine is the only drug that has proven effi- there are statistical limitations and a lack of standard con- cacy in treatment-refractory schizophrenia (68,69). It appears that ficacy rates for clozapine in treatment-refractory patients there could be significant differences among the atypical vary from 20% to more than 70% (11,70,71). In some drugs in terms of what types of cognition they improve. Clozapine, risperidone, and olanzapine, in particular, resistant patients. In this latter study, certain methodologic appear to have beneficial effects on the depressive compo- issues may have led to an overestimation of the efficacy of nent of schizophrenia (6,65) (Table 56. Further investigation is necessary they are not effective in all patients and against all symptom to adequately compare the relative efficacy of risperidone dimensions of psychotic disorders (Table 56. CLINICAL AND SIDE-EFFECT PROFILE OF ATYPICAL ANTIPSYCHOTIC DRUGS Clozapine Risperidone Olanzapine Quetiapine Ziprasidone Clinical effect Psychotic symptoms +++ +++? Side effect EPS — ++a +a — +a TD — Prolactin elevation — +++ — — — aDose dependent. EPS, extrapyramidal side effects; TD, tardive dyskinesia; + to +++, weakly (for clinical effect) or active (for side effect) to strongly active; – to —, weak to little activity;? National Institute of Mental Health, Division of Services and Intervention Research Workshop, July 14, 1998. Thus, the possi- zapine-related TD is low (1%) (87).

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Abnormalities in psychiatric disorders likely represent the However buy discount finax 1mg, such equilibrium binding conditions are achieved complex interaction of several neurotransmitter systems in for neither the tracer nor the displacer if each is injected the brain order finax 1mg on line. PET imaging has recently been used to examine as a bolus. Even under these conditions, the sensitivity of aspects of neurotransmitter interactions. For example, Dewy radioligand binding to endogenous dopamine levels is theo- and colleagues (44–46) have pioneered studies on interac- retically (at least based on the in vitro theories) independent tions among dopamine, GABA, and acetylcholine (ACh) of the affinity of the radioactively labeled ligand when both systems in striatum. GABA neurons in the striatum have the tracer and the displacer have achieved equilibrium bind- inhibitory effects on nigral dopamine neurons, nigral dopa- ing conditions. However, if either the radiotracer (as in the mine neurons have inhibitory effects on striatal ACh neu- bolus injection paradigm) or endogenous dopamine (as in rons, and striatal ACh neurons have facilitating effects on stimulant-induced release) changes dynamically over time, striatal GABA neurons. By estimating dopamine levels in the equilibrium condition is not achieved, and the apparent striatum as described above, Dewey and collaborators sensitivity of the radioligand to endogenous dopamine levels showed in human or anesthetized nonhuman primates that is determined by the kinetic properties of the radioligand the blockade of cholinergic transmission by benztropine 11 (34,35). Equilibrium conditions can be achieved for both (44) or scopolamine (45) decreased [ C]raclopride binding tracer and displacer in the dopamine depletion paradigm. The high-af- pine agonist) increased [ C]raclopride binding (decrease 123 finity D2 radioligand [ I]epidepride provides an instruc- in dopamine levels) (46). In addition, they showed that tive example of the differences seen in kinetic and equilib- a dopamine antagonist, N-methylspiroperidol, induced a rium studies. The kinetics of its uptake in brain are slow decrease in [N-11C-methyl]benztropine binding, indicating and do not show displacement by transiently increased do- an increase in ACh levels (44). However, Other interactions have also been studied with PET. In stable low levels of dopamine induced with AMPT show two human studies, an N-methyl-D-aspartate (NMDA) an- unmasking of D2 receptors (37). In two human studies with similar tech- niques, the binding of [11C]raclopride was decreased by In Vivo Confounding Factors stimulation of 5-hydroxytryptamine (5-HT) transmission Although the displacement of radioligand binding by neu- with fenfluramine (a 5-HT releaser) (49) or psilocybin (a rotransmitter can be simply described with in vitro tissue mixed 5-HT2A and 5-HT1A agonist) (50). However, these homogenates, several factors complicate the interpretation results are discordant with those of previous studies in ba- of in vivo experimental results. Key aspects of the by the receptor to guanyl nucleotide-binding proteins (38). For example, typical antipsychotic limitation of these studies is that no useful glutamatergic agents occupy 50% to 80% of striatal D2 receptors (54). PET probes have been developed to examine this important Thus, a new typical antipsychotic agent should show a rea- mediating neurotransmitter system. Furthermore, the link- sonably acceptable side effect profile when given at doses age of pharmacologic challenges can be difficult to interpret. With regard to dos- For example, if a disorder is associated with an abnormal ing interval, the drug may be retained in tissue much longer dopamine outcome measured with PET in response to a 5- than in plasma, and, therefore dosing intervals based on HT challenge, is the abnormal response caused by altered plasma pharmacokinetics may be too frequent. Such a situa- sensitivity of the dopamine or 5-HT system? This kinetics in brain combined with the evaluation of adverse simple assumption has been questioned by elaborate studies reactions in a small number of healthy subjects may provide by Tsukada et al. If targeted receptor occupancy [ -11C]methyldopa (L-[ -11C]DOPA), [11C] -CIT, and is achieved without causing adverse reactions, studies in pa- [11C]raclopride, respectively, in combination with microdi- tients are justified. If not, further studies may not be indi- alysis in conscious rhesus monkeys. Even in the absence of a target level for receptor change extracellular dopamine levels in the striatum but occupancy, it is reasonably safe to assume that doses associ- increased [11C]raclopride binding by decreasing its affinity ated with greater than 95% occupancy are unnecessarily at the dopamine D2 receptor (52) Furthermore, ketamine high, and that those with less than 10% occupancy are un- decreased [11C]raclopride binding in the striatum without likely to be efficacious. By measur- the pharmacokinetics of either the tracer or displacer and ing receptor occupancy with [11C]N-methylspiperone in changes in the synthesis and reuptake of neurotransmitters healthy human subjects, initially an appropriate amount of and affinity of receptor binding may complicate the experi- a single dose (57) and then an appropriate dose and dosing ment, the authors feel that challenges linked with radio- interval were determined (56). Further, a similar level of tracer imaging are likely to provide useful information to receptor occupancy was recently confirmed with allow a better understanding of the pathophysiology of neu- [11C]M100907 in a small number of patients with schizo- ropsychiatric disorders. Dopamine Transporter Imaging as a USE OF RADIOTRACER IMAGING IN Biological Marker in Parkinson Disease THERAPEUTIC DRUG DEVELOPMENT Imaging of a biological marker may provide information Radiotracer imaging can provide useful information about that is useful either for diagnosis or as a monitor of disease molecules that are either the direct target of or indirect progression. In Parkinson disease, the two most successful markers for the effects of therapeutic drugs. For example, imaging targets used as biological markers are measures of if both the tracer and therapeutic drug competitively bind dopamine synthesis with [18F]FDOPA and of dopamine to the same target, then imaging can provide direct informa- terminal innervation with ligands for dopamine transporter. In addition, the molecular target mea- progressive loss of dopamine neurons in the nigrostriatal sured by the tracer (e. Such measurements are possible with in vivo deposition). However, these tracers do not detect the same biological process. Whereas Measurement of Receptor Occupancy 18 [ F]FDOPA detects metabolic activities at dopamine nerve Molecular imaging can provide useful guidance for two as- terminals, the tracers for dopamine transporter simply mea- pects of drug administration: dose and dosing interval. Because of this differ- dose is most easily chosen with a known target occupancy ence, the sensitivity to detect the decrease in dopamine neu- 420 Neuropsychopharmacology: The Fifth Generation of Progress rons may be different.