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Clinical studies under controlled laboratory con- adult in the United States buy generic urispas canada muscle relaxant 303, the riskfor becoming a case of ditions have clarified that drug self-administration can be alcohol use disorder was estimated at 1 generic urispas 200mg on line muscle relaxant eperisone. Chapter 109: Epidemiology of Drug Dependence 1559 Roughly 10 years after the Epidemiology Catchment Area field studies order 200 mg urispas with mastercard spasms thumb joint, the National Comorbidity Survey pro- vided new epidemiologic evidence to complement these esti- mates of the riskfor becoming a case of drug use disorder order 200mg urispas overnight delivery muscle relaxant in renal failure. Although entirely retrospective and cross-sectional in char- acter and lacking the prospective features of the Epidemio- logic Catchment Area studies, the National Comorbidity Survey produced useful information necessary to estimate how many users of various classes of drugs had acquired a clinical syndrome of drug dependence, with the syndrome defined and made operational in relation to the DSM-IIIR criteria (8). Based on its nationally representative sample of community-dwelling Americans between 15 and 54 years of age in the early 1990s, the National Comorbidity Survey estimated how many persons had started taking each of several different drugs (e. On this basis, it was possible to derive a population-average estimate for each drug; once someone had started taking a drug, how likely was it that he or she would have become drug-dependent? From epidemiologic data derived retrospectively and cross-sectionally in the National Comorbidity Survey, it was FIGURE 109. Estimated probability of drug dependence determined that for persons who had consumed tobacco on among drug users, by drug group. Comparative epidemiology of dependence on to- bacco, alcohol, controlled substances, and inhalents: basic find- tobacco-dependent was an estimated 33%. Among persons ings from the National Comorbidity Survey. Exp Clin Psychophar- who had consumed heroin, DSM-IIIR heroin dependence macol 1994;2:244–268, with permission. Among those who had taken cocaine, cocaine dependence had developed in an estimated 16% to 17% (standard error, 1. In coun- dependence had developed was somewhat lower for users terpoint, the laboratory studies demonstrate more limited of cannabis, the psychostimulant drugs, anxiolytic–seda- reinforcing functions served by cannabis and LSD. None- tive–hypnotic drugs, hallucinogens such as lysergic acid di- theless, DSM-IIIR dependence syndromes appear to have ethylamide (LSD), and inhalant drugs (e. For cannabis users, it A slightly different, and more complex, epidemiologic was 1 in 11 (9%; standard error, 0. The complexity starts in The interpretation of epidemiologic estimates of this type estimating the numerator of the ratio; here, it is necessary can be tricky. These estimates certainly do not reflect which to mix the probability of becoming dependent with the drugs are associated with a greater potential for dependence probability of continuing to be dependent. In the community at large, exogenous factors, sustained in estimating the denominator of the ratio. An additional complexity enters users do not survive from the time of first use to the time the picture because drug dependence, as a process, becomes of field survey assessment, either dying or disappearing from one of the determinants of whether a person continues to the sampling frame of the epidemiologic survey before a use a drug once drug use has been initiated. Hence, the diagnostic assessment can be completed (see ref. Despite force of persisting drug dependence is exerted not only in limitations such as these, estimates of this type draw atten- the numerator of this ratio but also in its denominator. In 1560 Neuropsychopharmacology: The Fifth Generation of Progress TABLE 109. ESTIMATED PROPORTION OF ACTIVE DRUG USERS WHO REPORT FEATURES OF ACTIVE DRUG DEPENDENCE Estimated Proportion Number of Estimated Proportion with Three or More Active Drug with One or More Clinical Clinical Features Drug or Users in the Features of Active Drug of Active Drug Drug Group Sample Dependence (%) Dependence (%) Cocaine 709 38 18 Cannabis 3,444 42 17 Alcohol 14,596 23 8 Tobacco 8,187 60 34 Data from National household survey on drug abuse: main findings, 1998. Rockville, MD: Department of Health and Human Services, Substance abuse and Mental Health Services administration, 2000. For example, Grant (15,16) estimated that alcohol of relative dependence liability. At best, this estimated ratio dependence developed in about 20% of drinkers, that drug reflects the proportion of active drug users who may, in dependence developed in about 19% of persons initiating theory, require drug dependence treatment services—that illicit drug use, and that 16% of active illicit drug users were is, it is an indicator of burden. This kind of statistic may dependent on illicit drugs. Its utility in etiologic studies survey estimates for the number of active dependence cases is compromised by its complexity. Reading the table, one can see that 709 lence estimates based on cross-sectional epidemiologic sur- recently active cocaine users were included in the nationally veys, prospective studies and incidence estimates for the representative survey sample of community-dwelling re- drug dependence syndromes have progressed much more spondents ages 12 years and older. Although prospective studies are much more diffi- tion estimates, among active cocaine users in the study pop- cult to complete, they cannot be omitted if we are to under- ulation, 38% reported at least one of seven active clinical stand the force of drug-related morbidity, and distinguish signs or symptoms of cocaine dependence, and an estimated the separate conditions and processes that promote the initi- 18% reported at least three active clinical features. Applied ation of drug dependence, as distinct from the conditions in an estimate of burden in the general population, these and processes that sustain drug dependence once the syn- values indicate that about 0. In this respect, it is unfortunate that the have a cocaine-related problem and about 0. By comparison, the corre- for the riskfor the development of alcohol or other drug sponding estimates for cannabis, based on 3,444 active can- dependence in the U. Elsewhere in nabis users in the sample, indicate that 42% of active the world, prospectively gathered data on the incidence of cannabis users reported at least one cannabis dependence clinically defined syndromes of alcohol or other drug depen- problem and 17% reported three or more clinical features dence (21), sometimes obtained with rigorous methods in of cannabis dependence. In terms of population burden, quite isolated populations (e. Recent efforts to alcohol and for tobacco cigarettes are included in Table monitor the abuse potential of tramadol (Ultram) demon- 109. In the earliest reports, the approach involved drug users). Often, the analyses to disclose variation are not guessing the number of untreated or nonincarcerated drug intended to produce links in a chain of causal inferences. Examples of Epidemiologic Evidence This workis at the margin of the scientific enterprise. As a source of authoritative scientific evidence, it is of Two of the most robust findings from epidemiologic studies dubious value and based on assumptions that are not well on the location of drug dependence cases within population tested and may never be testable. In a brief, pithy article, subgroups are a male excess and an excess in the age group Newman and Cates (25) made this point 30 years ago, quot- 15 to 44 years old, disclosed by both prevalence differences ing from the classic study by Terry and Pellens (26): 'As and relative riskestimates (see ref. To be sure, the male a matter of fact, it is not necessary to know the exact number excess in the occurrence of drug dependence can be contra- of users or even the minimal extent, to realize that there dicted with certain evidence involving some specific drugs, are a large number [of addicts] and that the problem is such as those in the group of anxiolytic, sedative, and hyp- serious. In addition, in some places, the use of tion made by the very talented epidemiologist Leon G. Hunt years of middle age and among the elderly, and several stud- was quoted as saying, 'The question is not whether there ies have noted a slight upturn in the riskfor alcohol depen- are three or four million [addicts], but that the number is dence during the last decades of life, at least among men several million rather than only several hundred thousand' (27). Nonetheless, these exceptions help prove the more (25). The view espoused by Newman and Cates (25) actually A recent intriguing discovery about male–female differ- was much more harsh. They wrote, 'The great disparity of ences in drug use within the United States is that a male the findings of studies using different methods of enumera- excess is found at the earliest stages of drug involvement; tion generally ensures that data will be found to support any boys are more likely than girls to be exposed to opportunities position, and contradictory information is simply ignored. However, once presented with the oppor- They concluded, 'Objectives of studies that are intended tunity, they are equally likely to try a drug (28). Further- to measure the incidence and prevalence of addiction must more, once drug use has started, women are almost as likely be reassessed in terms of experience. It is necessary to ask as men to become drug-dependent (12. Analyses of retrospective estimate the number of active drug users in populations data from the Epidemiologic Catchment Area studies and at the state level, with sample sizes for the U.

Bicarbonate concentrate used to prepare dialysate is particularly prone to flux dialyzers are usually reused discount 200mg urispas with amex spasms detoxification. FIGURE 3-17 Potential benefits of high-flux dialysis purchase urispas amex muscle relaxant brands. Data are accum ulating that support m any potential benefits of high-flux dialysis buy urispas 200 mg fast delivery back spasms 40 weeks pregnant. Large-scale random ized prospective trials discount urispas online visa spasms 2, however, are unavailable. FIGURE 3-19 EXAM PLES OF COM M ONLY USED DIALYZERS Exam ples of com m only used dialyzers. Low-flux low-efficiency Cellulosic m em branes can be either low flux CA90 Cellulose acetate 0. Sim ilarly, synthetic m em branes CF12 Cuprammonium 0. H igh- Low-flux high-efficiency efficiency m em branes usually have large CA150 Cellulose acetate 1. Adapted from Leypoldt and coworkers and Van Stone. In contrast to volum es of plasm a water (which contains to pass through the dialysis membrane diffuse diffusive hem odialysis, fluid flux is a pre- the dissolved solutes), the rem oved fluid down a concentration gradient from a higher requisite for the rem oval of solutes during m ust be replaced. The replacem ent fluid plasma concentration (Cb) to a lower dialysate hem ofiltration, whereas the concentration can be infused into the extracorporeal concentration (Cd). For sm all solutes (eg, urea) circuit before the blood enters the filter the direction of solute transport. For som e m olecules of m id- required when it is given before filtration dle m olecular weight whose m ovem ent rather than after to provide equivalent across the m em brane is partially restricted, solute clearance because the plasm a in Cuf is lower than is Cb (ie, the sieving coef- the filter (and therefore the ultrafiltrate) ficient, defined as Cuf/Cb, is less than 1. FIGURE 3-23 Addition of diffusive transport in hemodiafiltration. In hemodiafiltration, diffusive transport Postdilution is added to hem ofiltration to augm ent the clearance of solutes (usually sm all solutes such as urea and potassium ). Solute clearance is accom plished by circulating dialysate in the dialysate-ultrafiltrate com partm ent. H em odiafiltration is particularly useful in patients Ultrafiltrate who have hypercatabolism with large urea generation. Reverse filtration of ET is particularly prone to occur when high-flux m em branes are used and the M acrophage dialysate is heavily contaminated with bacteria (>2000 CFU/mL) and may result in pyrogenic ET reactions. The dialysis m em branes are im perm eable to intact ET; however, their fragm ents (some of which still are pyrogenic) may be small enough to traverse the membrane. Although the membrane is impermeable to bacteria and blood cells, a mechanical break in the membrane could result in bacterem ia. ET fragments Dialysate M embrane Blood FIGURE 3-25 H2O Dialysis m em branes with sm all and large pores. Although a general correlation exists H2O between the (water) flux and the (middle molecular weight molecule) permeability of dialysis H2O m em branes, they are not synonym ous. A, M em brane with num erous sm all pores that allow H2O high water flux but no -m icroglobulin transport. B, M em brane with a sm aller surface 2 H2O area and fewer pores, with the pore size sufficiently large to allow 2-microglobulin transport. The ultrafiltration coefficient and hence the water flux of the two membranes are equivalent. A H2O H O H2O 2 H2O B A FIGURE 3-26 Scanning electron microscopy of a conventional low-flux-membrane hollow fiber (panel A) and a synthetic high-flux-membrane hollow fiber (panel B). The low-flux membrane consists of a single layer of relatively homogenous material. The high-flux membrane has a three-layer struc- ture, ie, finger, sponge, and skin. The skin is a thin semipermeable layer B that functions as the selective barrier; it is mechanically supported by the sponge and finger layers. W hen the blood flow rate is high 200 (>300 m L/m in), the higher Q d m aintains a higher concentration gradient for diffusion of urea, and therefore, the urea clearance 180 rate is higher. Recent studies have shown that the KoA value of dia- 160 lyzers also increases with higher dialysate flow rates, presumably because of more uniform distribution of dialysate flow. Therefore, the 140 Qd=800 actual urea clearance rate may increase further (red line). K — mass o 120 Qd=500 transfer coefficient; A— surface area. Garovoy istocompatibility and its current application in kidney trans- plantation are discussed. Both theoretic and clinical aspects of H human leukocyte antigen testing are described, including anti- gen typing, antibody detection, and lymphocyte crossmatching. Living related, living unrelated, and cadaveric donor-recipient matching algo- rithms are discussed with regard to mandatory organ sharing and graft outcomes. The class I region is com posed of other genes, m ost of contain the structural genes for transplantation antigens. The M H C class II M H C, located on the short arm of chrom osom e 6, is now recog- region is m ore com plex, with structural genes for both the a and nized to include m any other genes im portant in the regulation of b chains of the class II m olecules. The class II region includes four im m une responses. DP genes, one DN gene, one DO gene, five DQ genes, and a vary- The M H C can be divided into three regions, of which the class I ing num ber of DR genes (two to 10), depending on the halotype. FIGURE 8-2 Specific locus N om enclature of hum an leukocyte antigen (H LA) specificities. H LA nom enclature m ay be confusing to the newcom er, but the form at is logical. The prefix H LA precedes all antigens or alleles to define the m ajor histocom patibility com plex (M H C) of the species. The HLA C w 8 designation, A, B, C, DR, and so on, is next and defines the locus. The locus is followed by a num ber that denotes the serologically defined antigen or a num ber with an asterisk that denotes the m olecularly defined allele. In som e cases the letter w is placed The major histocompatibility Provisional before the serologic antigen, indicating it is a workshop designation complex in humans specificity and the specific assignm ent is provisional. Specific antigen Locus Allele designation HLA DRB1 * 04 03 Corresponding antigen Specific allele Histocompatibility Testing and Organ Sharing 8. The human leukocyte antigen (HLA) assignments are assigned by serologic methods (ie, complement-dependent cytotoxicity); however, molec- ular-based methodologies are becoming widely accepted. M ost laboratories now have the HLA phenotype capability of reporting at least low-resolution molecular class II types. Patient cells tested with known antisera The sera of patients awaiting cadaveric donor kidney transplantation are tested for the HLA antibody screen degree of alloim m unization by determ ining the percentage of panel reactive antibodies (PRAs). Current federal regulations require that the serum screening test use lym phocytes Known cells tested with patient sera as targets; however, because these sam e regulations no longer m andate m onthly screening, HLA crossmatch assays using soluble antigens m ay be used as adjuncts to the classic lym phocytotoxic assays.

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There have been in these regions than the cortex purchase 200mg urispas overnight delivery muscle relaxant otc usa, but cheap urispas 200 mg muscle relaxant and painkiller, as noted above discount 200mg urispas free shipping muscle relaxant and anti inflammatory, this only limited tests of this hypothesis in humans cheap urispas 200mg muscle relaxant liquid, mainly using is not the case. It is also not clear how this model could ritanserin, which is a mixed 5-HT2A/2B/2C antagonist (32). The evidence for this hypothesis will be dis- mimic the effects of the multireceptor antagonists such as cussed subsequently. Pharmacologic analysis of this impor- Counter to the hypothesis of the importance of 5-HT2A tant model for the action of atypical antipsychotic drugs receptor antagonism to the action of clozapine and other on cognition and negative symptoms strongly supports the atypical antipsychotic drugs is the proposal of Seeman and importance of combined blockade of 5-HT2A, D2, and pos- Tallerico (24) and Kapur and Seeman (38) that the basis sibly 1 receptors (36,37,44,45). It has also been proposed that rapid and extensive displacement of clozapine and que- tiapine from binding sites accounts for the reported low Ever since the cloning and characterization of the distribu- occupancy of striatal D2 receptors by these drugs (24). The tion of the D3 and D4 receptors, which revealed a limbic authors also suggested that this might account for more and cortical distribution, there has been considerable specu- rapid relapse following clozapine and quetiapine withdrawal lation about the role of these receptors in schizophrenia and (24). Although the evidence cited for clozapine-induced rel- the mechanism of action of antipsychotic drugs (19,46–48). See- cognition, and motor function, as well as to carry out some man and Tallerico found that the affinity for and rate of clinical trials in schizophrenia. Drugs with low affinity for the D2 recep- selectivity for the D3 receptor and good brain bioavailabil- tor, e. This com- higher dissociation rate constant than drugs with higher pound was active in preventing isolation-induced deficits in affinity, e. Rapid dissociation from the D2 prepulse inhibition but was not effective in blocking either receptor was reported to also permit easier displacement amphetamine- or phencyclidine (PCP)-induced locomotor of clozapine and quetiapine by endogenous DA, thereby activity or, by using microdialysis, to increase prefrontal avoiding side effects related to DA receptor blockade such cortical DA release in rats (49). However, subchronic ad- as EPSs and hyperprolactinemia (38). It was also reported ministration of SB-277011-A selectively decreased the firing that olanzapine, risperidone, and sertindole, all of which rate of A10, but not A9, DA neurons in the rat, indicating are well established as atypical antipsychotic drugs, are com- a clozapine-like profile (50). These are the most promising 822 Neuropsychopharmacology: The Fifth Generation of Progress data yet that a selective antagonist of D3 receptors might pothesis also have affinities for 5-HT2C, 5-HT3, 5-HT6,or be useful in the treatment of psychosis. However, this for the superiority of clozapine over the typical neuroleptic does not rule out that actions at various 5-HT receptors drugs in the treatment of schizophrenia. Other investigators contribute to low EPSs of specific drugs, or other actions, have found less of a difference between the affinity of cloza- e. For example, 5-HT1A receptor agonism has also chotic drugs, including haloperidol, have nearly equivalent been suggested to be able to contribute to an atypical anti- affinity for D2 and D4 receptors, suggesting that D4 affinity psychotic drug profile (62), and some of the atypical anti- per se does not convey any special advantages for an antipsy- psychotics are 5-HT1A partial agonists as well as 5-HT2A/ chotic drug (48). The preclinical behavioral and electro- 5-HT2C antagonists, e. The role of the 5-HT4 receptor vides mixed evidence with regard to antipsychotic action in cognition will be discussed subsequently. A D4/ 1 antagonist, there is some evidence of interactions among the 5-HT1A, NRA0025, appears to have promise as an antipsychotic 5-HT2A, and 5-HT2C receptors (19,35). Because of space agent based on its preclinical profile (26). A clinical trial of limitations, this chapter focuses on these three 5-HT recep- a selective D4 antagonist showed no sign of activity (55). A compound with potent 5-HT2A and D4 antagonist prop- erties, finanserin, was also ineffective (56). Further clinical trials of compounds that have D4 or D3 antagonism, or ATYPICAL ANTIPSYCHOTICS AND THE both, together with high affinities for 5-HT1A or 1 recep- 5-HT2A RECEPTOR tors, and without D2 affinity seems indicated. The hallu- cinogenic effect of indole hallucinogens has been related to stimulation of 5-HT2A rather than 5-HT2C receptors (65). Determining the biological basis for the advantages of clo- Numerous studies have examined the density of 5-HT2A zapine and other atypical antipsychotic drugs cited above receptors in various cortical regions of patients with schizo- and described in detail by Miyamoto et al. It is well established that some typical and psychotic drugs action. We now consider some of this evi- atypical antipsychotic drugs can decrease the density of dence. Other reviews of this topic should also be consulted 5-HT2A receptors (69,70), so the postmortem results noted (18,19,22,34–37,57). Positron emission tomography (PET) studies have not found decreased Serotonin Receptors Involved in 5-HT2A receptors in the cortex of never-medicated or un- Antipsychotic Drug Action medicated patients with schizophrenia (71). As mentioned The hypothesis that a relatively high affinity for the 5-HT2A above, the antipsychotic effect of clozapine has been attrib- receptor compared to an affinity for the D2 receptor was uted, in part, to its ability to block excessive 5-HT2A recep- the basis for the difference between atypical and typical tor stimulation without excessive blockade of D2 receptors antipsychotic agents contributed to the development of the (17). This conclusion is consistent with the high occupancy newer antipsychotic agents listed above, all of which support of 5-HT2A receptors produced by clozapine at clinically ef- the previously mentioned hypothesis of high affinity for fective doses and its low occupancy of D2 receptors (in the 5-HT and low affinity for D2 receptors (17,58,59). How- 30% to 50% range as measured with [3H]raclopride), the 2A ever, other 5-HT receptors may be important to the action latter being significantly below the 80% to 100% occupancy of clozapine and other recently introduced antipsychotic usually produced by typical neuroleptic drugs (35,72–75). These include the ied with other novel antipsychotic drugs such as risperidone, 5-HT1A, 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7 re- olanzapine, sertindole, and quetiapine with results similar ceptors (19,22,33). Although some of the atypical antipsy- to those of clozapine; all are more potent 5-HT2A and D2 chotic drugs developed on the basis of the 5-HT2A/D2 hy- antagonists at appropriate doses, but less so than clozapine Chapter 58: Mechanism of Action of Atypical Antipsychotic Drugs 823 (72–75). Recovery from zapine) produce high D2 occupancy at high doses (76,77). The bell-shaped dose–response curve of risperidone, An important effect of 5-HT2A (and 5-HT2C) receptors with higher doses being less effective than lower doses (78), that may be relevant to their contribution to psychosis is is consistent with the hypothesis that excessive D2 receptor their ability to influence dopaminergic activity in the meso- antagonism may diminish some of the beneficial effects of limbic and mesostriatal systems (19,33,90–94). The highly se- dopaminergic activity in the nucleus accumbens and other lective 5-HT2Aagonist M100907, formerly MDL 100907, mesolimbic and possibly cortical regions may contribute to has been found in a controlled study to have some efficacy positive symptoms, including formal thought disorder (2, for treating positive and negative symptoms in hospitalized 5). Increased dopaminergic activity in the striatum would schizophrenic patients (79). However, because it was less be expected to diminish EPSs (2,5). The 5-HT2A/2C agonist effective than haloperidol, no further testing in schizophre- DOI [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane], nia has been scheduled at present. Nevertheless, the concept which itself had no effect on basal DA release, potentiated that 5-HT antagonism may be useful to treat some forms amphetamine-induced DA release and attenuated the ability 2A of psychosis, especially when combined with weak D2 re- of apomorphine, a direct acting D1/D2/D3 agonist, to de- ceptor blockade, warrants further study. Other 5-HT se- crease DA release in the striatum (93). Increasing serotonin- 2A lective agents such as SR 46349B (80) are currently being ergic activity, e. Additional clinical evidence supporting the role of reuptake inhibitors (SSRIs) alone or in combination with 5-HT receptor blockade in the action of clozapine and the 5-HT1A receptor antagonist WAY 100635, has no effect 2A possibly other drugs with potent 5-HT affinities is avail- on basal DA output in the striatum. However, the SSRIs can 2A able from the several reports that the His452Tyr allele of significantly enhance the increase in DA outflow induced by haloperidol. These findings indicate that in the striatum, the 5-HT2A receptor, which is present in 10% to 12% of endogenous 5-HT positively modulates DA outflow when the population, is associated with a higher frequency of poor nigrostriatal DA transmission is activated (94). Taken together, the evidence considerable evidence from both behavioral and neuro- from clinical trial data suggests that 5-HT2A receptor block- chemical studies involving N-methyl-D-aspartate (NMDA) ade may contribute to antipsychotic drug action.

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Further development of MK-869 for depression agonists N-methyl-D-aspartate (NMDA) effective urispas 200mg quad spasms, -amino-3-hy- 1002 Neuropsychopharmacology: The Fifth Generation of Progress droxy-5-methyl-4-isoxazole propionic acid (AMPA) purchase genuine urispas line spasms after stent removal, and LY354740 (group II) purchase cheap urispas line muscle relaxant xanax, L-AP4 (group III) purchase urispas 200 mg free shipping spasms in back, and L-CCG-I kainic acid (KA). Pharmacologic agents for antagonizing metabo- dent and voltage-independent currents carried by Na ,K , tropic glutamate receptors are currently limited. NMDA receptors, which are selectively activated by Genetically Altered Mouse Models NMDA, form a receptor/channel complex that is allosteri- Site-directed mutagenesis studies have indicated that point cally regulated by several sites. Receptor activation results mutations in the glycine binding site of the NR1 subunit in depolarization and Ca influx. Allosteric binding sites result in mice that have reduced glycine affinity and have include a strychnine-insensitive glycine site, a polyamine an anxiolytic profile as seen by decreased natural aversion site, a zinc site, and a channel site that binds agents such to an exposed environment (105). These data supported as MK-801 or phencyclidine to block channel opening. The other pharmacologic lines of evidence (see below), indicat- NMDA receptor has been cloned and has two families of ing that blockade of the glycine site can have anxiolytic subunits, the NR1, with seven splice variants (1A–1G), and actions. NR1 receptors possess the receptor/ion channel complex, whereas the NR2 Current Drugs in Development receptors lack the ion channel and appear to be modulatory. NR2 receptors, however, can form functional heteromeric LY354740 is an orally active group II metabotropic receptor channels by combining with NR1 subtypes. NMDA antag- agonist (106) currently in clinical development. Preclini- onists include competitive antagonists at the NMDA recep- cally, the compound has anxiolytic activity in fear-poten- tor such as AP5, CPPene, and CGS 19755; noncompetitive tiated startle (107), the elevated plus maze (107), conflict antagonists at the ion channel site such as MK-801 and testing (108), the four-plate test (108), and in a lactate- phencyclidine; and noncompetitive antagonists that bind induced panic attack model (109). LY354740 has also been to the glycine site such as 5,7-dichlorokynurenic acid, shown to decrease withdrawal signs seen during naloxone- L689,560, ACEA 1021, and MDL 105,519 (104). Unfortunately, clinical develop- KA subunits (GluR5–GluR7 and KA-1–KA-2). Functional ment for many of these compounds was halted because of channels can be produced by homomeric expression of severe side effects, including psychotic-like symptoms. The GluR5 or GluR6 subunits, or by heteromeric expression of potential for these side effects has been a major deterrent for KA-1 or KA-2 with GluR5 or GluR6. KA sites are found using NMDA antagonists for the treatment of psychiatric in the hippocampus, cortex, and thalamus, whereas AMPA disorders. Although there are currently no drugs reported receptors are additionally localized in septal and cerebellar to be in development, preclinical studies have suggested that sites. Pharmacologic agents for blocking non-NMDA recep- selective antagonists of the strychnine-sensitive glycine site tors include the competitive antagonists CNQX, DNQX, can have anxiolytic properties with reduced side-effect po- and NBQX, and the noncompetitive antagonist GYKI tential relative to competitive and noncompetitive NMDA 52466. Recent Metabotropic glutamate receptors (mGluRs) mediate work has supported such a profile (112,113). Opposite effects to have anxiolytic actions in preclinical models. Thus, on cAMP may be mediated by either Gi or Gs stimulation. LY326325 was shown to have anxiolytic activity in the ele- Agonists include a conformationally restricted glutamate vated plus maze and in a conflict test (punished drinking) analogue, 1-aminocyclopentane-trans-1,3-dicarboxylic acid in rats (114), and CNQX injected directly into the peria- (trans-ACPD). Metabotropic receptors have been classified queductal gray produced anxiolytic effects on the elevated into three subgroups: group I (mGluR1, mGluR5), which plus maze (115). The antagonists CNQX and GYKI 52466 stimulate PI hydrolysis; and two groups that inhibit adenyl- were also able to block the anxiogenic responses produced ate cyclase, group II (mGluR2, mGluR3) and group III by bicuculline injected into the basolateral amygdala (116). Metabotropic receptors are widely distributed throughout the brain, in areas such as the hippo- campus, cerebellum, thalamus, olfactory bulb, and striatum, CCKB ANTAGONISTS though the precise distribution varies considerably between groups. In addition to the agonist trans-ACPD, other ago- Cholecystokinin (CCK) is a peptide found extensively both nists that are more specific for receptor subtypes include in the gut (where it was originally identified) and in the Chapter 68: Mechanism of Action of Anxiolytics 1003 brain (117). CCK exists in multiple forms, the most pre- depression and in the mechanism of action of antidepressant dominant of which is CCK octapeptide (CCK8) and, to a drugs. The role of cortico- lesser extent, CCK tetrapeptide (CCK4) (118). CCK is co- tropin-releasing factor in depression and anxiety disorders. J localized with a number of different neurotransmitters, in- Endocrinol 1999;160:1–12. CRF and restraint stress decrease ex- peptide Y, and VIP. CCK-like immunoreactivity has been ploratory behavior in hypophysectomized mice. Pharmacol Bio- demonstrated in anatomic regions that include the amyg- chem Behav 1989;34:517–519. Cerebrospinal fluid corti- dala, cerebral cortex, hippocampus, striatum, hypothala- cotropin-releasing hormone levels are elevated in monkeys with mus, and spinal cord (119). There are two subtypes of CCK patterns of brain activity associated with fearful temperament. The role of early adverse life accumbens, posterior hypothalamus, and area postrema. Ann NY Acad CCKB receptors are localized in cortex, olfactory bulb, nu- Sci 1997;821:194–207. Early postnatal experience alters hypo- A number of selective antagonists for the CCKB receptor thalamic corticotropin-releasing factor (CRF) mRNA, median have been synthesized, including LY288513 (Lilly), PD eminence CRF content and stress-induced release in adult rats. Griebel (34) reviewed the extensive literature on the effects 9. Corticotropin releasing factor receptors and their ligand family. Corticotropin-releas- that the results were contradictory and did not lead to a ing factor receptors: an overview. L-365,260 and CI-988 have been evalu- 1997;105:65–82. Localization of had significant anxiolytic effects (122–124). Autoradiographic locali- zation of CRF-1 and CRF-2 binding sites in adult rat brain. Many different neurotransmitter receptor systems have been Neuropsychopharmacology 1997;17:308–316. Autoradiographic and in situ shown to modulate anxiety and possess anxiolytic effects. J Comp Neurol 1999; control anatomic circuitry important in anxiety. Homologous by their side-effect profile than by their anxiolytic activity. Brain Res 1966; It will be interesting to see which of the mechanisms de- 710:287–292. Regulation of pituitary corticotropin tics in human populations. Corticotropin-releas- ing factor receptors: distribution and regulation in brain, pitui- ACKNOWLEDGMENT tary, and peripheral tissues. Tallman, Cassella, and Kehne are all full-time employ- rior pituitary and brain corticotropin-releasing factor receptors.