By M. Ateras. Walla Walla University.

Furthermore order cipro, it was found that chronic treatment of rats with THC causes an The nonmedical use of marijuana has a very long history generic 750mg cipro visa, almost fourfold increase of AEA levels (and no down-regula- primarily for its mind-altering effects and the sense of well- tion of cannabinoid receptors) in the limbic forebrain (67) cheap cipro 500mg on line. Therefore order cipro online now, the potential use of It is possible that dopamine released in the nucleus accum- marijuana for diseases of the brain is a logical extension of bens on chronic treatment with THC triggers AEA forma- the popularity of the use of the material in producing mood- tion, as previously shown for the dorsal striatum (85). The initial therapeutic uses proposed for versely, dopamine may be released in this region after the marijuana included the treatment of mental disorders and activation of CB1 receptors by AEA. As more information about the pharmacologic effects out with CB1-receptor knockout mice showed reduced opi- of the plant material emerged, other potential therapeutic oid dependence (35), as well as lack of morphine-induced uses became apparent. Since the 1970s, investigators have dopamine release in the nucleus accumbens of these proposed many different therapeutic uses for marijuana in- transgenic animals (88). Thus, contrary to the basal ganglia, cluding, but not limited to, nausea and vomiting induced endocannabinoids released in the nucleus accumbens may by cancer chemotherapeutic agents, the wasting syndrome act to enhance the action or release of dopamine, thereby accompanying AIDS, mental illness, convulsions, glau- participating in reward, craving, and pleasure or in the rein- coma, cognition disorders, muscle spasticity, and neuro- forcement of drug of abuse effects. Strong proponents relapse into drug addiction or in the reinforcing effects of of the use of smoked marijuana for the treatment of various drugs of abuse. Opponents are concerned The possibility that endocannabinoids may play a role in with the deleterious effects of the smoked marijuana, espe- diminishing cellular or neuronal damage is of particular rele- cially the prolonged use of this plant material. The suggestion that further complicated by the fact that many strong propo- endocannabinoids may have a neuroprotective function nents of the use of marijuana in medicine also advocate for during cell injury stems from the finding that a similar role its legal recreational use. Conversely, those who are opposed was proposed also for other ethanolamide of fatty acids (89), to its use, especially by adolescents and young adults who as well as for both psychoactive and nonpsychoactive canna- may be especially vulnerable to problems of abuse, effects binoids. This hypothesis is supported by the finding that on energy, memory, and acquisition of interpersonal skills, stimuli leading to high intracellular Ca2 concentrations have not always considered the possible benefits with the (e. One of the major problems contrib- of AEA and related compounds in neuronal cells. Canna- uting to this dilemma is the lack of well-controlled studies binoid receptors do not appear to be involved in this eleva- attesting to the efficacy and the safety of marijuana in hu- tion of Ca2. Such studies require a reasonable hypothesis to be 1 opposite effect. It inhibits Ca2 influx into neurons tested and an appropriate investigation under conditions through voltage-gated Ca2 channels and counteracts that completely eliminate the possibility of subjectivity in membrane permeability to Ca2 through N-methyl-D-as- the measurements. This controversy is not likely to be re- partate receptor–coupled channels. Therefore, endocannab- solved until such studies are forthcoming. THC was approved The identification of THC as the active agent in marijuana for the treatment of the nausea and vomiting associated with stimulated a concentrated effort to quantitate the amount cancer chemotherapy in the 1980s and for the treatment of of this material in various samples of the cannabis plant. The initially reported concentrations of THC in confiscated It has been moved from Schedule II to Schedule III. Mari- marijuana were approximately 2% but have increased to juana proponents counter that the therapeutic benefits de- more than 4% during the past few years (92). It was found rived from smoked marijuana are the result of many chemi- that by altering the soil conditions and the environment, cals in the plant, not solely THC. There are, however, toxic the concentration could be increased several fold. Further, would expect, the pharmacologic effects of smoking mari- the smoking route of administration used for marijuana has juana are directly related to the concentration of THC. Ad- advantages over the oral route used for the administration vances in biogenetic engineering as applied to agriculture of THC. The onset of action is faster while at the same suggest that manipulations could be made to increase the time allowing the smoker to titrate blood levels better. Concentrations of more heightened interest in medical marijuana has not yet been than 20% have been reported in some marijuana grown translated into a satisfactory resolution of the differences. How avail- There is no doubt of the severity of the conditions and able increased-potency marijuana is in the United states diseases for which marijuana or THC has been proposed. The availability of alternative delivery systems (e. Even then, however, it is likely that some As described earlier, the concentration of the active constitu- will argue that it is the intoxicating effect combined with ent in marijuana can vary over a large range. This variation the other effects that makes marijuana particularly useful. It would not be practical to quantitate the concentra- tion of the active ingredient in each cigarette before its con- Medication with Plant Material sumption. Most of the proposed indications for the medical Active Constituents use of marijuana require chronic administration, which magnifies the problem of inconsistent dosing. Administra- Hundreds of compounds have been isolated and identified tion of any drug through smoking presents an additional from the marijuana plant (91). Most have been shown to problem when a standard procedure does not exist for pre- have minimal pharmacologic activity, and most exist in the paring cigarettes with a constant quantity of plant material plant in very small quantities. Further, the variability from individual to in marijuana has been shown to be THC. The pharmaco- individual in the size and the rate of puffing produces an- logic profile of THC is essentially the same as that of other variable for the consumption of drugs by this route smoked marijuana, and the evidence is now overwhelming of administration. Even in the same patient, the volume of that the predominant effects of marijuana on the brain result smoke inhaled can often differ from time to time. Other cannabinoids such as 8-THC, cannabidiol, and cannabinol have been studied and have been shown to have interesting pharmacologic profiles. The Unwanted Side Products 8-THC isomer produces many of the same effects as the The administration of a drug by smoking plant material 9- isomer (THC), but it is generally less potent, and the causes other problems because many substances are being quantity of 8-THC in the plant material usually is less than taken in along with the active ingredient. Cannabidiol and cannabinol are of interest substances has its pharmacologic and toxicologic effects. It is abun- but also are considerably devoid of activity on the central dantly clear from the vast literature on the smoking of other nervous system, especially in relation to mental health, products, predominantly tobacco, that numerous com- memory, and cognition. The lack of effects on the central pounds are produced in the burning process. These pyrolysis nervous system is an advantage in the potential use of one products also have their own pharmacologic and toxicologic of these agents or an analogue to treat a disease or a condi- profile, and as with the other ingredients in the plant mate- tion with a locus of action outside the brain. The search rial, these pyrolysis products have the potential to alter the for other cannabinoids that could have therapeutic potential effects of the active ingredient. The major problem is the has shifted almost totally to the synthetic chemistry process. These investigations will be guided by the continued progress in the efforts of re- searchers to identify and understand the cellular and molec- Optimal Delivery ular effects of the cannabinoids. Mechanisms may be found One of the major concerns with the potential use of mari- that will help to provide selectivity resulting from the effects juana, and, for that matter with any of the cannabinoids, of the cannabinoids on an intracellular site of action. The is the observation that these agents produce a multiplicity more detail we know about the genetic influences and the of effects, and they all seem to occur at similar doses. One structural makeup of the receptors and other cellular ele- possible way to overcome this problem is to develop a deliv- ments, the better we will be able to design cannabinoids ery mechanism that limits the distribution of the drug to with selective activity. This is particularly difficult when Another approach to identifying cannabinoids with more the site of action is in the brain, as it is with the cannabinoids selectivity of action is to investigate the interactions of exog- and their potential usefulness in treating symptoms of men- enously administered substances with AEA and other en- tal illness. One potential therapeutic use of the cannabinoids dogenous cannabinoids. If one were to hypothesize that an is in the treatment of glaucoma. Local administration di- altered tonic activity of the endogenous cannabinoid system rectly into the eye is the preferred mechanism of drug deliv- is at the basis of some neurologic disorders, there are again ery. One of the problems of using cannabinoids in this two approaches that could be taken in the search for more fashion is that they are insoluble and must be administered selective agents. One would be to alter either the synthesis in a vehicle, which may have deleterious effects when it is or degradation of the endocannabinoids, and the other is placed in the eye. An optimal delivery for this indication to modulate their actions. An example of the latter approach would be to have a water-soluble cannabinoid (93) with would be to compete with or block the receptor or to inter- good efficacy in lowering intraocular pressure that can be fere with the signaling events through which the endoge- applied directly to the eye and not be irritating. The advantage of these application of such a drug would provide the intended ther- approaches would be that drugs interfering with endocan- apeutic effect and would not produce the undesirable side nabinoid metabolism or action would exhibit higher effects effects that would be observed if the drug were absorbed in those tissues where the levels and activity of endocannabi- into the general circulation.

Subsequent studies using have been used loosely with inadequate definitions buy cheap cipro 1000mg online, the diverse ligands and dosing regimens continued to give varied overall concept that chronic -opioid agonist administra- results discount cipro online american express, with up-regulation of -opioid receptors cipro 750mg mastercard, down- tion may cause reduced capacity to bind buy online cipro, or increased capac- regulation of -opioid receptors, and no change of -opi- ity to bind, or to have no effect, but each alternative with oid-receptor density or binding after chronic -opioid-ago- reduced capacity of activated receptors to have an effect nist administration all reported. The prevailing concept for (or 'tolerance'), has persisted, and repeatedly studied, with receptor-agonist ligands and, in this case, specifically ago- conflicting results. The earliest studies to address this issue nists for the -opioid-receptor system, has been that persis- of impact of chronic opioid administration effects on bind- tent activation of receptors would generally lead to down- ing were conducted to elucidate the well-documented and regulation, and conversely, the persistent deprivation of re- accepted phenomenon of tolerance, both in cell systems and ceptors of specific ligands would generally lead to persistent in whole animals. Morphine was the most common opiate lack of activation of receptors and thus to up-regulation. From 1996 to 2000, several intriguing articles appeared Later, the effects of specific opioid antagonists on opioid- concerning the effects of opioid-agonist administration on receptor binding or density were also conducted, primarily receptor internalization (44–52). The binding of opioid antagonists, of relevant studies on signal transduction, primarily through course, does not involve coupling; that is, no Gi/o-pro- G-protein–coupling mechanisms, but also alternative tein–coupled signal transduction mechanisms are involved, mechanisms, appeared and extended our earlier knowledge because the opioid antagonists (according to most current and may ultimately explain some of the apparently conflict- theories) do not activate receptors, but rather prevent activa- ing results concerning receptor binding and density (12–15, tion by endogenous or exogenous opioids. There is now animals was shown to alter, at a cellular level, the function essentially a consensus from many and diverse studies that of neurons, specifically in the locus ceruleus, and also to the chronic administration of opioid antagonists, primarily lead to tolerance and physical dependence (12,18,20,24). There has, how- inhibition by morphine of adenylyl cyclase, as well as result- ever, been some controversy regarding whether opioid an- ant inhibition of the cyclic adenosine monophosphate tagonist treatment and the resultant up-regulation of - (cAMP)–dependent cascade, followed by, during chronic opioid receptors leads to a sensitized state, that is, a state morphine treatment, a compensatory increase of activity of in which an opioid agonist would have a greater than usual adenylyl cyclase, with an increase in the cAMP-dependent effect on any system. This has been addressed both in animal cascade, including increases in protein kinase A and in- models and in humans, with some conflicting results. Nestler and Aghajanian hypothesized that this up- merous studies have used several different opioid agonists, regulation of the entire cAMP pathway in the locus ceruleus primarily morphine, given by different regimens, ranging represents a compensatory change to oppose or offset the from intermittent injections to repeated pellet implantation, initial inhibitory effects of morphine and thus could be con- to a few studies using chronic administration by pump, sidered to be one component of tolerance (18,20). They there have been conflicting study results and no consensus also suggested that these increases in the cAMP pathway on the effects on -opioid-receptor binding or density. The components could contribute to opiate dependence and results reported from studies conducted in living adult ani- thus withdrawal, because these changes could be involved mals, for the most part, have shown no overall net changes in a variety of functions once no longer opposed by mor- in -opioid-receptor–binding capacity, that is, no overall phine (18,20). This concept is of particular relevance be- changes in opioid-receptor density, as measured by quanti- cause this up-regulation of the entire cAMP pathway during tative autoradiography or by classic homogenate binding chronic morphine exposure has been shown to occur pre- assay studies, and, more recently, no overall changes in - dictably in the locus ceruleus of all strains and species of opioid-receptor mRNA levels. Because the locus ceruleus is the ducted in living adult animals by the groups that included major noradrenergic nucleus of the brain, diverse noradren- those who first defined opioid receptors, showed no altera- ergic functions that are known to be activated in opiate Chapter 104: Neurobiology and Pathophysiology of Opiate Addiction 1493 withdrawal could be affected. Nestler and other groups tein–coupled family of seven transmembrane receptors; showed that although these changes occur uniformly in the there has been further documentation of receptor phosphor- locus ceruleus neurons, and in a few other brain regions, ylation, desensitization, and uncoupling from G proteins, particularly in the nucleus accumbens, this type of change as well as new studies documenting internalization (endocy- in the nucleus accumbens is strain dependent, and also such tosis) of opioid receptors (36–52). However, studies in ani- changes do not occur in many other brain regions in any mals continue to produce very conflicting results concerning strain or species (12,18,20,24). They also do not occur in the effects of chronic opiate administration on opioid-recep- the gastrointestinal tract. Nestler and others did not find a tor binding and density or number. Similarly, despite docu- down-regulation of -opioid receptors during chronic mor- mentation by many groups that cellular adaptations may phine treatment in the locus ceruleus (18,20,24). They did, be directly involved in the development of tolerance and however, report an uncoupling of the -opioid receptor dependence, the mechanisms have yet to be fully elucidated. This is intriguing in the context of findings changes in G-protein–coupled signal transduction mecha- of the laboratories of Yu and Kreek, who reported that after nisms and changes in downstream effectors, such as in- binding of the long, 31-residue, endogenous opioid -en- creases in CREB and phosphorylated CREB, and also other dorphin to the variant -opioid receptor coded by the very changes such as increases in and accumulation of chronic common SNP, A118G, there is enhancement of activity FRAs (Fos-related antigens), are all nonspecific. For in- of these G-protein–coupled inwardly rectifying potassium stance, diverse stimuli such as cocaine, opiates, opiate with- channels (58). CREB is of Aghajanian, as well as more recent work of Nestler and one component of the enhanced cAMP response and is a others, have suggested that the locus ceruleus may be pri- transcription factor; chronic FRAs have now been identified marily involved in expression of opioid physical dependence as isoforms of FosB, which is a splice variant of the fosB and thus in opioid withdrawal (20). Each of these enhanced or altered transcription factors al. These increases in CREB and from the locus ceruleus and showed that chronic morphine in chronic FRAs, both results of chronic morphine adminis- treatment decreased the inhibitory G-protein activity in the tration, may yield enhanced or altered gene transcription locus ceruleus and yet did not produce any detectable desen- elements and, in turn, changes in levels of expression of sitization, a finding suggesting a potential adaptation at that specific genes and in specific brain regions. Chronic morphine treatment decreased both in chronic FRAs after long-term morphine administration basal and opioid stimulated guanosine triphosphatase occur exclusively in the striatum, whereas the increases in (GTPase) activity and yet caused no changes in the percent- chronic FRAs seen after stress occur in the prefrontal cortex age of stimulation by an opioid agonist. For 35 were extended by binding assays using [ S]GTP S (40). These increased and accumulated amounts of CREB nist–stimulated [35S]GTP S binding was observed in the and chronic FRAs are tangible examples of neuroplasticity locus ceruleus and in a few related regions during long-term of the brain and document one type of change that may heroin self-administration. These findings were similar to occur and persist with chronic exposure to a drug of abuse. Moreover, the decreased -opi- many such changes and, although related to specific addic- oid-stimulated [35S]GTP S binding was found in two addi- tion related phenomena, are not the sole cause of any of tional regions, the thalamus and the amygdala, which may the three distinct and separable phenomena of tolerance, be of importance for the reinforcing effects of drugs of abuse physical dependence, or addiction. Moreover, all the result- and thus self-administration (42). The opioid receptors involved have all been cloned with respect to the causative agent. In addition, these tran- and have been documented to be part of the G-pro- sient, but gene-specific, changes in gene expression can 1494 Neuropsychopharmacology: The Fifth Generation of Progress occur in specific brain regions after specific times of expo- Furthermore, Bohn and colleagues reported that no toler- sure to, or withdrawal from exposure to, a drug of abuse ance develops to the antinociceptive effects of morphine such as morphine (but also cocaine and other drugs of during chronic administration, but they also said that there abuse). Nestler hypothesized that the documented increases in amounts and phosphorylation Dopamine, Other Neurotransmitters, of CREB in the locus ceruleus caused by chronic morphine Neuropeptides, and Their Receptors: Molecular, administration may be directly involved in the regulation Cell Biological and Signal Transduction of the entire cAMP pathway through the CREB effects as Alterations, and Possible Implications for a transcription factor on gene expression (18). His group Pathophysiology of Opiate Addiction showed that application of CREB antisense oligonucleotides applied to the locus ceruleus of opiate-dependent rats de- The early work of many groups showed that opiates, like creases the opiate withdrawal-induced increases in neuronal most other drugs of abuse, appear to act to enhance dopami- firing that are usually seen (18). Further, the laboratory of nergic tone and through that enhancement achieve some, Nestler showed that accumulation of chronic FRAs during most, or all of their reinforcing effects. Moreover, through chronic morphine treatment, related to the transient early a variety of studies, primarily conducted in animals using gene protein products Fos and Jun, which, in turn, join to either surgical lesions or specifically directed neurotoxins, form a major gene transcription factor, activator protein 1, and also other specific chemicals to enhance or decrease may play a role in the effects of morphine and also of stimu- dopaminergic function, along with ultimately microdialysis lants (18). Using an effective construct involv- forcing effects of most or all drugs of abuse. This gene construct allows overproduction of FosB tion of those neurons (62). Thus, by inhibiting these inhibi- by the gene insertion, the overexpression of which can be tory neurons, which normally put a brake on the dopami- prevented by administration of a tetracycline congener, but nergic neurons in the ventral tegmental area, the result is it be started again by stopping treatment with the tetracy- activation of the dopaminergic neurons, with enhanced re- cline congener. The overexpression can be both brain region lease of dopamine in the nucleus accumbens, as well as in specific and time specific (12). To date, enhancement of the amygdala and probably in all other regions of the meso- FosB in the striatum has been shown to alter the behav- limbic-mesocortical dopaminergic fields (62). Using a different transgenic Although many investigators have attributed the rein- approach, a viral vector may be used to deliver a desired forcing effects of all drugs of abuse, including heroin and gene to a specific brain region to yield overexpression. There is an increasing consensus that the reinforcing ef- Studies have been conducted in animals with deletion fects of drugs of abuse, along with possibly physical depen- of the dopamine transporter gene, which many researchers dence, are not directly related to tolerance, and they also had hypothesized would eliminate cocaine self-administra- may not be directly related to any changes in receptor den- tion because of the very high constant levels of dopamine sity, number, desensitization, internalization, G-protein un- and the lack of further effects by superimposed cocaine (63). These findings are further supported by the report transporter knockout mice were found unequivocally to of Bohn, Lefkowitz, Caron, and colleagues that, in studies self-administer cocaine, although the acquisition of that be- in -arrestin knockout mice, one sees enhancement and havior was slower than in the wild-type mice (64). Thus, persistence of the antinociceptive effects of morphine (60). In that same animal model, the dopamine tion of opiates and no rewarding effects of opiates (reviewed reuptake transporter knockout mice, it has been found, in ref. Hemby and Smith in dopamine D1 mRNA levels, was found at the end of the and their colleagues also found a synergistic elevation of 6 days of morphine exposure (70). The mRNA levels for extracellular dopamine when cocaine was added to heroin both dopamine D1 and D2 receptors was reduced after 1 in self-administration studies (66). These findings may ex- day of withdrawal, and both returned toward normal by plain, in part, the common co-dependency in humans of the third day after drug withdrawal. These findings may be both heroin and cocaine addictions. However, curiously in this neurons completely in discrete brain regions by use of a study, but not in other studies, reductions of mRNA levels neurotoxin, 6-hydroxydopamine, self-administration of for dynorphin and enkephalin genes were found during morphine proceeded normally as in unlesioned animals. In contrast, enhanced dynorphin However, in such animals, cocaine self-administration was mRNA levels have been found at least after acute single and eliminated. Further studies will be needed to determine the time instance, in one study using the technique of in vivo fast course of dynorphin mRNA level changes during morphine cyclic voltammetry, it was found that heroin caused a dose- exposure. Trujillo, Akil, and their colleagues showed that dependent increase in dopamine in the nucleus accumbens chronic injection or infusion of morphine caused increases during heroin self-administration, and co-administration of in levels of dynorphin peptides in the dorsal striatum (cau- a -agonist (U-50,488 H) with the heroin, or alternatively, date putamen) but not in the ventral striatum (nucleus ac- intracerebroventricular administration of dynorphin A, sig- cumbens) (73). Moreover, installation of the -synthetic compound or only a few (approximately 20%) nucleus accumbens neu- natural ligand dynorphin A alone decreased basal dopamine rons seem to exhibit an inhibitory response after heroin self- release, as had also been shown by Claye and others (68). Thus, the multiple -agonist morphine activates the mesolimbic-mesocortical changes in signal transduction observed and discussed ear- dopaminergic pathway and that -opioid-receptor activa- lier, including the effects of chronic morphine administra- 35 tion offsets, or counterregulates, that activation (67). In related studies, these investigators result from a direct opiate effect or an indirect effect by found, as have numerous others, that cocaine caused a strik- alteration of the dopaminergic system (40,42). Similar find- ing increase in extracellular dopamine concentrations in the ings were made by the group of Sim-Selley, Selley, Childers, nucleus accumbens, and, moreover, the combination of co- and colleagues after chronic heroin self-administration, with caine and heroin caused a synergistic elevation (66). Their the greatest decrease in -opioid-receptor–stimulated 35 finding that heroin alone failed to cause an increase in dopa- [ S]GTP S binding in the brainstem and the lowest altera- mine in the nucleus accumbens complemented several ear- tions in binding in the striatum and cortex (42). Because lier findings that heroin self-administration is not attenu- the changes of dopamine D1-receptor activation would act ated by administration of dopamine antagonists, as well as in one direction and dopamine D2-receptor activation even earlier studies showing that integrity of dopamine would act in the opposite direction on adenylyl cyclase activ- pathways in the nucleus accumbens is not essential for her- ity, the effects on these receptors could also influence the oin self-administration.

Recently order discount cipro on-line, NRA0045 buy cipro overnight, which has potent 5-HT2A order cipro 750 mg otc, D4 cheap cipro 250 mg amex, either chemical class or pharmacologic profile. However, and 1 but no D2 or D3 receptor blockade has been found some clinical investigators find the term atypical antipsy- to have atypical antipsychotic properties (26). Partial DA chotic drug misleading because there are important clinical agonists, which may act as agonists at presynaptic DA recep- differences among the compounds with regard to the six tors, and antagonists at postsynaptic DA receptors are a new clinical features of clozapine noted above, and they prefer class of antipsychotic drugs that has promise (15,27,28). However, this temporal-based nomenclature and current data support only the view that they are atypical is not routed in any meaningful or enduring characteristic in the classic sense, i. Others prefer to call them multireceptor anti- or clinical testing at doses that produce weak or absent EPSs. It is our view that these atypical antipsychotic drug activity will be discussed subse- other designations have no specific advantages and some quently. The in vitro affinity of a drug at the DA D2 recep- Chapter 58: Mechanism of Action of Atypical Antipsychotic Drugs 821 tor is a useful predictor of the dose that produces EPSs and parable to haloperidol in their rate of dissociation from the control of positive symptoms for typical neuroleptic drugs D2 receptor and are not displaced by raclopride or iodoben- (2,29), although it does not do so for some atypical antipsy- zamide, as are clozapine and quetiapine (24). Furthermore, there is no hypothesis could not explain the basis for their low EPSs. There is little agreement even on the best dose for to support this selectivity with regard to displacement as haloperidol, the most widely used antipsychotic drug. Although there is evidence for higher occupancy of wide range of 2 to 15 mg/day has been suggested, far re- extrastriatal D2 receptors by clozapine and quetiapine in moved from the 20 to 40 mg/day thought to be most effec- patients with schizophrenia (40,41), and for atypical anti- tive in 1966 (9,10). To date, no clinically proven antipsy- psychotic drugs that show more potent 5-HT2A receptor chotic with the possible exception of amperozide lacks blockade in rodents (42), the same appears to be true for significant D2 receptor antagonist properties. As will be olanzapine, which does not show the higher off-rates of discussed, the combination of D2 and 5-HT2A receptor clozapine and quetiapine (R. Meltzer, in blockade, in the right ratio, produces some of the effects of preparation). Because clozapine produces a greater increase clozapine and other atypical antipsychotic drugs in rodents, in DA release in the cortex than in the accumbens or stria- e. There have been in these regions than the cortex, but, as noted above, this only limited tests of this hypothesis in humans, 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).

Patients usually have 1988 1989 1990 1991 1992 1993 1994 1995 type I diabetes mellitus and must have the Year physical stamina to undergo a major abdomi- nal operation 750 mg cipro mastercard. FIGURE 15-4 In some transplantation centers order generic cipro from india, the cutoff Relative proportion of simultaneous pancreas-kidney (SPK) transplantations versus cadaveric age is 50 years discount cipro online. The patient should demon- kidney transplantations in the United States order cipro amex. Despite an increasing number of SPK transplan- strate emotional and psychological stability, tations over the past 7 years, pancreas transplantation is a less com m on procedure than is and significant secondary complications of cadaveric kidney transplantation alone. Because M edicare does not pay for pancreas transplantations, recipients must use either private insurance or personal funds. EXCLUSION CRITERIA FOR 1000 PANCREAS TRANSPLANTATION SPK PTA 800 PAK Significant cardiac disease Substance abuse Psychiatric illness 600 History of noncompliance Extreme obesity Active infection or malignancy 400 No secondary complications of diabetes 200 FIGURE 15-6 The exclusion criteria for pancreas trans- 0 plantation include significant cardiac disease, 1988 1989 1990 1991 1992 1993 1994 1995 1996 substance abuse, psychiatric illness, and a history of noncom pliance. Extrem e obesity, Year active infection, and m alignancy are relative contraindications to transplantation. Patients with few or very m ild secondary com plica- FIGURE 15-7 tions of diabetes may be candidates for kidney Types of pancreas transplantation procedures and relative frequency per year (January 1988 transplantation alone. Three different indications for pancreas transplantation exist. Patients with type I insulin-dependent diabetes who require kidney transplantation m ay undergo a simultaneous pancreas-kidney (SPK) transplantation or receive a kidney transplan- tation followed by a pancreas transplantation during a separate operation (called pancreas after kidney [PAK] transplantation). Patients without significant renal disease may undergo pancreas transplantation alone (PTA). The relative proportion of the types of transplantations is shown. M ost pancreas transplantations performed in the United States are of the SPK type, followed by PAK transplantations. The portal vein of the allograft is anastomosed to the common iliac vein or distal inferior vena cava. Likewise, on the left side the renal artery and vein are anastom osed to the com m on iliac artery and vein, respectively. To restore the continuity of the urinary tract, a standard ureteroneocystostomy is constructed to the dom e of the bladder. Because the pancreas has dual endocrine and exocrine functions, it is necessary to perform another anastom osis to handle exocrine secretions. A variety of techniques to m anage pancreatic exocrine secretions have been proffered over the years with less than satisfac- tory results. These include duct occlusion, open drainage into the peritoneal cavity, and creation of a button of duodenum and anasto- mosing this or the pancreatic duct directly to the bladder. Currently, the m ost com m only perform ed technique in the United States is drainage of pancreatic exocrine secretions into the bladder (bladder drainage, BD), as depicted. The BD technique involves fashioning a short segm ent of donor duodenum , which is transplanted along with the pancreas. Then the donor duodenum is anastom osed to the dom e of the recipient bladder in a side-to-side m anner. In this way exocrine secretions, including enzym es, proenzym es, water, and sodium bicarbonate, are diverted into the urinary tract. This technique is safe, reliable, and well tolerated; however, it is associated with a num ber of specific urinary tract com plications. As a consequence of implantation into the iliac fossa, the pancreatic allograft is drained into the system ic venous circulation, as depicted. This results in systemic venous, rather than portal venous, insulin release and peripheral hyperinsulinem ia. An alternative approach practiced by som e surgeons is portal venous drainage. In this approach the portal vein of the allograft is anastomosed to the supe- FIGURE 15-8 rior mesenteric vein of the recipient in an end-to-side fashion. This Sim ultaneous pancreas-kidney allograft procedure. M ost pancreas technique establishes drainage of insulin into the portal venous transplantations perform ed in the United States are whole organ blood flow, perhaps a m ore physiologic situation (procedure not pancreaticoduodenal allografts from cadaveric donors transplanted shown). The results of the two techniques are largely com parable. Because Fortunately, patients have suffered no adverse effects of system ic the pancreas from a patient with diabetes still subserves digestive venous drainage and hyperinsulinem ia. Therefore, the pancreaticoduodenal Solitary pancreaticoduodenal allografts are im planted into either allograft is transplanted to an ectopic location, usually the right iliac fossa, at whichever point the iliac vessels perm it vascular anas- iliac fossa. Sim ilarly, the kidney allograft is transplanted ectopically tom oses. This procedure is done, usually and preferentially, on the to the contralateral iliac fossa. O therwise, the operative sequence duplicates that of the the pancreas, as shown in Figure 15-9, is anastomosed to the common com bined procedure. The donor pancreas, duodenum, and spleen are perfused in situ with cold University of W isconsin solution and harvested en bloc with the liver. The pancreaticoduodenal graft is separated from the liver graft and prepared on the surgical back table at 4oC. The spleen is first removed by ligating the splenic artery and vein. The duodenal segment is shortened to approximately 10 cm, and the suture lines are reinforced. The common bile duct (CBD) and the superior mesenteric FIGURE 15-10 artery and vein (SM A and SM V) have been ligated previously in the Enteric drainage (ED) technique. A variety of techniques exist to reconstruct the dual arterial drainage, ED is, perhaps, a m ore physiologic m ethod of handling blood supply to the pancreas. In our experience, the most favorable pancreatic exocrine secretions. ED is the preferred method in Europe approach entails using an iliac artery bifurcation graft harvested from and is rapidly gaining popularity in the United States. As shown, the external iliac arterial limb of the graft com m only, it is perform ed as depicted without a Roux-en-Y is anastomosed to the SM A, and the hypogastric arterial limb is anas- anastom osis. The donor duodenal segm ent is anastom osed in a tomosed to the splenic artery. This technique is reliable and associated side-to-side fashion to the ileum or distal jejunum. The venous anastomosis (portal vein survival, throm bosis rates, and prim ary nonfunction rates are no to iliac vein or inferior vena cava) can be performed without tension different when com paring the two techniques [1–3]. Perform ed by complete mobilization of both the donor portal vein and the recip- with expertise, both techniques should yield excellent results. A venous extension graft is rarely necessary and proba- Several significant advantages of the ED technique over bladder bly increases the risk of thrombosis. Decreased risk of perioperative intra-abdominal infections complications Less metabolic acidosis and chronic dehydration Shorter length of hospital stay secondary to less dehydration Early removal of urinary catheter and fewer UTIs Ability to perform portal venous drainage, if desired Disadvantages Disadvantages Risks of developing urologic complications in up to 25% of patients, including urethritis,? Increased risks of perioperative peripancreatic infections urethral disruption, and hematuria Difficult to diagnose pancreatic enzyme leaks Risk of recurrent UTIs greater for BD than for ED Prolonged urinary catheter drainage needed to decompress bladder anastomosis for healing Frequent postoperative admissions for dehydration and metabolic acidosis and need for bicarbonate replacement UTIs— urinary tract infections. FIGURE 15-11 Early attem pts using enteric drainage (ED) techniques resulted in recent retrospective studies have com pared BD pancreas transplants prohibitively high rates of intra-abdominal abscesses, wound infections, to ED transplants. These studies have dem onstrated equivalent and mycotic aneurysms threatening both graft and patient. Thereafter, short-term graft survival rates without increased risks of infectious bladder drainage (BD) via a duodenocystostom y evolved in the com plications and pancreatic enzym e leaks [1–3]. ED is associated United States as the safest and m ost frequently perform ed exocrine with fewer urinary tract infections (UTIs) and no hem aturia. It has been suggested that BD affords the ability Patients who have ED experience less dehydration and m etabolic to monitor urinary amylase levels as an indicator of rejection, which acidosis and, as a result, a reduced need for fluid resuscitation and may be useful in the setting of a solitary pancreas transplant. Finally, in patients who have ED in recipients of sim ultaneous pancreas-kidney (SPK) transplant in the Foley catheter can be rem oved within several days, whereas whom kidney function serves as a marker of rejection monitoring of patients who have BD require prolonged drainage (up to 14 days) urinary amylase levels is not necessary to achieve excellent long-term to permit healing of the duodenocystostomy. ED has proved As experience grew with BD, however, it was found that up to to be m ore physiologic and results in less m orbidity com pared 25% of patients with BD developed a significant urologic or metabolic with BD. Therefore, ED is rapidly gaining popularity as the com plication requiring surgical conversion of exocrine secretions to m ethod of choice for handling graft exocrine secretions in ED [4,5].