C. Volkar. College of Saint Catherine.

Ultimately 30caps diarex fast delivery, elevate mood in nondepressed healthy individuals even after only further research with each class of psychiatric treat- chronic treatment (27 purchase diarex us,28) buy discount diarex 30 caps line. Similarly, treatment with tri- ments will determine the relative utility of models that use cyclic antidepressants or SSRIs has no effect on behaviors an explicit inducing condition versus models that rely on assessing reward function in unperturbed animals. Moreover, recent findings indicated that the coadmin- istration of fluoxetine together with a relatively selective With the exception of paradigms assessing treatment effects serotonin 1A receptor antagonist had opposite effects in in nonperturbed animals, the inducing manipulations con- 'normal' rats (i. Recent ficult because the etiologies of psychiatric disorders are gen- clinical and preclinical findings have suggested that the erally unknown and are likely to be heterogeneous within coadministration of a SSRI together with a serotonin 1A each diagnostic category. Inducing conditions could be en- receptor antagonist leads to accelerated or augmented anti- vironmental manipulations, drug manipulations, lesions, depressant effects compared to those seen after treatment genetic manipulations, or combinations of the preceding. In conclusion, the study of animals that mental manipulations or factors. An inducing condition exhibit a deficit that is pathognomonic of depression, rather may be selected: (a) based on theoretic arguments about the than 'normal' healthy animals, may be critical to the study environmental and/or neurobiological factors that lead to of both the underlying pathophysiology and its treatment. For no theoretic arguments are made about the etiology of the example, known antipsychotic drugs can be identified with disorder; or (c) based on purely practical considerations reasonable predictive power using the conditioned avoid- about the predictive value of the model without theoretic ance response paradigm (42). The conditioned avoidance arguments about either the etiology of the disorder or the response paradigm has then been applied to the testing of relevance of the dependent measure to aspects of the symp- potentially novel mechanisms that may have efficacy in the tomatology characterizing the disorder. The selection of 450 Neuropsychopharmacology: The Fifth Generation of Progress each inducing condition has advantages and disadvantages lasting deficits in healthy subjects because a healthy system and is often based on the following considerations. Potential interactions, however, of probing the function of a specific receptor or neurotrans- between the environmental manipulation and a genetic pre- mitter system that either is implicated in the etiology of the disposition may lead to long-lasting behavioral or neuro- disorder or produces the desired deficit. The main disadvan- biological changes having relevance to the disorder of inter- tage of an acute drug manipulation, and often of chronic est. Finally, environmental manipulations are important to drug manipulations, is that it readily leads to 'receptor' or use and incorporate into animal models because it appears 'neurotransmitter tautology. Another advantage of environmen- receptor, as in the case of dopamine agonist–antagonist in- tal manipulations is that such manipulations are likely to teractions in most animal models of antipsychotic action. An advantage of lesion manipulations over chronic physiology and/or treatment of the disorder. Chronic drug drug manipulations is that lesions may lead to deficits and/ manipulations offer additional advantages and disadvan- or neuroadaptations in a variety of brain systems rather than tages. Chronic drug administration is likely to lead to com- just the one or few affected by a drug. A disadvantage of pensatory adaptations to the acute effects of the drug that traditional lesion manipulations is that the initial lesion ma- are likely to be longer lasting than the effects of a single nipulation in most cases is a rather large insult to a specific drug administration and to involve additional systems that brain site. Thus, the circuitry affected is dependent on the are not involved in the acute drug effects. Nevertheless, the interconnections of this specific brain site. Nevertheless, re- resulting neuroadaptations may be irrelevant to the disorder cent advances in genetic techniques are allowing very precise unless there is a relationship between the deficits induced 'lesions' (knockouts) or increased expression (knockins) of by the drug and etiology of the psychiatric symptoms. An example of a pharmacologic model is the use of the Such technological advances, when combined with more reward deficits seen during withdrawal from a variety of traditional behavioral and pharmacologic aspects of well- drugs of abuse as a model of the core symptom of 'dimin- developed models, are likely to advance our understanding ished interest or pleasure' in rewarding stimuli that charac- of psychiatric disorders. In rats, converging evidence indi- Developmental manipulations are gaining in popularity cates that withdrawal from psychostimulant drugs is primarily because there is increased awareness that many associated with reward deficits expressed as elevations in psychiatric disorders develop gradually through childhood brain reward thresholds (33,47), decreased breaking-points and adolescence and are lifelong. In some cases, investigators under a progressive ratio schedule for a sucrose reinforcer combine one of the previously discussed inducing manipu- (48), and decrements in motivation for sexual reinforcement lations with a developmental manipulation (e. The advantage of this model is the induction of deficits the inducing manipulations during development or in a in reward and motivational processes that are hypothesized genetically altered animal). For example, decreases in PPI to be, not only pathognomonic of depression, but also defi- of startle, an operational measure of sensorimotor gating cits expressed as negative symptoms of schizophrenia. Thus, deficits that are evident in patients with schizophrenia, have these paradigms focus on the study of a hypothetical con- been demonstrated to result from socially isolating rats from struct that may have relevance to core symptoms seen in weaning until after puberty (51). Social isolation of rats in multiple diagnostic categories. These deficits are most likely early stages of development has been used to produce a homologous to similar deficits seen in people abusing these variety of behavioral abnormalities that have been related drugs because the etiology of the deficit is the same in both to both schizophrenia and depression. Nevertheless, it is not shown that 6 to 8 weeks of social isolation during develop- known whether pharmacologically induced deficits in re- ment, but not during adulthood (52), produces deficits in ward and motivational processes are homologous, or just PPI that are at least partially reversible by the administration analogous, to similar deficits seen in nondrug abusing psy- of neuroleptic dopamine antagonists (51) or by clinically chiatric populations. That treatments with clinically effec- effective atypical antipsychotics having antagonist activity tive antidepressants reverse the drug-induced reward deficits at multiple receptors (53,54). Furthermore, postweaning in both rats and humans suggests that the deficits may be isolation rearing of rats also results in deficits in the gating homologous across species (32,34,38,50). Chapter 33: The Role of Preclinical Models 451 Because schizophrenia commonly emerges in early adult- stimuli and environments. Such an observation with an un- hood, developmental factors have provided the basis for known drug could as readily be interpreted as an increase some etiologic hypotheses (56,57). The fact that known anxiolytic establish a nonpharmacologic and developmentally relevant drugs increase approach behavior has provided substantive animal model of the gating deficits observed in patients with validation of approach/avoidance conflict tests for the iden- schizophrenia. Potentially, in contrast to the drug-induced tification of changes in state anxiety. Accordingly, such con- models of gating deficits, such a model might have etiologic flict tests are now being used widely in the characterization validity and might be sensitive to antipsychotic drugs having of mutant mice in attempts to identify changes in trait anxi- novel mechanisms of action. It should be recognized, however, that the validation Genetic manipulations are popular because of the recent of a measure as predictive of a change in state may or may surge of interest in genetic contributions to psychiatric dis- not validate the measure as reflective of a change in the orders. Such interest promises to enable the development conceptually related trait. That is, the observation of a shift of a class of animal models based on hypothesized etiologic in approach/avoidance behavior in a mutant mouse that is validity. As specific genes and gene products become linked similar to that produced by an anxiolytic drug cannot read- to specific disorders, molecular biologists will be able to ily support the conclusion that the mutant mouse exhibits generate mutant or transgenic animals having genetic ab- low levels of trait anxiety rather than high levels of approach normalities that are potentially homologous to those seen behavior, as in the trait of high novelty seeking. Behavioral and pharmacologic studies of these examining approach/avoidance behavior across a range of genetically engineered animals will then be important in contexts can one determine which pole of the approach/ identifying the phenotypic changes associated with the mu- avoidance conflict is altered in the mutant animal (58). The combi- Dependent Measures: Value of nation of genetic and molecular biological approaches with Analogousand HomologousMeasures behavioral and pharmacologic approaches may well revital- Across Species ize interest in etiologically based models of psychiatric disor- ders. It is important to recognize that genetic manipulations As with the choice of inducing manipulations, the choice of necessarily begin with the fetus and often lead to compensa- dependent measures is not simple when developing animal tory adaptations throughout the course of development.

D-Serine as a ketamine stimulate psychosis in schizophrenia order diarex. Neuropsycho- neuromodulator: regional and developmental localizations in pharmacology 1995;13:9–19 buy diarex 30 caps cheap. D-Serine order diarex on line, an endogenous in neuroleptic-free schizophrenics. Neuropsychopharmacology synaptic modulator: localization to astrocytes and glutamate- 1997;17:141–150. NMDAR1 subunit in Chinese hamster ovary cells fails to pro- 9. Synaptic develop- duce a functional N-methyl-D-aspartate receptor. Neurosc Lett ment of the cerebral cortex: implications for learning, memory, 1994;173:189–192. Cortical pruning and the development of schizo- human NMDA homomeric NMDAR1 receptors expressed in phrenia. Widespread cerebral tate receptors: different subunit requirements for binding of grey matter volume deficits in schizophrenia. Arch Gen Psychia- glutamate antagonists, glycine antagonists, and channel-block- try 1992;49:195–205. Excitatory amino acids and synaptic ence 1992;256:1217–1220. Divalent ion per- N-methyl-D-aspartate receptor by phencyclidine-like drugs is meability of AMPA receptor channels is dominated by the ed- influenced by alternative splicing. Neurosci Lett 1995;190: ited form of a single subunit. Interactions be- subunit mRNAs determines gating and Ca2 permeability of tween ifenprodil and the NR2B subunit of the N-methyl-D- AMPA receptors in principal neurons and interneurons in rat aspartate receptor. Ca2 permeability ization of alternative mRNA forms for the rat metabotropic of KA-AMPA-gated glutamate receptor channels depends on glutamate receptors mGluR7 and mGluR8. Metabotropic glutamate receptors: synaptic trans- ability of AMPA-type glutamate receptor channels in neocortical mission, modulation, and plasticity. Neuron 1994;13: neurons caused by differential GluR-B subunit expression. Pharmacological charac- editing, splice variation, and subunit composition. J Neurosci terization of metabotropic glutamate receptors in several types 1997;17:58–69. Developmental and re- distinct pharmacological profile. Mol Pharmacol 1997;51: gional expression pattern of a novel NMDA receptor-like sub- 119–125. Novel functions for subtypes of metabotropic 6509–6520. Signal transduction and pharmacologi- terization of NR3A: a developmentally regulated member of a cal characteristics of a metabotropic glutamate receptor, novel class of the ionotropic glutamate receptor family. Splice variants of the pharmacological characterization of the metabotropic glutamate N-methyl-D-aspartate receptor NR1 identify domains involved receptor type 5 splice variants: comparison with mGluR1. Molecular diversity of glutamate receptors and of two alternatively spliced forms of a metabotropic glutamate implications for brain function. Serine racemase: a glial calcium release in Xenopus oocytes. Proc Natl Acad SciUSA enzyme synthesizing D-serine to regulate glutamate-N-methyl- 1992;89:10331–10335. Chapter 52: Neurochemistry of Schizophrenia: Glutamatergic Abnormalities 727 45. Pharmacology and functions of metabotropic and KA2 transcripts in schizophrenia. Functional coupling of kainate receptor expression in prefrontal cortex in schizophre- rat group II metabotropic glutamate receptors to an omega- nia. Reversal of phencyclidine effects J Neurochem 1989;52:1781–1786. NMDA receptor tors GluR1 and GluR2 in medial temporal lobe neurons in mRNA correlation with antemortem cognitive impairment in schizophrenia. Immunoautoradio- loss of cerebral cortical sigma, but not PCP binding sites, in graphic evidence for a loss of alpha-amino-3-hydroxy-5-methly- schizophrenia. Alterations in glutamate receptors within the medial temporal lobe in schizo- phencyclidine and sigma binding sites in schizophrenic brains. Increases in strychnine- type expression in human postmortem brain tissue from schizo- insensitive glycine binding sites in cerebral cortex of chronic phrenics and alcohol abusers. Increased tion in normal and schizophrenic brain post mortem. Neurosci- density of glutamate/N-methyl-D-aspartate receptors in puta- ence 1990;39:25–32. Expression of the human units in subregions of human hippocampus: effects of schizo- excitatory amino acid transporter 2 and metabotropic glutamate phrenia. Mol Brain Res 1998;56: binding and subunit mRNA expression in prefrontal cortex and 207–217. Richardson-Burns SM, Haroutunian V, Davis DL, et al. The family of sodium-dependent glutamate der, and major depressive disorder. Glycine uptake governs [3H]AMPA binding in postmortem human brain from psy- glycine site occupancy at NMDA receptors of excitatory syn- chotic subjects and controls: increases in caudate nucleus associ- apses. Expression of NMDAR1, GluR1, GluR7, and KA1 methyl-D-aspartate receptor function by glycine transport. Proc glutamate receptor mRNAs is decreased in frontal cortex of Natl Acad SciUSA1998;95:15730–15734. Reversal of phencycli- ulation of typical neuroleptics. J Neurochem 1998;71: dine-induced hyperactivity by glycine and the glycine uptake 2454–2564. Control of NMDA receptor activa- pharmacol 1992;2:241–243.

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Since prior Together discount 30 caps diarex amex, these findings provide strong evidence that the treatment with morphine intensifies its rewarding actions increase in cocaine sensitivity seen in FosB transgenic mice in the place-conditioning paradigm (33) trusted 30caps diarex, these data suggest is attributable discount diarex 30 caps free shipping, at least in part, to elevated expression of that the behavioral consequences of morphine preexposure GluR2 in the NAc. Rats given mi- in motivational states can result from altered expression of croinjections of HSV-GluR1 into the NAc spent dramati- a single, localized gene product. Drug-related increases in cally less time than control rats in the cocaine-associated GluR1 expression in the VTA, a region known to be in- environments, suggesting that elevated expression of this volved in the induction of sensitization (42,44), may them- AMPA receptor subunit in this region increases sensitivity selves be sufficient to explain sensitization (13,41), or they 2 to the aversive effects of the drug. Additionally, some rats may lead to Ca -dependent adaptations (45) that also con- were tested after intra-NAc microinjections of HSV- tribute to changes in drug sensitivity (Fig. This form of studies have added strength to the hypothesized association GluR2 lacks the final transcriptional edit (Q N R) that between the VTA and sensitization, and identified biobe- 2 produces the motif that blocks Ca flux (38,39). Use of havioral relevance for the drug-induced regulation of the this construct showed that the ability of GluR2 to increase GluR1 protein in the VTA. First, GluR2 is a target gene of FosB, a stable Ca2 flux in the NAc might influence drug reward, consid- and long-lasting variant of the fos family of transcription ering the role of Ca2 in cellular functions including mem- factors that is regulated in the Nac by drugs of abuse (46). Certainly, cocaine-induced sensitized rats during long-term drug withdrawal (47). Studies with FosB (46) sug- Dose-response analyses revealed that microinjections of gest that these electrophysiologic adaptations are associated HSV-mCREB and HSV-CREB in the NAc were produc- with increases in the rewarding efficacy of cocaine, because ing, respectively, approximately parallel leftward (more re- elevations in GluR2 expression (which would be expected to warding) and rightward (less rewarding) shifts in the effects minimize Ca2 flux and/or neuronal excitability) increase of cocaine. At a high dose of cocaine, there were no differ- cocaine reward, whereas elevations in GluR1 (which would ences in the preferences for the drug-associated environment be expected to increase Ca2 flux and/or neuronal excitabil- between rats given HSV-mCREB and those given vehicle, ity) decrease (or oppose) cocaine reward. Treatment with high doses of cocaine established place NAc has important consequences on motivated behaviors preferences in some rats given HSV-CREB, suggesting that (Fig. Moreover, they suggest that altered GluR1 the aversive consequences of increased levels of CREB in expression in this region seen during long-term (3-week) the NAc can be counteracted by more drug. Re- expression in the NAc increases local dynorphin function. To determine if dy- norphin is involved in the cocaine aversion caused by HSV- CREB, brain receptors for dynorphin were blocked with CREB in the NAc the long-lasting receptor antagonist norBNI. Treatment Chronic cocaine exposure increases 3′,5′-cyclic adenosine with norBNI [intracerebroventricular (ICV)] before cocaine monophosphate (cAMP) formation and protein kinase A place conditioning blocked the aversive effects associated (PKA) activity in the NAc (37). Direct stimulation of PKA with cocaine in animals given HSV-CREB into the NAc, in the NAc counteracts the rewarding properties of cocaine but not in rats given microinjections of vehicle or HSV- (56), suggesting that drug-induced up-regulation of the mCREB. The fact that only the aversive properties of co- cAMP system is a neural mechanism of drug tolerance. In- caine are altered significantly by nor-Binaltorphimine (nor- creased PKA activity leads to increased CREB phosphoryla- BNI) suggests that microinjections of HSV-CREB into the tion, which activates CREB-mediated gene transcription NAc enhance the aversive aspects of cocaine via increased and could be an important step in producing long-lasting stimulation of opioid receptors by dynorphin. To determine the functional role of These results suggest that drug-induced increases in CREB and its transcriptional consequences in the NAc, its CREB activity (62) is a homeostatic change that opposes expression in this region was increased directly by microin- drug reward. Mimicking increases in CREB activity by in- jecting HSV-CREB (57). In other rats, a dominant negative creasing levels with HSV-CREB or by stimulating PKA- mutant CREB (mCREB) was overexpressed, which is tran- induced phosphorylation (56) decreases the rewarding ef- scriptionally inactive and competes with endogenous CREB fects of cocaine. Moreover, these data implicate opioid for cAMP response element binding sites (CREs) (58). These data also suggest not altered by control treatments, this dose established dra- matic conditioned place preferences in rats given bilateral a sequence of D1 receptor–mediated intracellular events, microinjections of HSV-mCREB (which acts as a CREB culminating with altered gene transcription, through which antagonist) into this region. Augmented release of dynorphin could inhibit in the NAc; rats given HSV-CREB avoided drug-associated local DA release through actions at opioid receptors on environments, suggesting that this dose of cocaine was made terminals of mesolimbic DA neurons that innervate the aversive by gene transfer. Diminished release of dopamine in the NAc may a week (rather than 3 days) after microinjections of the HSV itself be aversive, or it may unmask other actions of cocaine vectors into the NAc, cocaine was devoid of rewarding or that are aversive or that oppose drug reward. This finding confirms that the behavioral these viral vector studies have identified biobehavioral rele- consequences of HSV viral vectors are transient and reversi- vance for alterations in CREB function in the NAc. Fourth, because of the small volume of material that can be delivered stereotactically, it will be necessary to increase both the viral titers and the transduction efficiencies for all the known vectors. Fifth, a high degree of cell specificity of gene transfer must be achieved, by the use of targeted vectors that selec- tively infect particular cell types, cell-specific promoters, and routing via normal neuronal projections in the brain. Fi- nally, nontoxic vectors that do not induce an immune re- sponse must be developed. The development of gene therapy for neuropsychiatric FIGURE 20. Elevated dynorphin, in turn, decreases cocaine reward at high doses of drug, and makes cocaine aversive pose particular problems for gene therapy because neurons at low doses of drug. Conversely, disruption of CREB activity by in the CNS cannot undergo regeneration. Therefore, gene overexpression of dominant-negative CREB (mCREB)decreases therapeutic approaches must target the remaining brain dynorphin transcription, which increases cocaine reward. Another set of hurdles arises from the complex etiology of most neuropsychiatric disease. It is not clear that a single gene product will cure any of these diseases. In addition, the molecular mechanisms Conclusions of different neuropsychiatric diseases may be restricted to The use of viral-mediated gene transfer in addiction research subsets of neurons at specific times during development and is leading to an understanding of where certain changes in maturity. Consequently, as noted above, optimal strategies gene expression occur within the cascade of molecular events for gene therapy must utilize vectors that persist stably in that lead to the addicted phenotype. This approach comple- postmitotic cells and that can be targeted both spatially and ments and extends the predominantly pharmacologic ap- temporally in the nervous system. These therapeutics may be the prototypes for a new generation of We thank Dr. REFERENCES GENE DELIVERY INTO THE BRAIN AS A MEANS FOR GENE THERAPY 1. Genetic engineering of AOR1 genomes of large DNA virus. Gene transfer to neurons The recent rapid advancements in gene transfer technologies using herpes simplex virus-based vectors. Annu Rev Neurosci have raised hopes that central nervous system (CNS) gene 1996;19:265–287. The herpes simplex virus amplicon: a new rate neuropsychiatric diseases, is closer to reality. Propagation of foreign DNA sequences before it can become a reality. First, and most important, linked to a herpes simplex virus origin of replication.

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Rapidly absorbed order genuine diarex on line, naltrexone reaches peak plasma Background levels between 60 and 90 minutes buy generic diarex. Naltrexone undergoes The role of the alcohol-induced activation of the endoge­ first-pass hepatic metabolism buy generic diarex 30 caps line, and there is some evidence nous opioid system in the reinforcing effects of alcohol has of dose-related hepatotoxicity at doses four to five times been well established in dozens of animal models of alcohol higher than the currently recommended 50-mg daily dos- Chapter 101: Alcoholism Pharmacotherapy 1447 age. In alcohol-dependent patients, adverse events reported riod. Samples have been composed primarily of male sub­ by at least 2% of those participating in an open-label safety jects (ranging from 71% to 100%) without other complicat­ study were nausea (10%), headache (8%), dizziness (4%), ing psychiatric or substance abuse problems, although there nervousness (4%), fatigue (4%), insomnia (3%), vomiting have been smaller studies in specialized populations, includ­ (3%), anxiety (2%), and somnolence (2%) (45). In addition ing those who use cocaine and alcohol (53) and older alco­ to these new-onset adverse events, naltrexone is contraindi­ holics (50). The behavioral interventions provided in con- cated for patients who are currently opioid dependent, are junction with naltrexone include day-hospital treatment, in acute opioid withdrawal, or require opioid analgesics for cognitive behavioral therapy, and supportive therapy. These management of pain, and those with acute hepatitis or liver studies have tested the efficacy of a 50-mg daily dose against failure. Special considerations are involved in the manage­ placebo; although several studies in progress are evaluating ment of medical emergencies requiring pain management the utility of higher doses (e. Although there majority of studies, which have found naltrexone to be supe­ has been little formal research on drug–drug interactions, rior to placebo in treatment outcomes, have initiated treat­ with the exception of opiate-containing medications, sub­ ment in subjects following a period of abstinence ranging jects on naltrexone who were on concurrent treatment with from 5 to 7 days (46–48,51). Other ongoing studies are antidepressant therapy did not experience any increase in testing whether an opioid antagonist can be effectively used adverse events relative to those not on antidepressant ther­ in a treatment sample to help subjects reduce and possibly apy in the aforementioned safety trial. The most consistent finding in the studies of alcohol- Efficacy dependent subjects is that naltrexone decreases the risk of Naltrexone is currently approved for use in the treatment drinking at hazardous levels and the percentage of drinking of alcoholism in the United States, Canada, and many Euro­ days. In three studies, this finding was observed in the over- pean and Asian countries. The efficacy of naltrexone has all sample (46,48,51), and an additional investigation found been tested in several double-blind placebo controlled trials that naltrexone significantly reduced hazardous drinking in (Table 101. In contrast, no evidence of efficacy was with one study (52) reporting on a 6-month follow-up pe- found in a recent randomized study (54) comparing pla- TABLE 101. DOUBLE-BLIND, PLACEBO-CONTROLLED TRIALS OF OPIOID ANTAGONISTS 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. CBT, cognitive behavioral treatment; NR, result not reported. In this inves­ rates of nausea have been noted in alcohol administration tigation, naltrexone therapy was associated with a higher studies in non–alcohol-dependent subjects maintained on incidence of adverse effects, poorer medication compliance, naltrexone, suggesting that naltrexone may make alcohol and greater attrition than placebo, leading the authors to more aversive in some subjects, particularly at higher doses suggest that adverse events may limit the effectiveness of of alcohol and naltrexone (63). Interestingly, nausea in interaction with one is unknown, efficacy data are available for 12 weeks. A alcohol has not been a common complaint in the clinical 6-month follow-up study (55) found that subjects who had trials. This suggests that these alcohol-dependent individu­ originally been treated with naltrexone for 12 weeks were als either may be less vulnerable to nausea or may limit less likely to experience a day of heavy drinking during the their alcohol intake (both the rate of consumption and the follow-up period or to meet criteria for a diagnosis of alcohol amount consumed) to levels that do not cause nausea in dependence than subjects treated with placebo during that interaction with naltrexone. However, there was evidence that the effects treatment is associated with reduced speed of drinking and of naltrexone appeared to decline over time, raising the the number of drinks consumed has been obtained using ad question of whether longer-term therapy may be needed. Evidence that naltrexone In this regard, initial evidence supporting the potential value reduces craving or urge to drink is also accruing from this of longer-term naltrexone therapy for some patients has body of research (63,64). Nalmefene, a newer opioid antagonist that is structurally similar to naltrexone, has also been reported to reduce the Summary risk of relapse to heavy drinking. In a 3-month double- The evidence suggests that naltrexone 50 mg daily is effica­ blind pilot study, there was initial evidence of reduced risk cious in reducing the risk of heavy drinking and in increas­ of heavy drinking among subjects treated with 40-mg doses ing the percentage of days abstinent. Although the hypothe­ of nalmefene compared to 10-mg or 0-mg doses (49). In a sized effect of naltrexone on reduction of craving has been larger double-blind study (56) in which patients were ran­ somewhat elusive in the clinical trials, laboratory studies domized to placebo, 20 mg daily or 80 mg daily, lower provide support for this hypothesis. Additional studies are relapse rates were observed for patients treated with nalmef­ under way to test the optimal duration of therapy and the ene (combined across the 20-mg and 80-mg doses). Although the side-effect profile Since the initial published reports of naltrexone for use of naltrexone is acceptable, efforts to minimize adverse in alcoholism, several smaller studies have been conducted events should be investigated given that these events are evaluating its potential in special populations of alcoholics. Pending additional research with larger samples at Ethanol has also been shown to alter levels of, and have higher doses, naltrexone treatment does not appear indi­ high affinity for receptors of, two other neurotransmitters, cated for the management of individuals with concurrent glutamate and GABA. In vitro studies indicate that ethanol cocaine and alcohol use disorders. A small study in older inhibits function of the glutamatergic N-methyl-D-aspartate alcohol-dependent men suggests that it may be efficacious (NMDA) receptor by inhibiting ion flux through this iono­ (50), and in an open-label trial it was found to be helpful tropic receptor. Both in vitro and preclinical in vivo studies for adolescents (58). Microinjections of mechanisms underlying this effect. In the clinical trials, al­ glutamate antagonists into the nucleus accumbens of rats cohol-dependent subjects retrospectively reported feeling not dependent on alcohol has been shown to significantly less 'high' (59) and lower levels of craving and incentive to decrease self-administration of alcohol. Fixed alcohol dose administration ies, chronic alcohol administration results in an up-regula­ studies in non–alcohol-dependent subjects suggest that nal­ tion of NMDA receptors, and NMDA antagonists given trexone may attenuate some of the positive mood altering during withdrawal from alcohol have been shown to sup- effects (e. High creased cerebrospinal fluid (CSF) levels of glutamate during Chapter 101: Alcoholism Pharmacotherapy 1449 ethanol withdrawal may be associated with the development 0 to 12 months following the discontinuation of therapy of seizures, and that repeated withdrawals increases the risk (Table 101. Similarly, ethanol has also been shown to modu­ The treatment period generally began following comple­ late the GABA system particularly GABAAreceptor func­ tion of inpatient detoxification. Chronic administration of ethanol results in decreases studies typically adjusted the dose of acamprosate for body in the messenger RNA (mRNA) and protein for the � sub- weight, whereas more recent studies have used a fixed dose unit of the GABAAreceptor. GABA levels are also found of 1,998 mg/day, 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.

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