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Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist with psychotogenic and dissociative effects in healthy humans. These cognitive and perceptual effects in humans are reportedly reduced by benzodiazepine premedication. This study assessed the interactive effects of a ketamine (i.v. bolus of 0.26 mg/kg followed by an infusion of 0.65 mg/kg per hour) and lorazepam 2 mg., PO, in humans. Twenty-three healthy subjects completed 4 test days involving the oral administration of lorazepam or matched placebo 2 h prior to the i.v. infusion of ketamine or placebo. Ketamine: 1) produced behaviors similar to the positive and negative symptoms of schizophrenia as assessed by the Brief Psychiatric Rating Scale (BPRS); 2) evoked perceptual alterations as measured by the Clinician-Administered Dissociative States Scale (CADSS); 3) impaired performance on the Wisconsin Card Sorting Test (WCST) and other tests sensitive to frontal cortical impairment; and 4) had amnestic effects. Lorazepam produced attention impairments, concrete proverb interpretations, and recall impairments. Lorazepam reduced ketamine-associated emotional distress and there was a non-significant trend for it to decrease perceptual alterations produced by ketamine. However, it failed to reduce many cognitive and behavioral effects of ketamine, including psychosis. Further, lorazepam exacerbated the sedative, attention-impairing, and amnestic effects of ketamine. There was no evidence of pharmacokinetic interaction between these medications. These data suggest that subhypnotic lorazepam and ketamine show a spectrum of interactive effects, ranging from antagonism to potentiation.

Antagonists of the N-methyl-D-aspartate ( Lamotrigine; Serotonin; 5-HT2A; LY354740; M100907; MDL 100,907 The field of schizophrenia research is rapidly moving from a focus on the contributions of single neurotransmitters or brain regions toward an appreciation of the interactions of multiple neurotransmitter systems, neural networks, and intracellular mechanisms (Aghajanian and Marek 1999;Carlsson et al. 1997;Krystal et al. 1999b). Investigators are abandoning oversimplified dopaminergic models suggesting that all activation is detrimental to symptoms in schizophrenic patients. Instead, optimal levels of stimulation of particular dopamine-receptor subtypes are needed to sustain behavior and higher cognitive functions (Arnsten 1997;Goldman-Rakic and Selemon 1997 shortcomings of both typical and atypical neuroleptics (Meltzer 1997). As a result, it is now timely to consider the possibility that the next era in medications development for treating schizophrenia will involve mechanisms other than dopamine-2 (D 2 )-receptor antagonism. This review highlights a novel perspective on the neurobiology and treatment of schizophrenia growing from the study of the effects of the N-methyl-D-aspartate (NMDA) glutamate-receptor antagonists in animals and humans. It considers parallels between the transient symptomatic effects of single doses of NMDA antagonists in healthy human subjects and findings in schizophrenic patients. It then highlights similarities between disturbances in information processing produced by NMDA antagonists and deficits observed in schizophrenic patients. Next, this review attempts to provide some insights into mechanisms that link NMDA-receptor antagonism to glutamatergic activation and information-processing deficits. This review then summarizes evidence that dopaminergic systems have limited contributions to positive and negative symptoms produced by NMDA antagonists. Finally, it considers the utility of facilitation of the glycine-B site of the NMDA-receptor complex and drugs that attenuate glutamate release as pharmacotherapies for schizophrenia based on their capacity to attenuate the effects of NMDA antagonists in animals and humans. Because glutamate has both neurotrophic and neurotoxic effects in the brain, potential implications of glutamatergic pharmacotherapies for the course of schizophrenia is considered. PARALLELS BETWEEN NMDA-ANTAGONIST EFFECTS IN HEALTHY SUBJECTS AND SCHIZOPHRENIC PATIENTSLuby and his colleagues coined the term "schizophrenomimetic" to describe the striking similarities between the effects of phencyclidine (PCP), and the symptoms of schizophrenia (Luby et al. 1959). The identification of NMDA-receptor antagonism as the mechanism of action of PCP, the implication of NMDA receptors in many fundamental aspects of neural plasticity and neurotoxicity, and reports of altered glutamate-receptor binding in postmortem tissue from schizophrenic patients rekindled interest in the effects of PCP (Anis et al. 1983;Krystal et al. 1999b;Madison et al. 1991;Rothman and Olney 198...

The γ-aminobutyric acid-A (GABAA) and N-methyl-D-aspartate (NMDA) receptors mediate aspects of the behavioural effects of alcohol. Prior studies reported drugs that block NMDA receptors or facilitate GABAA receptor function produce ethanol-like effects in humans. The purpose of this study was to compare the ethanol-related effects of two pharmacological agents with known NMDA and GABAA receptor activity. As part of an ongoing, larger study, 28 subjects (age, 21–30) with no personal or family histories of alcoholism were administered subanesthetic doses of the GABAA receptor agonist thiopental, the NMDA receptor antagonist, ketamine and placebo on three separate test days. Various ethanol-related measures were administered. At doses of thiopental and ketamine that produced similar levels of sedation and cognitive effects, both agents produced significant ethanol-like effects and subjective intoxication. However, the intensity of the ethanol-like effects of ketamine was greater than that of thiopental. In addition, ketamine produced alterations in perception that were not produced by thiopental. These data provide further support for a model where GABAA receptor facilitation may contribute significantly to ethanol effects associated with social drinking, whereas NMDA receptor antagonism may contribute to relatively greater extent to features of ethanol ‘intoxication’.

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Background Psychiatric comorbidity is common among individuals with addictive disorders, with patients frequently suffering from anxiety disorders. While the genetic architecture of comorbid addictive and anxiety disorders remains unclear, elucidating the genes involved could provide important insights into the underlying etiology. Methods Here we examine a sample of 1284 Mexican-Americans from randomly selected extended pedigrees. Variance decomposition methods were used to examine the role of genetics in addiction phenotypes (lifetime history of alcohol dependence, drug dependence or chronic smoking) and various forms of clinically relevant anxiety. Genome-wide univariate and bivariate linkage scans were conducted to localize the chromosomal regions influencing these traits. Results Addiction phenotypes and anxiety were shown to be heritable and univariate genome-wide linkage scans revealed significant quantitative trait loci for drug dependence (14q13.2–q21.2, LOD = 3.322) and a broad anxiety phenotype (12q24.32–q24.33, LOD = 2.918). Significant positive genetic correlations were observed between anxiety and each of the addiction subtypes (ρg = 0.550–0.655) and further investigation with bivariate linkage analyses identified significant pleiotropic signals for alcohol dependence-anxiety (9q33.1–q33.2, LOD = 3.054) and drug dependence-anxiety (18p11.23–p11.22, LOD = 3.425). Conclusions This study confirms the shared genetic underpinnings of addiction and anxiety and identifies genomic loci involved in the etiology of these comorbid disorders. The linkage signal for anxiety on 12q24 spans the location of TMEM132D, an emerging gene of interest from previous GWAS of anxiety traits, whilst the bivariate linkage signal identified for anxiety-alcohol on 9q33 peak coincides with a region where rare CNVs have been associated with psychiatric disorders. Other signals identified implicate novel regions of the genome in addiction genetics.

Two previous large genetic linkage studies in the US population have implicated an area in chromosome 1p to contain a susceptibility gene for alcohol dependence. The 1-LOD support interval of the linkage signal spans about 30 cM and contains 430 000 000 DNA base pairs (bp) and 700 predicted genes. In order to reduce the size of the candidate area and potentially identify novel candidate genes within this region, we fine-mapped this area using closely spaced short tandem repeat (STR) markers and the transmission disequilibrium test (TDT) in small nuclear families. The subjects were 87 European-American families including one or more alcohol-dependent offspring (93 children and 174 parents). The initial marker set consisted of 30 STR markers, spanning the Marshfield map interval between 101.48 and 130.73 cM. Using the TDTPHASE program, we identified three markers in the distal part of this region (125-126 cM), which showed evidence of transmission disequilibrium. On the basis of this result, an additional 12 STR markers were genotyped in this region; some of these markers provided additional evidence for linkage disequilibrium. The strongest evidence for transmission disequilibrium was obtained at the marker D1S406 (P¼0.005, 126.16 cM), with supporting evidence from three neighboring STR markers D1S424 (126.16 cM, P¼0.01), D1S2804 (126.16 cM, P¼0.04), and D1S2776 (126.16 cM, P¼0.02), which are all located within a o350 000 bp interval. These findings suggest that a gene (or genes) causing susceptibility to alcohol dependence resides near location 126.16 cM on chromosome 1. In addition, these results provide independent confirmation of the linkage finding regarding the identification of at least one gene in this region increasing the risk for alcohol dependence.

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