D. Cyril D’Souza

Dissociation of ketamine effects on rule acquisition and rule implementation: possible relevance to NMDA receptor contributions to executive cognitive functions.

BACKGROUND The demands of the Wisconsin Card Sorting Test (WCST) change with experience. This report contains two studies designed to examine N-methyl-D-aspartate (NMDA) receptor contributions to the executive components of WCST performance. These aspects of WCST performance figure more prominently in the initial completion of this task than in subsequent task repetitions in healthy populations. METHODS In the first study, healthy subjects (n = 15) completed the WCST on two occasions separated by 1 week. In the second study, healthy subjects (n = 22) completed two test days spaced by approximately 1 week, during which, they completed the WCST and other assessments after administration of the NMDA antagonist ketamine (intravenous bolus 0.26 mg/kg followed by infusion of 0.65 mg/kg/hour) or matched placebo. RESULTS In the first study, subjects reduced the number of total and perseverative errors with a single repetition of the WCST. In the second study, ketamine significantly increased the number of total errors and the number and percent of perseverative errors on the first, but not the second test day. Similarly, it reduced the number of category criteria met on the first, but not second test day. Ketamine also increased distractibility, impaired recall, produced psychosis, altered perception, and had effects resembling the negative symptoms of schizophrenia. However, only WCST performance showed order dependency. CONCLUSIONS This order dependency further implicates NMDA receptors in executive cognitive functions associated with the frontal cortex.

Potential Psychiatric Applications of Metabotropic Glutamate Receptor Agonists and Antagonists

Drugs acting at metabotropic glutamate receptors (mGluRs) are among the most promising agents under development for the treatment of psychiatric disorders. The research in this area is at a relatively early stage, as there are no drugs acting at mGluRs that have been approved for the treatment of any psychiatric disorder. However, in the areas of schizophrenia, anxiety disorders and mood disorders, research conducted in animal models appears to translate well into efficacy in human laboratory-based models of psychopathology and in preliminary clinical trials. Further, the genes coding for mGluRs are implicated in the risk for a growing number of psychiatric disorders. This review highlights the best studied mGluR strategies for psychiatry, based on human molecular genetics, studies in animal models and preliminary clinical trials. It describes the potential value of mGluR2 and mGluR5 agonists and positive allosteric modulators for the treatment of schizophrenia. It also reviews evidence that group II mGluR agonists and positive allosteric modulators as well as group I mGluR antagonists might also treat anxiety disorders and some forms of depression, while mGluR2 and group I mGluR antagonists (particularly mGluR5 antagonists) might have antidepressant properties. This review also links growing insights into the role of glutamate in the pathophysiology of these disorders to hypothesized mGluR-related treatment mechanisms.

The vulnerability to alcohol and substance abuse in individuals diagnosed with schizophrenia.

Individuals with schizophrenia are at increased risk for developing substance abuse disorders. Here, we consider factors that might elevate their risk for substance abuse. The tendency among schizophrenic individuals to overvalue drug-like rewards and to devalue the potential negative consequences of substance abuse may be a contributing factor to their substance abuse risk. This bias, which may partly reflect the convergence of glutamatergic and dopaminergic input to the limbicstriatum, also may contribute to disadvantageous decision-making and other impulsive behavior. This propensity to seek drug-like rewards is augmented by alterations in nicotinic cholinergic, GABAergic, glutamatergic, and cannabinnoid receptor function associated with schizophrenia that increase the abuse liability of low doses of nicotine,ethanol, and perhaps cannabis, and augment the dysphoric effects of higher doses of ethanol and cannabis. The distortions in reward processing and altered response to substances of abuse also increase the likelihood that individuals with schizophrenia will self-medicate their subjective distress with abused substances. The focus on distinctions between motivation and reward with respect to substance abuse risk by schizophrenic patients suggests a need for a reconsideration of the construct of “negative symptoms” for this duallydiagnosed patient group.

Symptom provocation studies in psychiatric disorders: scientific value, risks, and future.

Several lines of investigation have contributed to the increasing recognition of the biological basis of psychiatric disorders. Symptom provocation studies have made important contributions toward this. With the emergence of novel methodologies, the role of symptom provocation studies has come under increasing scrutiny and debate. The scientific contributions and risks of symptom provocation studies are discussed using the psychostimulant paradigm in schizophrenia research as the prototypical study. The application of studies in other areas of medicine that carry risks similar to those associated with symptom provocation studies, are also reviewed. The authors draw on the parallel of cardiac stress testing to highlight risks: benefits issues. Finally, the authors discuss the future of symptom provocation studies and emphasize that these studies will need to meet the highest scientific standards, ethical standards and safeguards.

In Vivo Evidence for β2 Nicotinic Acetylcholine Receptor Subunit Upregulation in Smokers as Compared With Nonsmokers With Schizophrenia

BACKGROUND Schizophrenia is associated with very high rates of tobacco smoking. The latter may be related to an attempt to self-medicate symptoms and/or to alterations in function of high-affinity β2-subunit-containing nicotinic acetylcholine receptors (β2*-nAChRs). METHODS Smoking and nonsmoking subjects with schizophrenia (n=31) and age-, smoking-, and sex-matched comparison subjects (n=31) participated in one [123I]5-IA-85380 single photon emission computed tomography scan to quantify β2*-nAChR availability. Psychiatric, cognitive, nicotine craving, and mood assessments were obtained during active smoking, as well as smoking abstinence. RESULTS There were no differences in smoking characteristics between smokers with and without schizophrenia. Subjects with schizophrenia had lower β2*-nAChR availability relative to comparison group, and nonsmokers had lower β2*-nAChR availability relative to smokers. However, there was no smoking by diagnosis interaction. Relative to nonsmokers with schizophrenia, smokers with schizophrenia had higher β2*-nAChR availability in limited brain regions. In smokers with schizophrenia, higher β2*-nAChR availability was associated with lower negative symptoms of schizophrenia and better performance on tests of executive control. Chronic exposure to antipsychotic drugs was not associated with changes in β2*-nAChR availability in schizophrenia. CONCLUSIONS Although subjects with schizophrenia have lower β2*-nAChR availability relative to comparison group, smokers with schizophrenia appear to upregulate in the cortical regions. Lower receptor availability in smokers with schizophrenia in the cortical regions is associated with a greater number of negative symptoms and worse performance on tests of executive function, suggesting smoking subjects with schizophrenia who upregulate to a lesser degree may be at risk for poorer outcomes.

The Emerging Neurobiology of Dissociative States

Sensory perception often appears to be a fixed process that produces an exact transcription of the world. This view conflicts with the increasingly well-characterized distortions in perception, identity, and memory that are commonplace in everyday life (Krystal et al., 1995; Ray 1996). Generally, modest levels of stress distort perception in a manner that optimizes information processing. For example, stress may enhance the focusing of attention and the efficiency of several cognitive processes at the expense of reduced processing of peripheral stimuli in the environment. As stress becomes extreme, gross perceptual distortions emerge, including illusions and hallucinations. These perceptual alterations may occur in association with identity-related disturbances such as derealization and depersonalization. Equally profound perceptual alterations take place as people fall asleep or undergo prolonged sensory deprivation.

Alcohol and Glutamate Neurotransmission in Humans

Ethanol has multiple specific targets in the brain that combine to yield a complexly nuanced psychoactive agent (1). However, the study of glutamatergic targets of ethanol have been a recent development (2). The recency of these clinical studies may be surprising. Glutamate is the most prevalent excitatory neurotransmitter in the cerebral cortex and it mediates most output of the cortex and limbic system (3). Also, the N-methyl-D-aspartate (NMDA) subtype of glutamate receptor is among the highest-affinity targets of ethanol inthe brain (4). This chapter will provide an introduction to studies indicating that NMDA receptor blockade contributes to the behavioral effects of ethanol in humans. In doing so, it will provide clinical insights into the neurobiology of the rewarding and dysphoric effects associated with the blockade of NMDA receptors by ethanol. This chapter will then describe evidence of glutamatergic dysregulation in ethanol-dependent patients. In doing so, it will emphasize the hypothesis that ethanol tolerance may be associated with alterations in the reward valence of the NMDA antagonist component of ethanol action. It will also describe evidence that the familial vulnerability to alcoholism may be associated with alterations in NMDA receptor function that promote its use.