Current Neuropharmacology - Volume 1, Issue 4, 2003

Smooth pursuit (SPEM) and antisaccade eye movements have been studied to elucidate the genetics and the pathophysiology of schizophrenia. In recent years, a rapidly growing literature has emerged on pharmacological influences on eye movements. This review focuses on pharmacological studies of the SPEM and antisaccade tasks with relevance to schizophrenia and aims to answer the particular questions: (1) whether pharmacological compounds with relevance to the treatment or pathophysiology of schizophrenia affect performance, and (2) whether SPEM or antisaccade measures may be useful in the development of novel therapeutic targets for this illness. We conclude that (i) short- or medium-term typical antipsychotic treatment of schizophrenia patients has no or little effect on either measure, (ii) treatment with clozapine appears to impair SPEM, (iii) treatment with risperidone and 5-HT2 antagonists improves schizophrenia patients' antisaccade error rate deficit, (iv) anticholiner gics, ofte n use d to contr ol extr apyra midal symptoms induc ed by typical a ntipsychotics, may w orsen pe rf ormance, ( v) be nzodiaze pines impa ir SPEM and antisacc ade per for ma nce in hea lthy individuals, (vi) nicotine, selfadministered via cigarette smoking or given via experimental procedures, improves SPEM and antisaccade performance, and (vii) SPEM has the potential to be a useful phenotype for the ketamine model of psychosis, with implications for antipsychotic drug development. Finally, we discuss methodological issues pertaining to the study of eye movements in pharmacological and genetic schizophrenia research and suggest that the SPEM and antisaccade tasks may be profitably used in the development of antipsychotic drugs.

Parkinson's disease is a neurodegenerative movement disorder caused by a combination of environmental and genetic factors. Recent human genetic studies have identified five genes that are linked to Parkinson's disease (PD): α-synuclein, parkin, UCH-L1, DJ-1 and NR4A2. Among these genes, a variety of mutations in the human parkin locus have been found in many PD cases, both familial and sporadic. Parkin appears to be the most prevalent genetic factor in PD. It encodes for a protein-ubiquitin E3 ligase, whose loss-offunction mutations cause specific degeneration of dopamine (DA) neurons in substantia nigra in human patients. The accumulation of parkin substrates is thought to be the key factor in the selective death of DA neurons. Rapid progress in the identification of these substrates and the generation of genetic animal models has produced a plethora of knowledge about the biological function of parkin and its role in PD. These studies also offer novel pharmacological targets for the development of more selective therapeutic strategies. In this review, I will summarize results from this fast expanding field and discuss their potential implication in the treatment of Parkinson's disease.

The ability to adapt to stress is an important defensive function of a living body, and impairment of this ability may contribute to some stress-related disorders. Thus, the examination of brain mechanisms involved in stress adaptation could help to pave the way for new therapeutic strategies for stress-related affective disorders, such as anxiety and depression. The present review focuses on the roles of brain serotonin (5-hydroxytryptamine; 5-HT) neuronal systems, and especially 5-HT1A receptors, on the development of stress adaptation. Although animals exposed to acute stress stimuli exhibit various stress responses, these disappear after chronic exposure to the same type of stress stimuli, indicating the development of stress adaptation. The evidence obtained from studies using stress-adapted animals suggests that maintenance of the 5- HT neuronal response to stress stimuli together with down-regulation of 5-HT1A autoreceptors, as well as up-regulation of postsynaptic 5-HT1A receptors, may contribute to the formation of stress adaptation. In contrast, disappearance of the 5- HT neuronal response to stress stimuli and dysfunction of postsynaptic 5-HT1A receptors are observed in animals subjected to inadaptable stress stimuli. Furthermore, exogenous activation of 5-HT1A receptors by injection of 5-HT1A receptor agonists facilitates the ability to adapt to stressful situations, confirming that 5-HT1A receptors play an important role in the formation of stress adaptation. These findings suggest that the brain 5-HT neuronal system, and particularly 5- HT1A receptors, may play a key role in the development of stress adaptation, and maintenance of this system may be particularly important for preventing and / or treating affective disorders.

Approximately 15% of cerebral strokes in adults are due to bleeding into the brain (intracerebral hemorrhage, ICH). This can be related to hypertension, vascular anomalies, or coagulopathy. Prognosis following ICH is worse than that following ischemic stroke. In addition, head trauma and premature birth are associated with ICH. Inflammation occurs after ICH and might be an important part of the pathogenesis of brain damage. The goal of this review is to bring together recent diverse data concerning inflammation after ICH. There has been little investigation of the role of inflammation following ICH despite the fact that inflammation is more severe than in ischemic stroke. Inflammation in the brain follows a temporal sequence similar to that in other organs. Some cytokines and inflammatory cells may possess dual roles both deleterious and beneficial to brain after ICH. At present, experimental data only weakly support pursuit of pharmacologic anti-inflammatory strategies following ICH.

Considerable evidence indicates that the GABAA receptor is a molecular target for general anesthetics in the CNS. However, most clinical anesthetists are puzzled by this (unifying) observation as the clinical features of anesthesia differ among anesthetics. Central noradrenergic neurons are known to regulate physiological functions including the sleep-wake cycle, motor activity, and autonomic nervous function. These physiological responses are depressed during general anesthesia. In addition, animal experiments have shown that general anesthetics, which activate GABAA receptors, depress brain noradrenergic neurons. Thus, we have focused on this neuronal system as a “wiring” target for general anesthetic action. However, ketamine, nitrous oxide and xenon, which act as NMDA receptor antagonists, markedly increase noradrenaline release in tissues from several brain regions. Consistent with the clinical features of anesthesia modulation of noradrenergic neurons could differ between the type of anesthetic agents. Therefore, loss of consciousness could be produced by cerebral depression but also over-excitation (e.g. convulsion). Sleep is also induced by not only hypothermia (hibernation) but also body heating that activates heat-sensitive neurons in the preoptic area. Wakefulness, that is to say, may maintain within a set range and that when this range is exceeded (above or below), unconsciousness may be induced. Recently we have accumulated several pieces of evidence supporting this hypothesis. In addition, we found that orexins, wakefulness-promoting neuropeptides, predominantly evoke noradrenaline release from rat cerebrocortical slices, and that activation of orexinergic neurons reduces the duration of anesthesia. Thus, noradrenergic and orexinergic neurons may be involved in the mechanism of general anesthesia.

Borna Disease Virus (BDV) is a neurotropic RNA virus worldwide in distribution that causes movement, behavior or cognitive disorders in animal species. Borna Disease the illness ranges from asymptomatic to fatal meningoencephalitis across naturally infected warmblooded (mammalian and bird) species. There are also reported associations of the virus with neuropsychiatric diseases of man. Development of experimentally infected rodents, frequently rats, as models for examining behavioral, pharmacologic and biochemical responses to viral challenge at different stages of life have contributed to understanding the role of CNS viral injury in vulnerability to neurodevelopmental, behavioral and degenerative diseases.

Schizophrenia is a complex and chronic disease that affects multiple aspects of cognition and behavior, including attention, perception, thought processes, emotion and volition. However, the pathophysiology of schizophrenia has not yet been fully clarified. For more than a decade, the dopamine hypothesis has been the most influential hypothesis in schizophrenia research. It postulates that schizophrenia is a manifestation of a hyperdopaminergic state in some regions of the brain. However, several studies have reported results that are inconsistent with the dopamine theory of schizophrenia and it is now believed that other neurotransmitter systems are probably involved. Interest in the role of excitatory amino acids in schizophrenia is rapidly increasing. Excitatory amino acids and their receptors are thought to play a role in the pathology of schizophrenia, based on several lines of evidence, such as the psychomimetic effects of glutamate receptor antagonists in non-schizophrenic subjects and patients with schizophrenia, postmortem studies of reporting changes in glutamate receptors in schizophrenia, and studies that have treated schizophrenic patients with glutamate receptor agonists. This review will focus on clinical evidence contributing to the “glutamate hypothesis of schizophrenia”.