THE BEHAVIOURAL PHARMACOLOGY OF SCHIZOPHRENIA

Schizophrenia is a devasatating disease affecting a significant proportion of the world's poulation. There are encouraging signs, however, that the amount of fundamental and clinical research on this disease is increasing, stimulated at least partially, no doubt, by new techniques that can be applied to this problem. These include advances in brain imaging methodology and ways of investigating the function of the living brain in experimental animals. In addition, behavioural techniques for modelling aspects of schizophrenia and for investigating the mechanisms of action of antipsychotic drugs have been evolving in recent years. It is this area of research which is represented in the current Special Issue. This volume contains the usual mix of scholarly reviews, thoughful commentaries and research reports describing novel findings. The issue begins with a major review of ‘Models of deficient sensorimotor gating’ by Swerdlow, Braff and Geyer. This research group discovered some years ago that schizophrenic patients showed a deficit in the prepulse inhibition of the startle response, consistent with previous ideas about the behavioural and cognitive aspects of schizophrenia being related to difficient attentional mechanisms. With admirable scientific rigour they decided to investigate this phenomenon in detail and have made many contributions to the literature. The present review provides an overview of several aspects of sensorimotor gating including methodological and genetic factors and its relationship to drug abuse as well as schizophrenia. It is clear that the neural and neurochemical mechanisms underlying prepulse inhibition are complex, as might have been expected, and this probably accounts for the fact that research with this technique seems not, as yet, to have made a major contribution to the discovery of new antipsychotic drugs. Koch and Kumari provide expert commentaries on the review by Swerdlow and colleagues and focus on the extent to which prepulse inhibition of the startle response, as a relatively simple form of animal behavior, can be expected to form a laboratory model of the complexities of human pathology. They note several limitations of current experimental data but also point to some areas where results obtained in the laboratory might usefully be verified in human subjects. In general, these commentators are clearly enthusiastic about prepulse inhibition and optimistic about its role in this research area. The review by Ohmori and colleagues also focusses on a phenomenon of potential significance for both psychotic disorders and drug abuse, the sensitization which often occurs following repeated administration of psychostimulant drugs. Much research has been carried out in attempts to distinquish the relative importance of pharmacological and environmental factors in the development of sensitization. Ohmori et al. review some of this literature and formulate a hypothesis aiming to to integrate pharmacological and environmental viewpoints. Ellenbroek and Cools continue the discussion of how best to model schizohrenia in animals with their review of ‘Animal models for the negative symptoms of schizophrenia.’ Clinicians have recently been placing greater emphasis on the importance of the negative, deficit and cognitive symptoms of the disease which, some have argued, may represent more directly than the positive symptoms the fundamental disease process. It is appropriate, therefore, that behavioural pharmacologists should contribute to this research area. Such model building is a relatively new enterprise and, as this paper shows, relatively few of our colleagues have yet decided to contribute. It is to be hoped, however, that despite the traditional problems of validation, described clearly by Ellenbroek and Cools, we will see greater efforts in this area in the future. The significance of neurodevelopmental processes in schizophrenia may be of major importance, particularly perhaps for the development of negative symptoms. This is an issue taken up in the fourth review article by Aloe and colleagues titled ‘Studies in animal models and humans suggesting a role of nerve growth facture in schizophrenia-like disorders.’ In this paper the authors argue that, as neurotrophic factors (NGF, BDNF etc.) are known to play major roles in brain development, and schizophrenia may have a neurodevelopmental cause, disordered mechanisms associated with neurotrophic factors may be of fundamental importance. Such mechanisms may help explain the origins of the disease and also, it is proposed, the therapeutic actions of at least some antipsychotic drugs. Although there is limited evidence for these hypotheses at present this speculative review provides some pointers towards a potentially fruitful area of research. One can hope that other researchers will soon join in this debate and make empirial contributions to research in this area. In the fifth review by Scatton and Sanger the emphasis shifts from modelling of the schizophrenic disease process to ‘Pharmacological and molecular targets in the research for novel antipsychotics.’ It has been known for some time that all effective antipsychotic drugs block dopamine receptors, an observation which has formed one of of mainstays of the so-called dopamine hypothesis of schizophrenia. However, there is a pressing need for better treatments for the disease as current drugs have limited efficacy and a number of unpleasant side effects. The more recently developed drugs, known as atypical antipsychotics, have provided advantages, particularly in terms of reduced side effects, and seem to have mechanisms of action which differ in some respects from the classical neuroleptics. These include high affinities for serotonin receptors, selectivity for dopamine neurons in the limbic system and activity at presynaptic receptors. Scatton and Sanger discuss the evidence indicating the importance of these and other pharmacological mechanisms and describe some of the novel compounds which are currently being tested in the laboratory and in clinical trials. It is particularly intriguing to note that several novel agents under clinical investigation have no direct actions at dopamine receptors and may modulate dopaminergic activity indirectly. If any of these compounds turn out to be effective in patients this may offer a real advance in therapy. The studies described in the research reports deal with many of the issues discussed in the reviews. The first two papers by Le Pen and colleagues and Al-Amin et al. relate to neurodevelopmental aspects of schizophrenia by presenting experiments in rats subjected to neonatal lesions of the hippocampus. This sophisticated techique has stimulated a great deal of interest in recent years as it may provide a novel animal model of the disease covering neurodevelopmental, neurochemical and behavioural aspects. The two papers in this issue contribute to the validation of this model from the behavioural and pharmacological perspectives. Le Pen et al. describe the cognitive disturbances present in lesioned animals while Al-Amin et al. found that lesioned rats were more sensitive to the effects of MK-801 than were controls. Like many other recent studies, this finding emphasizes the potential significance of glutamatergic mechanisms in schizophrenia. Although neurochemical mechanisms involving glutamate, serotonin and probably a number of other transmitters may play important roles in the pathophysiology of schizophrenia and the actions of antipsychotics, there seems little likelihood that we will lose sight of the significance of dopamine. The paper by Spielowoy et al. continues the tradition of focussing on this neurotransmitter but with a study which could hardly be more timely. Spielowoy and colleagues provide a detailed analysis of the behavioural profile of mice genetically modified to ‘knock-out’ the dopamine transporter. If any researchers in behavioural pharmacology still need convincing that genetically modified animals provide an essential tool for our work, this paper should help convince them. The papers by Sanchez and Arnt and Prinssen and colleagues turn their attention to the potential importance of serotonin receptor subtypes in the mechanisms of action of antipsychotic drugs. Following the observation that several of the newer antipsychotic drugs, including clozapine and risperidone, have high affinities for 5HT2 receptors emphasis has shifted somewhat from dopamine to serotonin. Sanchez and Arnt present data from behavioural experiments which may help to distinquish activity at the 5HT2A and 5HT2C subtypes. The results, however, show a lack of concordance between in vivo and in vito findings. Prinssen and colleagues provide data showing that the catalepsy provoked by haloperidol, which is believed to predict extrapyramidal side effects of neuroleptic drugs in the clinic, is blocked by 8-OH-DPAT and that this action is maintained on repeated treatment. The authors suggest that molecules with combined dopamine antagonist and 5HT1A agonist actions might be important new antipsychotics. As several such compounds are currently being developed, we may soon learn whether this hypothesis is accurate. Murphy and Feldon describe the results of a study which addresses one of the oldest questions in modern behavioural pharmacology, is the disruption of conditioned avoidance responding produced by antipsychotic drugs in rats predictive of antipsychotic efficacy or motor side effects in the clinic? Although many studies have investigated this issue it seems never to have been resolved in over 40 years of research. Murphy and Feldon report that the deficit produced by haloperidol can be partially blocked by clozapine and conclude that conditioned avoidance deficits are more likely to represent motor deficits. The last full paper in this issue, by Oades and colleagues, is the only one to describe novel data obtained with schizophrenic patients. It is, however, a behavioural pharmacological study which sought to investigate whether cognitive deficits in these patients could be related to the level of dopamine receptor occupation produced by antipsychotic drugs. The conclusions of the study, although difficult because of the methodological limitations of such an ambitious study, do point towards a relationship between these two factors. The authors hope that their results will stimulate further research on this important question. The publication of this Special Issue is timed to coincide with the workshop on schizophrenia being held in the Free University of Amsterdam (June 21–24, 2000). The workshop is jointly organized by the European Behavioural Pharmacology Society and the Dutch Interdisciplinary Society for Biological Psychiatry. Abstracts of the papers presented at the workshop are published in this issue. Announcement of Special Issues for 2001 and 2002 As announced in last year's Special Issue, the 2001 Special Issue of Behavioural Pharmacology will be devoted to ‘Behavioural Genomics’. Although Behavioural Genomics was one of the areas included in our 1996 Special Issue on ‘The Application of Neurobiolocial Techniques in Behavioural Pharmacology’, the rapid growth of behavioural genomic research justifies returning to this exciting area. We now invite behavioural pharmacologists to submit reports of original unpublished research for inclusion in the Special Issue, which should describe important new empirical findings in Behavioural Genomics. You are also welcome to discuss ideas for review articles with one of the editors; please do this as soon as possible. There is no formal deadline for submission of manuscripts, but contributors are advised to submit no later than the end of March 2001, and preferably earlier. Please bear in mind that the later your submission, the higher the possibility that its final acceptance may be too late for inclusion in the Special Issue, which is planned to be published in September 2001. We also take this opportunity to announce that the 2002 Special Issue of Behavioural Pharmacology will be dedicated to ‘New Advances in the Understanding and Treatment of Addiction’. Publication will coincide with the joint European Behavioural Pharmacology Society / British Association for Psychopharmacology workshop on the same topic, which is planned for September 2002. We make this announcement now to give behavioural pharmacologists working in this area the opportunity to plan ahead, with a view to submitting papers towards the end of 2001 or early in 2002. David Sanger, Alice Young and Paul Willner May, 2000