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Motivational salience — The variable linking dopamine, psychosis, antipsychotics
100 were obtained at 20 minute intervals for one hour pilot" to and 4 horn's following the beginning of the infusion. Seven normals were studied twice, once receiving a control infusion of saline, and seven schizophrenics were studied once with the active cortisol infusion. ACTH levels fell markedly in response to cortisol in normals, relative to their response to saline infusion (Repeated measures ANOVA: condition X time F = 22.1, df = 3,12, P<.0001). CORT levels in schizophrenics were similar at baseline to those of normals but tended to be higher after the infusion (group X time quadratic trend: t = 2.55, P = .02). Despite the greater rise in CORT, the ACTtt response to this negative feedback signal was blunted in the schizophrenics; falling later and to a lesser extent than in controls (group X time cubic trend t = 2.1, P = .05). This response resembles that of animals with HF damage and maternal deprivation, and is consistent with the previous reports of diminished HF adrenocortical hormone receptors in schizophrenia, it thus further supports the concept that HF constraint of the HPA axis is impaired in schizophrenia. Research supported by NIH R01 56525 and GCRC M01 RR13987.
MOTIVATIONAL SALIENCE - THE VARIABLE LINKING DOPAMINE, PSYCHOSIS, ANTIPSYCHOTICS S. Kapur Schizophrenia and PET hnaging, CAMH and University of Toronto, Toronto, ON, Canada The clinical halhnark of schizophrenia is psychosis - an experience at the mind or phenomenological level. Yet, the most prominent theories accord this to dopamine - - a neurotransmitter; and the most effective treatments for it are antipsychoties - - a chemical. How does one unite these different levels of analyses? It is proposed that the concept of motivational salience provides a good linking variable that unites the biology-phenomenology-pharmacologyof psychosis while at the same time providing a bridge from the animal studies to clinical experience, it has been proposed by Berridge et al. (and others) that dopamine release, particularly within the mesolimbic system, has a central role in mediating the salience of the environment and its internal representations. We propose that in the context of psychosis a dysregulated hyperdopaminergic state (whatever its primary orgins) results in aberrant assignment of salience to environmental stimuli and their internal representations which expresses itself as psychosis in humans. Delusions are a cognitive scheme devised by the patient to make sense of these aberrantly salient experiences and associations, whereas hallucinations reflect a direct experience of the aberrant salience of internal representations. The critical mechanism whereby antipsychotics are anti-psychotic is that they dampen the salience of these abnormal experiences and associations. As a result of dampened salience the symptoms recede to the background of the patient's consideration, they do not influence her thought and behaviour to the same extent and allow her to function. However, if the antipsychotics are stopped the dysregulated neurochemistry re-expresses itself, the dormant ideas and stimuli reinvested with aberrmlt salience and a clinical relapse occurs. One implication of this idea is that resolution of psychosis is like extinction and should follow the classical extinction curve - a hypothesis tested and supported in an accompanying abstract (see Agid et al.). Other predictions of this framework, particularly regarding the possibility of synergy between psychological and pharmacological therapy will be presented. The complementarity of this hypothesis to other ideas about psychosis and the limitations of the hypothesis will be discussedl
9. Neurochemistry, Clinical A C U T E EFFECTS OF ANTIPSYCHOTICS A N D DIAZEPAM ON PREPULSE INHIBITION OF THE
STARTLE RESPONSE K. T. Kristiansen,* T. Mackeprang, B. Y. Glenthoj
Dept. of Psychiatry E., University Hospital Bispebjerg, Copenhagen ARE.,Denmark Prepulse inhibition (PPI) of the startle response is an informative widely used cross-species operational measure af sensory gating. Dopamine (DA) agonist-induced disruption of PPI is a valid preclinical model for prediction of antipsychotic efficacy, since only clinical effective antipsychotics are able to restore the deficit. Nmethyl-D-aspartate (NMDA) antagonist-induced disruption of PPI has, on the other hand, been used to differentiate drugs with an atypical antipsychotic profile from typical compounds, since atypical antipsyehotics in contrast to typical antipsychotics are able to reverse the deficit. Whereas a large number of preclinical studies have examined the effects of antipsychotics and other agents on PPI, clinical data are scarce. We have recently in the first longitudinal within-group study on the effects of antipsychotics on PPI disturbances in drug-naive schizophrenia patients failed to demonstrate any effect of chronic antipsychotic treatment. The few existing clinical data on the acute effects of antipsychotics on PPI in healthy humans are contradictory, but generally fail to find any influence. Fnther clinical studies on the effects of drugs used in the treatment of schizophrenia patients on PPI are needed both to clarify the correspondence between pharmacological effects on PPI in humans and animals, and to examine the effects of these compounds on PPI in the clinic. To meet these problems we studied the effects of different doses of a typical (zuclopenthixol) and two atypical (risperidone and olanzapine) antipsychotic drugs and of diazepam on PPI in humans. Methods: Placebo or 2 different doses of risperidone (0.5 or 3.0 mg), olanzapine (2.5 or 7.5 nag), zuclopenthixol (2.0 or 8.0 mg) or diazepam (2.5 or 5.0 rag) were administered to healthy humans prior to PPI testing. Results: No significant drug-effects on PPI were observed in any of the treatment groups. Conclusions: Neither typical, nor atypical antipsychotics or diazepam influenced PPI following acute administration. The different compounds could, however, be differentiated as regards to the effects on amplitudes, habituation and latencies to onset or peak. Future studies must clarify whether the observed differeuces have any clinical implications.
DISTRIBUTION AND DENSITY OF RGS4 MRNA IN HUMAN POSTMORTEM BRAIN SECTIONS R. A. Lahti,* tf. A. Erdely, M. B. Lopez, C. S. Myers, R. C. Roberts, C. A. Tamminga
Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, USA RGS proteins are found throughout the body and are well distributed in the brain. There are about 20 RGS proteins, which are Regulators of G-protein Signaling. They enhance the rate of inactivation of the active form of the G proteins, by dramatically increasing the rate of hydrolysis of GTP to GDE Of special interest was the finding that RGS4 nfltNA levels were decreased in the PFC of postmortem brain tissue obtained from schizophrenic subjects compare to normal controls (Mirnics, 2001). A more extensive distribution of RGS4 mRNA
International Congress on Schizophrenia Research 2003
MOTIVATIONAL SALIENCE - THE VARIABLE LINKING DOPAMINE, PSYCHOSIS, ANTIPSYCHOTICS S. Kapur Schizophrenia and PET hnaging, CAMH and University of Toronto, Toronto, ON, Canada The clinical halhnark of schizophrenia is psychosis - an experience at the mind or phenomenological level. Yet, the most prominent theories accord this to dopamine - - a neurotransmitter; and the most effective treatments for it are antipsychoties - - a chemical. How does one unite these different levels of analyses? It is proposed that the concept of motivational salience provides a good linking variable that unites the biology-phenomenology-pharmacologyof psychosis while at the same time providing a bridge from the animal studies to clinical experience, it has been proposed by Berridge et al. (and others) that dopamine release, particularly within the mesolimbic system, has a central role in mediating the salience of the environment and its internal representations. We propose that in the context of psychosis a dysregulated hyperdopaminergic state (whatever its primary orgins) results in aberrant assignment of salience to environmental stimuli and their internal representations which expresses itself as psychosis in humans. Delusions are a cognitive scheme devised by the patient to make sense of these aberrantly salient experiences and associations, whereas hallucinations reflect a direct experience of the aberrant salience of internal representations. The critical mechanism whereby antipsychotics are anti-psychotic is that they dampen the salience of these abnormal experiences and associations. As a result of dampened salience the symptoms recede to the background of the patient's consideration, they do not influence her thought and behaviour to the same extent and allow her to function. However, if the antipsychotics are stopped the dysregulated neurochemistry re-expresses itself, the dormant ideas and stimuli reinvested with aberrmlt salience and a clinical relapse occurs. One implication of this idea is that resolution of psychosis is like extinction and should follow the classical extinction curve - a hypothesis tested and supported in an accompanying abstract (see Agid et al.). Other predictions of this framework, particularly regarding the possibility of synergy between psychological and pharmacological therapy will be presented. The complementarity of this hypothesis to other ideas about psychosis and the limitations of the hypothesis will be discussedl
9. Neurochemistry, Clinical A C U T E EFFECTS OF ANTIPSYCHOTICS A N D DIAZEPAM ON PREPULSE INHIBITION OF THE
STARTLE RESPONSE K. T. Kristiansen,* T. Mackeprang, B. Y. Glenthoj
Dept. of Psychiatry E., University Hospital Bispebjerg, Copenhagen ARE.,Denmark Prepulse inhibition (PPI) of the startle response is an informative widely used cross-species operational measure af sensory gating. Dopamine (DA) agonist-induced disruption of PPI is a valid preclinical model for prediction of antipsychotic efficacy, since only clinical effective antipsychotics are able to restore the deficit. Nmethyl-D-aspartate (NMDA) antagonist-induced disruption of PPI has, on the other hand, been used to differentiate drugs with an atypical antipsychotic profile from typical compounds, since atypical antipsyehotics in contrast to typical antipsychotics are able to reverse the deficit. Whereas a large number of preclinical studies have examined the effects of antipsychotics and other agents on PPI, clinical data are scarce. We have recently in the first longitudinal within-group study on the effects of antipsychotics on PPI disturbances in drug-naive schizophrenia patients failed to demonstrate any effect of chronic antipsychotic treatment. The few existing clinical data on the acute effects of antipsychotics on PPI in healthy humans are contradictory, but generally fail to find any influence. Fnther clinical studies on the effects of drugs used in the treatment of schizophrenia patients on PPI are needed both to clarify the correspondence between pharmacological effects on PPI in humans and animals, and to examine the effects of these compounds on PPI in the clinic. To meet these problems we studied the effects of different doses of a typical (zuclopenthixol) and two atypical (risperidone and olanzapine) antipsychotic drugs and of diazepam on PPI in humans. Methods: Placebo or 2 different doses of risperidone (0.5 or 3.0 mg), olanzapine (2.5 or 7.5 nag), zuclopenthixol (2.0 or 8.0 mg) or diazepam (2.5 or 5.0 rag) were administered to healthy humans prior to PPI testing. Results: No significant drug-effects on PPI were observed in any of the treatment groups. Conclusions: Neither typical, nor atypical antipsychotics or diazepam influenced PPI following acute administration. The different compounds could, however, be differentiated as regards to the effects on amplitudes, habituation and latencies to onset or peak. Future studies must clarify whether the observed differeuces have any clinical implications.
DISTRIBUTION AND DENSITY OF RGS4 MRNA IN HUMAN POSTMORTEM BRAIN SECTIONS R. A. Lahti,* tf. A. Erdely, M. B. Lopez, C. S. Myers, R. C. Roberts, C. A. Tamminga
Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore, MD, USA RGS proteins are found throughout the body and are well distributed in the brain. There are about 20 RGS proteins, which are Regulators of G-protein Signaling. They enhance the rate of inactivation of the active form of the G proteins, by dramatically increasing the rate of hydrolysis of GTP to GDE Of special interest was the finding that RGS4 nfltNA levels were decreased in the PFC of postmortem brain tissue obtained from schizophrenic subjects compare to normal controls (Mirnics, 2001). A more extensive distribution of RGS4 mRNA
International Congress on Schizophrenia Research 2003