ArticleA systems model of altered consciousness: integrating natural and drug-induced psychoses
Introduction
This review summarizes recent experiments assessing commonalities between naturally occurring psychoses and the effects of both serotonergic hallucinogens such as psilocybin, and N-methyl-D-aspartate (NMDA) antagonists such as ketamine, in humans. Converging approaches to understanding the pharmacological effects of hallucinogens on brain functions have been utilized in these studies. The major approaches include the investigation of drug-induced changes of brain activation patterns as indexed by [18F]fluorodeoxyglucose (FDG) and the characterization of functional interactions among neurotransmitter systems by assessing drug-induced displacement of specific radiolabeled receptor ligands using positron emission tomography (PET). Furthermore, receptor mechanisms of hallucinogenic and related drugs are investigated by exploring the effects of specific receptor antagonists on drug-induced psychological alterations and on information processing functions such as sensorimotor gating as indexed by prepulse inhibition (PPI) of startle.
The premise of the present review is that schizophrenia cannot be understood adequately by any single-transmitter model. First, it has long been recognized that a number of distinct etiologies are likely to be responsible for a group of disorders that have sufficiently overlapping symptomatology to be classified phenomenologically as schizophrenia. Second, even within one of these etiologically distinct subtypes of schizophrenia, multiple neurotransmitter systems are likely to be functionally abnormal and contribute to the symptomatology. This review attempts to summarize a systems model that should have heuristic value in the further explication of the complex interactions that are evident in the recent literature on the group of schizophrenias. The proposed model is based on the integration of information from studies of patients suffering from schizophrenia and studies of drug-induced human and animal models of psychoses.
Indoleamine hallucinogens, such as LSD or psilocybin, and dissociative anesthetics, such as phencyclidine (PCP) or ketamine, produce a number of psychotic symptoms, as well as both cognitive and behavioral deficits associated with schizophrenic psychoses 64, 142, 144. Hence, exploring the mechanisms responsible for these actions of psychotomimetics may provide new insights into the neurobiology of the group of schizophrenias. Indeed, recent research into psychotomimetic drug actions has revitalized a number of alternative hypotheses to the classic dopamine hyperactivity model of schizophrenia. In particular, the serotonin hypothesis of schizophrenia was derived from early studies of the pharmacology of LSD and its structural relationship to serotonin (5-Hydroxytryptamine, 5-HT) 45, 157. More recently, this hypothesis has received renewed support: first by the finding that indoleamine hallucinogens (e.g., LSD or psilocybin) produce their psychotomimetic effects through excessive 5-HT2A receptor activation 90, 151; second, by the finding of 5-HT2 receptor abnormalities in the brains of schizophrenic patients 8, 59, 69, 81; and third, by the role of 5-HT2 receptor antagonism in the effects of atypical neuroleptics such as clozapine and risperidone in patients and animal models of schizophrenia 84, 96. Similarly, the discovery that PCP and ketamine are antagonists at the NMDA subtype of glutamate receptors [6] added strong support to the glutamate deficiency hypothesis of schizophrenia [74]. The glutamate deficiency hypothesis is consistent with findings of decreased glutamate concentrations in the cerebrospinal fluid of schizophrenic patients [74], alterations in cortical and subcortical NMDA receptor densities 7, 31, 67, 75, and reduced glutamate release in postmortem brains of schizophrenic patients 32, 58, 117.
One recently identified commonality that is critical to the development of this systems model is the hyper-frontality that is seen in both the initial stages of psychosis and in drug-induced psychoses in humans. For example, we have found that both serotonergic hallucinogens (e.g., psilocybin) and NMDA antagonists (e.g., ketamine) produce a marked activation of the prefrontal cortex (hyper-frontality) as well as other overlapping changes in cortical, striatal, and thalamic regions 149, 150. This commonality [145] suggests that some of the psychotic symptoms induced by these drugs may relate to a common final pathway or neurotransmitter system. This view is consistent with the “thalamic filter” hypothesis of psychoses, which posits that cortico-striatal pathways exert a modulatory influence on thalamic gating of sensory information to the cortex 23, 142, 143. Theoretically, thalamic gating deficits should result in sensory overload with excessive processing of exteroceptive and interoceptive stimuli leading to a collapse of integrative cortical functions, and subsequently to cognitive fragmentation and psychosis. This view is also derived from animal model studies of the gating deficits in schizophrenia, which demonstrate that both serotonergic hallucinogens and NMDA antagonists disrupt prepulse inhibition (PPI) of the acoustic startle reflex, a measure of sensorimotor gating and information processing [46]. Extensive lesion and drug studies have shown that PPI is subject to considerable forebrain modulation from cortical, limbic, striatal, pallidal, and thalamic structures, including the cortico-striato-pallido-thalamic (CSPT) circuitry 135, 137, 138.
Section snippets
Parallels between psilocybin- and ketamine-induced altered states of consciousness (ASC) and symptoms of schizophrenia
Psychotomimetic drugs have been shown to provide useful tools to study the neurobiology underlying the symptomatology of the group of schizophrenias. In this respect, standardized assessments of the common denominator of drug-induced Altered States of Consciousness (ASC) and endogenous psychoses are of fundamental importance. However, only recently have standardized assessments been used to characterize and to compare hallucinogen-induced states and naturally occurring psychoses. According to
The role of cortico-striato-thalamic (CST) pathways in schizophrenia
First, the common activation of the frontal cortex, anterior cingulate, temporomedial cortex, and thalamus seen in subjects treated with psilocybin or ketamine accords with the thalamic filter theory suggesting that a disruption of the CST loop should lead to a sensory overload of the frontal cortex and its limbic relay stations. A strikingly similar pattern of correlations between hyper-perfusion in the frontal, anterior cingulate, parietal, and temporal cortices with formal thought disorder
Conclusions
The present review discussed evidence suggesting that serotonergic hallucinogens and NMDA antagonists produce psychological changes that resemble to a considerable degree the symptoms characteristic of incipient stages of schizophrenic psychoses. These commonalities in drug- and non-drug-induced psychoses are mirrored in similar alterations in patterns of neurometabolic activity observed in acutely ill schizophrenic patients or in healthy humans after administration of either classical
Acknowledgements
The authors especially thank Dr. M. F. I. Vollenweider-Scherpenhuyzen, for critical comments on the manuscript. Some of the work summarized here was supported by the Heffter Research Institute (HRI 41-101.98; HRI 41-102.99), the Swiss National Science Foundation (SNF 32-040 900; 32-53001.97), and the U.S. National Institute of Mental Health (MH42228).
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