Objective: Phencyclidine (PCP, “angel dust”) induces a psychotomimetic state that closely resembles schizophrenia. As opposed to amphetamine-induced psychosis, PCP-induced psychosis incorporates both positive (e.g., hallucinations, paranoia) and negative (e.g., emotional withdrawal, motor retardation) schizophrenic symptoms. PCP-induced psychosis also uniquely incorporates the formal thought disorder and neuropsychological deficits associated with schizophrenia. The purpose of the present paper is to review recent advances in the study of the molecular mechanisms of PCP action and to describe their implications for the understanding ofschizophrenic pathophysiology. Methoc�: Twenty-five papers were identified that described the clinicaldose and serum and CSF levelsat which PCP induces its psychotomimetic effects. The dose range ofPCP-induced effects were compared to the dose range at which PCP interacts with specific molecular targets and affects neurotransmission. Results: It was found that PCP-induced psychotomimetic effects are associated with submicromolar serum concentrations of PCP. At these concentrations PCP interacts selectively with a specific binding site (PCP receptor) that is associated with the N-methyl-D-aspartate (NMDA)-type excitatory amino acid receptor. Occupation ofits receptor by PCP induces noncompetitive inhibition of NMDA receptor-mediated neurotransmission. Other NMDA antagonists such as the dissociative anesthetic ketamine induce PCP-like neurobehavioral effects in proportion to their potency in binding to the PCP receptor and inducing NMDA receptor inhibition. Conclusions: These findings suggestthat endogenous dysfunction ofNMDA receptor-mediated neurotransmission might contribute to the pathogenesis of schizophrenia. The relative implications of the PCP and amphetamine models ofschizophrenia are discussedin relationship to the diagnosis and etiology of schizophrenia. (Am J Psychiatry1991;148:1301-1308)

Recent advances in the phencyclidine model of schizophrenia.

The Prefrontal Cortex, Fifth Edition, provides users with a thoroughly updated version of this comprehensive work that has historically served as the classic reference on this part of the brain. The book offers a unifying, interdisciplinary perspective that is lacking in other volumes written about the frontal lobes, and is, once again, written by the award-winning author who discovered "memory cells," the physiological substrate of working memory. The fifth edition constitutes a comprehensive update, including all the major advances made on the physiology and cognitive neuroscience of the region since publication in 2008. All chapters have been fully revised, and the overview of prefrontal functions now interprets experimental data within the theoretical framework of the new paradigm of cortical structure and dynamics (the Cognit Paradigm), addressing the accompanying social, economic, and cultural implications. * Provides a distinctly interdisciplinary view of the prefrontal cortex, covering all major methodologies, from comparative anatomy to modern imaging* Unique analysis and synthesis of a large body of basic and clinical data on the subject (more than 2000 references)* Written by an award-winning author who discovered "memory cells," the physiological substrate of working memory* Synthesizes evidence that the prefrontal cortex constitutes a complex pre-adaptive system* Incorporates emerging study of the role of the frontal lobes in social, economic, and cultural adaptation

The prefrontal cortex

• To evaluate dorsolateral prefrontal cortex (DLPFC) physiology and function simultaneously, 20 medication-free patients with chronic schizophrenia and 25 normal controls underwent three separate xenon Xe 133 inhalation procedures for determination of regional cerebral blood flow (rCBF): first at rest, then while performing an automated version of the Wisconsin Card Sort (WCS), a DLPFC-specific cognitive test, and while peforming a simple number-matching (NM) test. During rest, patients had significantly reduced relative, but not absolute, rCBF to DLPFC. During NM, no specific region differentiated patients from controls. During WCS, however, both absolute and relative rCBF to DLPFC significantly distinguished patients from controls. While controls showed a clear increase in DLPFC rCBF, patients did not. The changes were regionally specific, involving only DLPFC. Furthermore, in patients, DLPFC rCBF correlated positively with WCS cognitive performance, suggesting that the better DLPFC was able to function, the better patients could perform. Autonomic arousal measures, the pattern of WCS errors, and results of complementary studies suggest that the DLPFC finding is linked to regionally specific cognitive function and is not a nonspecific epiphenomenon.

Physiologic dysfunction of dorsolateral prefrontal cortex in schizophrenia. I. Regional cerebral blood flow evidence.

Positive affect systematically influences performance on many cognitive tasks. A new neuropsychological theory is proposed that accounts for many of these effects by assuming that positive affect is associated with increased brain dopamine levels. The theory predicts or accounts for influences of positive affect on olfaction, the consolidation of long-term (i.e., episodic) memories, working memory, and creative problem solving. For example, the theory assumes that creative problem solving is improved, in part, because increased dopamine release in the anterior cingulate improves cognitive flexibility and facilitates the selection of cognitive perspective.

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A neuropsychological theory of positive affect and its influence on cognition.

Objective: The initial hypothesis that schizophrenia is a manifestation of hyperdopaminergia has recently been faulted. However, several new findings suggest that abnormal, although not necessarily excessive, dopamine activity is an important factor in schizophrenia. The authors discuss these findings and their implications. Method: All published studies regarding dopamine and schizophrenia and all studies on the role of dopamine in cognition were reviewed. Attention has focused on post-mortem studies, positron emission tomography, neuroleptic drug actions, plasma levels of the dopamine metabolite homovanillic acid (HVA), and cerebral blood flow. Results: Evidence, particularly from intracellular recording studies in animals and plasma HVA measurements, suggests that neuroleptics act by reducing dopamine activity in mesolimbic dopamine neurons. Post-mortem studies have shown high dopamine and HVA concentrations in various subcortical brain regions and greater than normal dopamine receptor densities in the brains of schizophrenic patients. On the other hand, the negative/deficit symptom complex of schizophrenia may be associated with low dopamine activity in the prefrontal cortex. Recent animal and human studies suggest that prefrontal dopamine neurons inhibit subcortical dopamine activity. The authors hypothesize that schizophrenia is characterized by abnormally low prefrontal dopamine activity (causing deficit symptoms) leading to excessive dopamine activity in mesolimbic dopamine neurons (causing positive symptoms). Conclusions: The possible co-occurrence of high and low dopamine activity in schizophrenia has implications for the conceptualization of dopamine ‘s role in schizophrenia. It would explain the concurrent presence of negative and positive symptoms. This hypothesis is testable and has important implications for treatment of schizophrenia and schizophrenia spectrum disorders.

Dopamine in Schizophrenia: A Review and Reconceptualization

Twenty patients with chronic schizophrenia were studied, m e younger group (four women and seven men, mean age 25 years) and one older group (nine women, mean age 61 years) with a mean duration of the disease of 5 years and 40 years respectively. All patients showed classical symptoms of schizophrenia with cognitive and emotional disturbances. The younger patients were well preserved intellectually. A11 the older o n e showed advanced deterioration with autism, bizarre behavior, symptoms of catatonia, ongoing hallucinations, etc. Regional cerebral blood flow (rCBF) was measured with the lS8Xenon method in the dominant hemisphere at rest and during attempts at mental activation, using a computer operated 32-detector type of equipment. Both groups showed normal mean rCBF variables. In the older group, and to some extent in the younger one, significant correlations were established between the mean hemisphere flow level and the degree of psychosis (rated with the Rockland and Pollin scale (RP-scale)). The regional rCBF distribution was by and large normal in the younger group with a predominance of high flows in frontal regions. In the older patients, another pattern was found with relatively low flows frontally, and, in many cases, relatively high flows occipito-temporally. This “hypofrontal” rCBF pattern in the deteriorated schizophrenics differed not only from the pattern found in the non-psychotic, neurologically normal reference group but afso from a group of older patients with Alzheimer’s disease. The flow level in occipito-temporal parts of the hemisphere in the schizophrenics correlated positively to the degree of cognitive disturbance rated with the RP-scale. Psychological testing with Raven’s matrices in the younger group gave by and large normal flow augmentations within expected hemisphere regions. In the most autistic older patients, only very slight flow changes, if any at all, were recorded postcentrally in connection with a simple picture test. Some of the older patients with whom contact was established, did, however, show fairly normal rCBF changes during this test. The “hypofrontal” rCBF distribution pattern at a normal flow level found in older deteriorated schizophrenics indicates that an abnormally low level of activity may prevail within the frontal lobe in such patients. Some similarities between the emotional defects, the speech and motor abnormalities seen in chronic schizophrenia, and symptoms found in patients with frontal lobe lesions are pointed out.

G. Franzén

Papers

Abnormalities of cerebral blood flow distribution in patients with chronic schizophrenia