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

Connectionist models are used to explore the relationship between cognitive deficits and biological abnormalities in schizophrenia. Schizophrenic deficits in tasks that tap attention and language processing are reviewed, as are biological disturbances involving prefrontal cortex and the mesocortical dopamine system. Three computer models are then presented that simulate normal and schizophrenic performance in the Stroop task, the continuous performance test, and a lexical disambiguation task. They demonstrate that a disturbance in the internal representation of contextual information can provide a common explanation for schizophrenic deficits in several attention- and language-related tasks. The models also show that these behavioral deficits may arise from a disturbance in a model parameter (gain) corresponding to the neuromodulatory effects of dopamine, in a model component corresponding to the function of prefrontal cortex.

Context, cortex, and dopamine: a connectionist approach to behavior and biology in schizophrenia.

• Schizophrenic patients exhibit impairments in both sensorimotor gating and habituation in a number of paradigms. Through human and animal model research, these fundamental cognitive deficits have well-described neurobiologic bases and offer insights into the neuroanatomic and neurotransmitter abnormalities that characterize patients with schizophrenic spectrum disorders. In this context, the startle response is particularly interesting, because it is a crossspecies response to strong stimuli that is plastic or alterable using experimental and neurobiologic manipulations. Thirty-nine medicated schizophrenic patients and 37 normal control subjects were studied in a new electromyography based startle response paradigm in which both prepulse inhibition (an operational measure of sensorimotor gating) and habituation (the normal decrease in response magnitude to repeated stimuli over time) can be separated and assessed in one test session. The results indicate that schizophrenic patients have extensive deficits in both intramodal and cross-modal sensorimotor gating and a trend to show acoustic startle habituation deficits. The deficit in prepulse inhibition of startle amplitude exhibited by schizophrenic patients was evident when an acoustic prepulse stimulus preceded either an acoustic or a tactile startle stimulus. No deficit was observed in the prepulseinduced facilitation of startle latencies, indicating that the failure of gating was not due to a failure of stimulus detection. These findings suggest centrally mediated deficits in sensorimotor gating in schizophrenic patients.

Gating and habituation of the startle reflex in schizophrenic patients.

In an earlier, separate study, the authors found that human aggression and suicide (a specific aggression-related behavior) were associated with lower levels of CSF 5-hydroxyindoleacetic acid (5-HIAA), a serotonin metabolite. That study focused on subjects with personality disorders without affective illness. In the present study they examine the life history of aggression and history of suicidal behavior in 12 subjects with borderline personality disorders without major affective disorder. Histories of aggressive behaviors and of suicide attempts were significantly associated with each other, and each was significantly associated with lower 5-HIAA levels. Altered serotonin metabolism may be a highly significant contributing factor to these behaviors in whatever diagnostic group they occur. Language: en

Aggression, suicide, and serotonin: relationships to CSF amine metabolites.

The discovery of neuroleptic drugs in 1952 provided a new strategy for seeking a biological basis of schizophrenia. This entailed a search for a primary site of neuroleptic action. The Parkinsonian effects caused by neuroleptics suggested that dopamine transmission may be disrupted by these drugs. In 1963 it was proposed that neuroleptics blocked "monoamine receptors" or impeded the release of monoamine metabolites. The neuroleptic concentration in plasma water or cerebrospinal fluid was of the order of 2 nM for haloperidol in clinical therapy. A systematic research was made between 1963 and 1974 for a primary site of neuroleptic action which would be sensitive to 2 nM haloperidol and stereoselective for (+)-butaclamol. Direct evidence that neuroleptics selectively blocked dopamine receptors occurred in 1974 with the finding that nanomolar concentrations of these drugs stereoselectively inhibited the binding of [3H]-dopamine or [3H]-haloperidol. These binding sites, now termed D2 dopamine receptors (which inhibit adenylate cyclase), are blocked by neuroleptics in direct relation to the antipsychotic potencies of the neuroleptics. No such correlation exists for D1 receptors (which stimulate adenylate cyclase). Based on the fact that dopamine-mimetic drugs elicited hallucinations, and that neuroleptics caused rigidity, Van Rossum in 1966 had suggested a hypothesis that dopamine pathways may be overactive in schizophrenia. The D2-selective blockade by all neuroleptics (except the monoamine-depleting reserpine) provided strong support for the dopamine hypothesis. Further support now comes from postmortem data and in vivo positron tomographic data, both of which indicate that the density of D2 receptors are elevated in the schizophrenic brain. The postmortem data indicate a bimodal pattern with half the schizophrenics having striatal D2 densities of 14 pmol/g (control is 13 pmol/g) and the other half having 26 pmol/g. Current positron tomographic data indicate D2 densities of 14 pmol/g in control subjects, but values of 34 pmol/g in drug-naive schizophrenics. Future tests of the dopamine hypothesis of schizophrenia may entail an examination of the amino acid composition and genes for D2 receptors in schizophrenic tissue, an examination of the ability of the D2 receptor to become phosphorylated and to desensitize into the low-affinity state, and an examination of the interaction of D2 receptors with D1 receptors or other neurotransmitters.

Dopamine receptors and the dopamine hypothesis of schizophrenia.

Concentrations of norepinephrine in cerebrospinal fluid are higher in schizophrenic patients, particularly in those with paranoid features, than in normal volunteer subjects of the same age. This observation supports recent reports of elevated concentrations of norepinephrine in specific brain areas adjacent to the cerebral ventricles of paranoid schizophrenic patients. Overflow of the amine from periventricular regions into the cerebrospinal fluid may reflect abnormally high release or diminished enzymatic destruction of norepinephrine in patients with schizophrenia.

Schizophrenia: elevated cerebrospinal fluid norepinephrine

Schizophrenic patients with high ventricle brain ratios and cortical brain atrophy, as shown by computerized tomography, had decreased spinal fluid concentrations of homovanillic acid and dopamine-beta-hydroxylase activity. These decreased cerebral spinal fluid concentrations in patients with brain atrophy support the proposal of disturbed noradrenaline and dopamine neurotransmission in a subgroup of schizophrenic patients.

https://science.sciencemag.org/content/sci/220/4600/974.full.pdf

Dopamine-beta-hydroxylase activity and homovanillic acid in spinal fluid of schizophrenics with brain atrophy

The authors measured CSF norepinephrine concentrations in drug-free schizophrenic patients with and without probenecid administration and in drug-free normal control subjects. Schizophrenic patients had significantly higher baseline norepinephrine values. The dopamine metabolite homovanillic acid correlated significantly with norepinephrine. During chronic treatment with the neuroleptic pimozide, patients' norepinephrine levels were significantly decreased. The pimozide-induced decrease in norepinephrine, as well as the percent decrease, correlated significantly with the patients' decrease in global psychosis. These data are consistent with recent reports of elevated concentrations of norepinephrine in specific brain areas of schizophrenic patients, and they support a role for norepinephrine metabolism in the pharmacological effects of antipsychotic drugs.

The effect of pimozide on CSF norepinephrine in schizophrenia.

The group of disorders known collectively as schizophrenia15 continues to be a critical problem for modern psychiatry and accounts for large expenditures for the community (estimated at $19.6 billion annually)66 and tragedy for many families. The chance that a person will be treated for schizophrenia in his lifetime has been reported to be about 2% (4 million people in the United States). Schizophrenia accounts for about 50% of the available mental hospital beds, or about 25% of all available hospital beds in the United States.86 The disorder is equally common in males and females.

D. E. Sternberg

Papers

Schizophrenia: elevated cerebrospinal fluid norepinephrine

Dopamine-beta-hydroxylase activity and homovanillic acid in spinal fluid of schizophrenics with brain atrophy

The effect of pimozide on CSF norepinephrine in schizophrenia.

Cerebrospinal Fluid Studies in Schizophrenia

Schizophrenia: Low spinal fluid GABA levels?