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

Phasic versus tonic dopamine release and the modulation of dopamine system responsivity: a hypothesis for the etiology of schizophrenia

A model is proposed for integrating the neural and cognitive aspects of the positive symptoms of acute schizophrenia, using evidence from postmortem neuropathology and neurochemistry, clinical and preclinical studies of dopaminergic neurotransmission, anatomical connections between the limbic system and basal ganglia, attentional and other cognitive abnormalities underlying the positive symptoms of schizophrenia, specific animal models of some of these abnormalities, and previous attempts to model the cognitive functions of the septohippocampal system and the motor functions of the basal ganglia Anatomically, the model emphasises the projections from the septohippocampal system, via the subiculum, and the amygdala to nucleus accumbens, and their interaction with the ascending dopaminergic projection to the accumbens Psychologically, the model emphasises a failure in acute schizophrenia to integrate stored memories of past regularities of perceptual input with ongoing motor programs in the control of current perception A number of recent experiments that offer support for the model are briefly described, including anatomical studies of limbic-striatal connections, studies in the rat of the effects of damage to these connections, and of the effects of amphetamine and neuroleptics, on the partial reinforcement extinction effect, latent inhibition and the Kamin blocking effect; and studies of the latter two phenomena in acute and chronic schizophrenics

The neuropsychology of schizophrenia.

Population-based study からみた神経予後不良因子の検討

Clozapine administration to schizophrenic patients was found to produce dopamine2 (D-2) and serotonin2 (5-HT2) receptor blockade, as evidenced by the ability to block the increases in growth hormone and cortisol secretion produced by apomorphine and MK-212, respectively, direct acting dopamine (DA) and 5-HT2 agonists. Clozapine did not increase plasma prolactin (PRL) levels nor did it block the apomorphine-induced decrease in plasma PRL concentration, as would be expected from a D-2 receptor antagonist. These PRL results are consistent with the observation that clozapine may increase DA release. Clozapine also decreased plasma tryptophan, plasma homovanillac acid (HVA) and basal plasma cortisol levels. Rodent studies suggest clozapine also increases 5-HT release. We hypothesize that antagonism of D-2 and 5-HT2 receptors and enhancement of DA and 5-HT release are critical elements in the action of clozapine to minimize both positive and negative symptoms without producing significant extrapyramidal symptoms or plasma PRL increases. It is proposed that schizophrenia may also involve a dysregulation of 5-HT2- and D-2-mediated neurotransmission, and that a more normal balance in serotonergic and dopaminergic neurotransmission is at least partially restored by clozapine.

Clinical studies on the mechanism of action of clozapine: the dopamine-serotonin hypothesis of schizophrenia.

• Fourteen schizophrenic subjects were evaluated for degree of psychosis before and after treatment with the antipsychotic drug haloperidol and for plasma homovanillic acid concentration after four and 28 days of treatment. A significant correlation was found between an increase in homovanillic acid concentration on day 4 or a decrease from day 4 to day 28 and the degree of improvement after four weeks of treatment. Thus, those patients who had the greatest change in plasma homovanillic acid in response to neuroleptic blockade showed the greatest improvement. These and other observations have led us to propose that the central dopaminergic system, through adaptive changes in activity, serves as a physiologic buffer system protecting against destabilization of mental function from diverse biologic or psychologic insults.

Plasma Homovanillic Acid as a Predictor of Response to Neuroleptics

Plasma HVA, neuroleptics, and dopaminergic plasticity.

Persistence of cyclicity of the plasma dopamine metabolite, homovanillic acid, in neuroleptic treated schizophrenic patients.

We have determined the plasma (p) concentration of gamma-aminobutyric acid (GABA) and the dopamine metabolite homovanillic acid (HVA), and the pHVA/pGABA ratio in schizophrenic and bipolar patients. The research was undertaken in a geographic area with an ethnically homogeneous population. The HVA plasma concentrations were significantly elevated in the schizophrenic patients compared to the bipolar patients. The levels of pGABA was significantly lower in the two groups of patients compared to the control group, while the pHVA/pGABA ratio was significantly greater in the both groups of patients compared to the controls. As the levels of pHVA and pGABA are partially under genetic control it is better to compare their concentrations within an homogeneous population. The values of the ratio pHVA/pGABA are compatible with the idea of an abnormal dopamine-GABA interaction in schizophrenic and bipolar patients. The pHVA/pGABA ratio may be a good peripheral marker in psychiatric research.

GABA and homovanillic acid in the plasma of Schizophrenic and bipolar I patients.

To the Editor.— The increase in homovanillic acid (HVA) concentration in rat plasma occurring after treatment with neuroleptic drugs has been found to be largely of central nervous system origin, 1 although basal levels derive from both the periphery and the central nervous system. 2 The findings on the effect of neuroleptic drugs on plasma HVA level in humans have not been entirely consistent. Pickar et al 3 failed to demonstrate an acute neuroleptic drug-induced increase in plasma HVA level in schizophrenic patients, and Davis et al 4 originally were unable to detect this effect in subjects studied six hours after treatment. Recently, this latter group reported that an increase did occur 24 hours after treatment. 5 They administered haloperidol intramuscularly at 11 AM (0.2 mg/kg) and later, at 6 PM, orally (10 mg). The level of HVA in plasma was determined before administration of haloperidol and again the next

Ricardo Dávila

Papers

Plasma Homovanillic Acid as a Predictor of Response to Neuroleptics

Plasma HVA, neuroleptics, and dopaminergic plasticity.

Persistence of cyclicity of the plasma dopamine metabolite, homovanillic acid, in neuroleptic treated schizophrenic patients.

GABA and homovanillic acid in the plasma of Schizophrenic and bipolar I patients.

Elevation of plasma homovanillic acid level can be detected within four hours after initiation of haloperidol treatment.