The action of L-dopa on schizophrenic patients (a preliminary report).

The Dopamine Hypothesis of Schizophrenia: A Review*

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.

https://science.sciencemag.org/content/sci/184/4143/1243.full.pdf

Drugs, neurotransmitters, and schizophrenia.

Alleviation of schizophrenic symptoms by phenothiazines and butyrophenones is associated with blockade of dopamine receptors, while exacerbation of symptoms by amphetamines appears to result from enhanced synaptic activity of dopamine and/or norepinephrine. The author suggests that biochemical labeling of the dopamine receptor with 3H-dopamine and 3H-haloperidol may clarify mechanisms of drug effects on the dopamine receptor.

The dopamine hypothesis of schizophrenia: focus on the dopamine receptor

Tetrahydroisoquinoline alkaloids have been unequivocally demonstrated in vivo for the first time in parkinsonian patients on L-dopa treatment. Their biosynthesis may have a profound bearing on how L-dopa acts.

The action of L-dopa on schizophrenic patients (a preliminary report).

Citations

The Dopamine Hypothesis of Schizophrenia: A Review*

Dopamine receptors and the dopamine hypothesis of schizophrenia.

Drugs, neurotransmitters, and schizophrenia.

The dopamine hypothesis of schizophrenia: focus on the dopamine receptor

Tetrahydroisoquinoline alkaloids: in vivo metabolites of L-dopa in man.

Related Papers (5)

Provocation of Schizophrenic Symptoms by Intravenous Administration of Methylphenidate

Effect of chlorpromazine or haloperidol on formation of 3methoxytyramine and normetanephrine in mouse brain.

The phenomenology of experimentally induced amphetamine psychosis--preliminary observations.

Drugs, neurotransmitters, and schizophrenia.

Possible Etiology of Schizophrenia: Progressive Damage to the Noradrenergic Reward System by 6-Hydroxydopamine