The Dopamine Hypothesis in Schizophrenia

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The Dopamine Hypothesis in Schizophrenia

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The Dopamine Hypothesis in Schizophrenia
Theories and claims of experimental evidence of biochemical abnormalities in schizophrenia(s) have been legion, including speculations about roles for nearly all of the neurotransmitter compounds or their derivatives. Dopamine is the neurotransmitter currently most strongly implicated in the actions of antipsychotic drugs and in the mediation of amphetamine-induced psychosis, the leading experimental model for schizophrenic psychosis. Phenothiazines reverse the primary symptoms of schizophrenia-the thought disorder, disturbances of affect and interpersonal withdrawal-while little affecting delusions, hallucinations, or nonspecific symptoms of anxiety and depression. It must be emphasized, however, that a dopamine hypothesis of antipsychotic drug action does not necessarily imply any primary role of dopamine in the pathogenesis of schizophrenia. There is no direct evidence of dopaminergic hyperactivity in schizophrenic patients; the major metabolite (homovanillic acid) has normal concentration in the cerebrospinal fluid, and serum prolactin, the release of which is strongly influenced by DA neurons, is also normal.

Carlsson and Lindqvist first suggested that phenothiazine and butyrophenone drugs blocked DA receptors, since these drugs increased concentrations of DA metabolites in brain, while the ineffective phenothiazine, promethazine, an antihistaminic drug, produced no such metabolic changes. The potency of antipsychotic phenothiazines is correlated with their conformational similarity to DA as it would fit into DA receptors. In an attempt to differentiate antipsychotic actions from parkinsonian actions of phenothiazines, thioridazine and clozapine, potent antipsychotic drugs with relatively weak parkinsonian effects, have been investigated extensively in animals. These agents are highly active in several DA test systems. Parallel studies of the affinity of antischizophrenic drugs for muscarinic cholinergic receptors show inverse correlation with their tendency to elicit extrapyramidal side effects; clozapine and thioridazine act on DA receptors just like other phenothiazines but avoid the extrapyramidal side effects by a balancing blockade of ACh receptors in the striatum.

Amphetamines and related stimulant drugs in small doses can exacerbate the symptoms of schizophrenic patients and in large doses can elicit a psychosis clinically indistinguishable from acute paranoid schizophrenia. These behavioral changes are reversed by phenothiazines and butyrophenones, the DA receptor-blockers. Amphetamine is now considered a far better mimic of schizophrenia, at least the acute paranoid type, than such psychedelic drugs as LSD, mescaline and dimethyltryptamine. Animal studies show that these stimulant drugs induce stereotyped, repetitive, apparently purposeless activities to the exclusion of normal behaviors. Such activities include sniffing, licking, biting and gnawing-while eating, grooming and sleeping are neglected. Amphetamines, cocaine, phenmetrazine, and Ldopa all elicit a desynchronized electroencephalogram, with associated increase in reticular formation multiple unit activity, a reflection of central nervous system stimulation. These electroencephalographic effects are entirely different from the hypersynchronous electroencephalographic changes induced by perception-distorting psychedelic agents. Local stimulation of DA receptors and chemical sympathectomy with 6-hydroxy-dopamine provide strong evidence that amphetamineinduced stereotypy is mediated by DA pathways.

This overview of research on schizophrenia presents the current focus on dopamine mechanisms. Work on urinary metabolites, including the "pink spot" (dimethylphenylethylamine), plasma proteins and methylated derivatives of neurotransmitter metabolites in brain all have fallen into the background. However, the transmethylation hypothesis might still apply in certain inborn errors of sulfur metabolism, especially those intrinsic to brain. Given compelling evidence for genetic predisposition to schizophrenia, it is necessary to seek primary gene products, enzymes or polypeptide receptors, rather than just altered metabolic relationships. Dopamine-/l-hydroxylase activity in brains of schizophrenics has been reported to be decreased, possibly accounting for deficiency of NE in a NE-mediated reward system. However, these observations have not been confirmable. Other investigators have assayed monoamine oxidase (MAO) in platelets, a potential peripheral source of at least one type of brain MAO. MAO activity is reduced in platelets of schizophrenics and in nonschizophrenic identical co-twins of schizophrenic twins. Reduced MAO activity, opresumably determined genetically, could cause relative excess of DA (and other biogenic amines), but the effect is not specific for schizophrenia. Assay of brain MAO has failed to show similar deficiency.
Neurochemistry and Behavior in Man [1976] - ... 2/?page=13 , ... 2/?page=14
PDF file of the complete article [3.7 MB] ... 0-0026.pdf
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