The Dopamine Hypothesis of Schizophrenia: An Historical and ...

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Kendler and Schaffner / Dopamine Hypothesis of Schizophrenia ■ 43 Table 1. Abbreviations Abbreviation CSF Meaning Cerebrospinal fluid D1, D2, D3, D4 and D5 Names for five distinct brain DA receptors DA DHADA DHS GH HVA IT IRF TET Dopamine Dopamine hypothesis of antipsychotic drug action Dopamine hypothesis of schizophrenia Growth hormone Homovanillic acid (main breakdown product of DA in humans) Increased turnover Increased receptor function Temporally extended theory 1968 review by Faurbye and briefly discussed in a 1972 symposium summary by Snyder, Aghajanian, and Matthysse, the first detailed and widely cited articulation of the DHS was by Matthysse in 1973. Matthysse reviews evidence that clinically effective neuroleptic drugs are distinguished from other similar agents ineffective in treating schizophrenia by their effect on DA turnover. He then asks Suppose we now assume that the hypothesis of specific blockade of DA transmission by neuroleptic drugs is true; . . . does the theory give us any clues to the neuropathological basis of schizophrenia? (p. 203) He reviews what was then known about DA tracts in the brain, arguing that, although the nigrostriatal, retinal, or tubero-infundibular DA systems are unlikely candidates for involvement in psychosis, the mesolimbic DA system could likely influence the emotional, perceptual, and cognitive functions disturbed in schizophrenia. He concludes From the blocking action of neuroleptics on DA synapses, it is a relatively small step to postulate over-activity of dopaminergic transmission in schizophrenia, whether generalized or confined to one nuclear group. (p. 204) In a review paper published in 1975 (Matthysse and Lipinski 1975), Matthysse provides a more focused definition of the DHS: “too much dopamine is released at synapses in the central nervous system” (p. 558). He then states that, in fact, “there are several dopamine hypotheses of the etiology of schizophrenia,” including excessive release of DA at synapses, hypersensitive DA receptors, underactive antagonistic neurochemical systems and/or defective feedback loops. Presciently, Matthysse’s comment about “several dopamine hypotheses” illustrates his early awareness that the “general” DHS fact in fact required elaboration or further specification using more precise subsidiary hypotheses (e.g., specifying whether there is excess release or whether the DA receptors are hypersensitive). This is a point to which we return in the next section. The DHS was also influenced by observations that chronic administration of high doses of amphetamines could produce a paranoid or
44 ■ PPP / Vol. 18, No. 1 / March 2011 schizophrenia-like psychosis (Connell 1958). Two studies in 1968 (Griffiths et al. 1968) and 1974 (Angrist et al. 1974) showed that these effects occurred in non-psychotic individuals and did not result from sleep deprivation. This work was emphasized in Snyder’s early formulation of the DHS (Snyder 1976). Shortly after the initial articulations of the DHS, new scientific results began to appear of relevance to the nascent theory. In 1974, Hökfelt et al. demonstrated DA terminals in limbic cortex. Shortly thereafter, the first DA receptors were isolated and it was demonstrated, in 1976, that the clinical potency of neuroleptic drugs correlated strongly with their ability to inhibit binding of specific ligands at the DA receptor (Creese et al. 1976; Seeman et al. 1976). The early status of the DHS was summarized in a detailed 1976 review by Meltzer and Stahl. Their definition of the DHS was “schizophrenia may be related to a relative excess of DA-dependent neuronal activity.” In addition to the mesolimbic DA system, Meltzer and Stahl focus extensively on the mesocortical DA system about which they write: It is tempting to assume that the disturbances of thinking and symbolic processes that are an essential feature of many . . . [p]atients in the schizophrenia spectrum are based on dysfunction of these dopaminergic neurons with cerebral cortical terminals. (p. 24) As emphasized earlier by Matthysse, Meltzer and Stahl’s review makes clear that the “relative excess” of DA function could arise in many places in complex neuronal and biochemical systems. A number of further scientific advances had direct impact on the DHS. These include the discovery in 1977 that low doses of the DA agonist drug apomorphine inhibits DA functioning (Aghajanian and Bunney 1977), which led to the development of the concept of the autoreceptor—receptors that sit on the pre-synaptic neuron and typically, when stimulated, inhibit neuronal firing. In 1979, two subtypes of DA receptors were isolated then termed D1 and D2 (Kebabian and Calne 1979). Genes were identified for these and other DA subtypes for D2 in 1988 (Bunzow et al. 1988), D3 in 1990 (Sokoloff et al. 1990), and D4 and D5 both in 1991 (Sunahara et al. 1991; Van Tol et al. 1991). Attempts at Empirical Validation The dopamine hypothesis of schizophrenia is . . . supported by no direct evidence. No one has found anything conclusively abnormal about dopamine in body fluids or brains or schizophrenics. (Snyder 1976, 197–8) Although by the late 1970s, the DHS was the leading biological theory for schizophrenia, it was widely appreciated that the supporting evidence for the hypothesis was entirely indirect. There then began a wide-spread effort, continuing up to the present day, to test empirical prediction of the DHS—that individuals with schizophrenia should demonstrate a functional DA excess somewhere in their brains. This italicized expression represents a high-level-of-abstraction, central hypothesis that is common to a range of more specific elaborations or subforms of a theory. Usually, the specific elaborations arise over time, as different investigators provide the details of the theory that elaborate on the abstract central hypothesis. Those details typically specify the etiology and mode of action of the excess DA (e.g., increased turnover [IT] or increased post-synaptic receptor function), the causal consequences of the excess DA (both chemical and symptomatic), as well as the location of action of the DA in the brain (is action global or regional and if the latter which region?). The abstract central hypothesis of the DHS and one possible manner of its elaboration is shown graphically in Figure 1. This way of understanding the nature of theory in psychiatry parallels the accounts developed both in Schaffner (1993, Chapters 3 and 5) and in Thagard (2000, Chapter 2, especially pages 34–5). From this immense literature, we review six research areas, in part because of the availability of good quality reviews: (i) Cerebrospinal fluid (CSF) DA metabolites, (ii) neuroendocrine measures, (iii) clinical response to psychostimulants, (iv) brain levels of DA and its metabolites, (v) brain studies of DA receptors, and (vi) genetic association studies. These areas, outlined in Table 2, are chosen to be representative of efforts to validate the DHS and do not reflect all relevant information about the DHS. Furthermore, the first four areas are no longer actively under investigation and so may be viewed with some historical detachment and
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