The Dopamine Hypothesis of Schizophrenia: Version III--The Final Common Pathway

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Abstract

The dopamine hypothesis of schizophrenia has been one of the most enduring ideas in psychiatry. Initially, the emphasis was on a role of hyperdopaminergia in the etiology of schizophrenia (version I), but it was subsequently reconceptualized to specify subcortical hyperdopaminergia with prefrontal hypodopaminergia (version II). However, these hypotheses focused too narrowly on dopamine itself, conflated psychosis and schizophrenia, and predated advances in the genetics, molecular biology, and imaging research in schizophrenia. Since version II, there have been over 6700 articles about dopamine and schizophrenia. We selectively review these data to provide an overview of the 5 critical streams of new evidence: neurochemical imaging studies, genetic evidence, findings on environmental risk factors, research into the extended phenotype, and animal studies. We synthesize this evidence into a new dopamine hypothesis of schizophrenia-version III: the final common pathway. This hypothesis seeks to be comprehensive in providing a framework that links risk factors, including pregnancy and obstetric complications, stress and trauma, drug use, and genes, to increased presynaptic striatal dopaminergic function. It explains how a complex array of pathological, positron emission tomography, magnetic resonance imaging, and other findings, such as frontotemporal structural and functional abnormalities and cognitive impairments, may converge neurochemically to cause psychosis through aberrant salience and lead to a diagnosis of schizophrenia. The hypothesis has one major implication for treatment approaches. Current treatments are acting downstream of the critical neurotransmitter abnormality. Future drug development and research into etiopathogenesis should focus on identifying and manipulating the upstream factors that converge on the dopaminergic funnel point.

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Large recurrent microdeletions associated with schizophrenia.

Hreinn Stefansson, Dan Rujescu, Sven Cichon … (2008)

Reduced fecundity, associated with severe mental disorders, places negative selection pressure on risk alleles and may explain, in part, why common variants have not been found that confer risk of disorders such as autism, schizophrenia and mental retardation. Thus, rare variants may account for a larger fraction of the overall genetic risk than previously assumed. In contrast to rare single nucleotide mutations, rare copy number variations (CNVs) can be detected using genome-wide single nucleotide polymorphism arrays. This has led to the identification of CNVs associated with mental retardation and autism. In a genome-wide search for CNVs associating with schizophrenia, we used a population-based sample to identify de novo CNVs by analysing 9,878 transmissions from parents to offspring. The 66 de novo CNVs identified were tested for association in a sample of 1,433 schizophrenia cases and 33,250 controls. Three deletions at 1q21.1, 15q11.2 and 15q13.3 showing nominal association with schizophrenia in the first sample (phase I) were followed up in a second sample of 3,285 cases and 7,951 controls (phase II). All three deletions significantly associate with schizophrenia and related psychoses in the combined sample. The identification of these rare, recurrent risk variants, having occurred independently in multiple founders and being subject to negative selection, is important in itself. CNV analysis may also point the way to the identification of additional and more prevalent risk variants in genes and pathways involved in schizophrenia.

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The principal features and mechanisms of dopamine modulation in the prefrontal cortex.

Jeremy Seamans, Charles Yang (2004)

Mesocortical [corrected] dopamine (DA) inputs to the prefrontal cortex (PFC) play a critical role in normal cognitive process and neuropsychiatic pathologies. This DA input regulates aspects of working memory function, planning and attention, and its dysfunctions may underlie positive and negative symptoms and cognitive deficits associated with schizophrenia. Despite intense research, there is still a lack of clear understanding of the basic principles of actions of DA in the PFC. In recent years, there has been considerable efforts by many groups to understand the cellular mechanisms of DA modulation of PFC neurons. However, the results of these efforts often lead to contradictions and controversies. One principal feature of DA that is agreed by most researchers is that DA is a neuromodulator and is clearly not an excitatory or inhibitory neurotransmitter. The present article aims to identify certain principles of DA mechanisms by drawing on published, as well as unpublished data from PFC and other CNS sites to shed light on aspects of DA neuromodulation and address some of the existing controversies. Eighteen key features about DA modulation have been identified. These points directly impact on the end result of DA neuromodulation, and in some cases explain why DA does not yield identical effects under all experimental conditions. It will become apparent that DA's actions in PFC are subtle and depend on a variety of factors that can no longer be ignored. Some of these key factors include distinct bell-shaped dose-response profiles of postsynaptic DA effects, different postsynaptic responses that are contingent on the duration of DA receptor stimulation, prolonged duration effects, bidirectional effects following activation of D1 and D2 classes of receptors and membrane potential state and history dependence of subsequent DA actions. It is hoped that these factors will be borne in mind in future research and as a result a more consistent picture of DA neuromodulation in the PFC will emerge. Based on these factors, a theory is proposed for DA's action in PFC. This theory suggests that DA acts to expand or contract the breadth of information held in working memory buffers in PFC networks.

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Role of endogenous cannabinoids in synaptic signaling.

Tamás Freund, István Katona, Daniele Piomelli (2003)

Research of cannabinoid actions was boosted in the 1990s by remarkable discoveries including identification of endogenous compounds with cannabimimetic activity (endocannabinoids) and the cloning of their molecular targets, the CB1 and CB2 receptors. Although the existence of an endogenous cannabinoid signaling system has been established for a decade, its physiological roles have just begun to unfold. In addition, the behavioral effects of exogenous cannabinoids such as delta-9-tetrahydrocannabinol, the major active compound of hashish and marijuana, await explanation at the cellular and network levels. Recent physiological, pharmacological, and high-resolution anatomical studies provided evidence that the major physiological effect of cannabinoids is the regulation of neurotransmitter release via activation of presynaptic CB1 receptors located on distinct types of axon terminals throughout the brain. Subsequent discoveries shed light on the functional consequences of this localization by demonstrating the involvement of endocannabinoids in retrograde signaling at GABAergic and glutamatergic synapses. In this review, we aim to synthesize recent progress in our understanding of the physiological roles of endocannabinoids in the brain. First, the synthetic pathways of endocannabinoids are discussed, along with the putative mechanisms of their release, uptake, and degradation. The fine-grain anatomical distribution of the neuronal cannabinoid receptor CB1 is described in most brain areas, emphasizing its general presynaptic localization and role in controlling neurotransmitter release. Finally, the possible functions of endocannabinoids as retrograde synaptic signal molecules are discussed in relation to synaptic plasticity and network activity patterns.