This essay selectively reviews, from an historical and philosophical perspective, the dopamine (DA) hypothesis of schizophrenia (DHS; Table 1 lists the abbreviations used in this essay). Our goal is not to adjudicate the validity of the theory—although we arrive at a generally skeptical conclusion—but to focus on the process whereby the DHS has evolved over time and been evaluated. Since its inception, the DHS has been the most prominent etiologic theory in psychiatry and is still referred to widely in (...) current textbooks (e.g., Buchanan and Carpenter, Jr. 2005, 1336; Cohen 2003, 225; Gazzaniga 2004, 1257;Kandel et al. 2000, 1200). Understanding its origins and evolution should help to clarify the nature of modern .. (shrink)

Kendler and Schaffner have written an exemplary case study of the rise of the dopamine hypothesis and, if not its fall, at least its stagnation and transmutation. They bring out well both the state of the science and the opportunities offered by the theory to consider some famous philosophical theories of scientific progress. So well, in fact, have they done this, that I do not have a lot to say about it. I will just mention one or two points (...) that I found interesting, and then say a little about what looks to me like an omission from the story that the two Kens recount.One point they raise is the importance of competitor theories: now, there is supposed to be an old story about a quack who was apprehended during .. (shrink)

Disruptions in dopamine transmission within the basal ganglia (BG) produce deficits in voluntary actions, that is, in the interface between cortically-generated goal representation and BG-mediated response selection. Under conditions of dopamine loss in humans and other animals, responses are impaired when they require internal generation, but are relatively intact when elicited by external stimuli.

Impaired performance in verbal fluency tasks is a frequent observation in Parkinson’s disease. As to the nature of the underlying cognitive deficit, it is commonly attributed to a frontal-type dysexecutive syndrome due to nigrostriatal dopamine depletion. Whereas dopaminergic medication typically improves VF performance in PD, e.g., by ameliorating impaired lexical switching, its effect on semantic network activation is unclear. Data from priming studies suggest that dopamine causes a faster decay of semantic activation spread. The aim of the current (...) study was to examine the impact of dopaminergic medication on the dynamic change of word frequency during VF performance as a measure of semantic spreading activation. To this end, we performed a median split analysis of word frequency during phonemic and semantic VF task performance in a PD group tested while receiving dopaminergic medication as well as after drug withdrawal, and in a sample of age-matched healthy volunteers. Dopaminergic medication in the PD group significantly affected phonemic VF with improved word production as well as increased error-rates. The expected decrease of word frequency during VF task performance was significantly smaller in the PD group ON medication than in healthy volunteers across semantic and phonemic VF. No significant group-difference emerged between controls and the PD group in the OFF condition. The comparison between both treatment conditions within the PD group did not reach statistical significance. The observed pattern of results indicates a faster decay of semantic network activation during lexical access in PD patients on dopaminergic medication. In view of improved word generation, this finding is consistent with a concept of more focused neural activity by an increased signal-to-noise ratio due to dopaminergic neuromodulation. However, the effect of dopaminergic stimulation on VF output suggests a trade-off between these beneficial effects and increased error-rates. (shrink)

Depue & Collins propose that extraversion should be separated from the impulsivity-constraint dimension of personality, and that the VTA dopamine system is the primary engine of extraversion. Although their focus is on personality traits, it may be useful to consider the evidence on psychological state changes, related both to affective arousal and to drug effects. This evidence shows that there are inherent relations between extraversion and impulsivity-constraint, and that there are influences of dopamine on impulsivity-constraint that are not (...) consistent with the Depue & Collins model. Increased positive affect leads to increased extraversion, and this is associated with more impulsivity and less constraint. The evidence on drug effects shows that greater dopaminergic control is associated with more constraint, and with anxiety and vigilance rather than positive affect. (shrink)

Interpreting VTA dopamine activity as a facilitator of affective engagement fits Depue & Collins's agency dimension of extraverted personality and also Watson's and Tellegen's (1985) engagement dimension of state mood. Serotonin, by turning down the gain on dopaminergic affective engagement, would permit already prepotent responses or habits to prevail against the behavior-switching incentive-simulation-driven temptations of the moment facilitated by fickle VTA DA. Intelligent switching between openly responsive affective engagement and constraint by long-term plans, goals, or values presumably involves environment-sensitive (...) balancing of these neuromodulators, such as socially dominant primates may show. (shrink)

Sensitivity to incentive motivation has a formative influence on extraversion. Mesoamygdaloid dopamine (DA) activity may, at one level, act as a micro-gate permitting an incentive to influence behavioral organization – “Go/No-Go” in this scheme. Data on function elsewhere in the mesocorticolimbic DA system are taken to support this particular function. At another level of analysis, the data in Depue & Collins's review, along with those on the rest of the ventral tegmental area (VTA) system, may fit better with a (...) “switching” function in information processing. This link is supported by correlations between measures of extraversion, learned inattention, and overall DA activity. The point is extended to the novelty-seeking feature of the extraverted personality. (shrink)

The effects of striatal dopamine (DA) on behavior have been widely investigated over the past decades, with “phasic” burst firings considered as the key expression of a reward prediction error responsible for reinforcement learning. Less well studied is “tonic” DA, where putative functions include the idea that it is a regulator of vigor, incentive salience, disposition to exert an effort and a modulator of approach strategies. We present a model combining tonic and phasic DA to show how different outflows (...) triggered by either intrinsically or extrinsically motivating stimuli dynamically affect the basal ganglia by impacting on a selection process this system performs on its cortical input. The model, which has been tested on the simulated humanoid robot iCub interacting with a mechatronic board, shows the putative functions ascribed to DA emerging from the combination of a standard computational mechanism coupled to a differential sensitivity to the presence of DA across the striatum. (shrink)

Patients with schizophrenia have an impairment in the inhibition of reflexive saccades, as a consequence of a functional impairment of the prefrontal cortex, which has not yet been encapsulated in terms of a formal model. A number of novel and testable hypotheses can be generated from the framework proposed by Findlay & Walker that will stimulate further research. Their framework therefore marks an important step in the development of a comprehensive functional model of saccadic eye movements. Further advances will be (...) assisted by (1) a recognition of important distinctions in the executive control of volitional saccades and (2) addressing the capacity for cross-model integration of spatial information in the generation of the spatial properties of saccadic eye movements. (shrink)

Depue & Collins's general idea of a functional relationship between DA activity and extraversion is an important step toward an integrative biological model of personality. However, focusing primarily on incentive motivation and variations in VTA DA activity as basic behavioral and biological components underlying extraversion appears too limited. Existing data suggest that responsivity to changes in DA activity is higher in introverts than in extraverts. This may reflect a general, extraversion- related characteristic of the entire dopaminergic network in the brain.

Whether or not trait affiliation correlates with human behaviour needs investigating. One should be careful generalizing neuropsychological mechanisms for affiliation, and generalizing an analysis based on one or two neuropsychological mechanisms and mostly studies on rodents, to complex human social interactions. Serotonin is an example of a neurotransmitter playing an important role in cooperation and interacting with the dopaminergic system.

New findings point to a role for mesolimbic DA circuits in the generation of dreaming. We disagree with Solms about these structures having an exclusive role in generating dreams. We review data suggesting that dreaming can be interrupted at different levels of processing and that anterior-subcortical lesions associated with dream cessation are unlikely to produce selective hypodopaminergic dynamic impairments. [Hobson et al.; Nielsen; Solms].

We are gratified at the largely positive comments on our essay on the dopamine hypothesis of schizophrenia (DHS) by these two distinguished commentators from the fields of biological psychiatry (Dr. Tamminga) and the philosophy of psychiatry (Dr. Murphy). There is little that they have said with which we disagree. Rather, we want to expand briefly on their commentaries.We found Dr. Tamminga's reactions to be particularly fascinating because she has been an "insider" to the story of the DHS as it (...) has unfolded. She provides substantial insight into the "extra-scientific" reasons for the persistence of the DHS despite its poor empirical record.She validates our impression that the DHS was in its first years of .. (shrink)

Dopamine is critically important in the neural manifestation of motivated behavior, and alterations in the human dopaminergic system have been implicated in the etiology of motivation-related psychiatric disorders, most prominently addiction. Patients with chronic addiction exhibit reduced dopamine D2 receptor (DRD2) availability in the striatum, and the DRD2 TaqIA (rs1800497) and C957T (rs6277) genetic polymorphisms have previously been linked to individual differences in striatal dopamine metabolism and clinical risk for alcohol and nicotine dependence. Here, we investigated the (...) hypothesis that the variants of these polymorphisms would show increased reward-related memory formation, which has previously been shown to jointly engage the mesolimbic dopaminergic system and the hippocampus, as a potential intermediate phenotype for addiction memory. To this end, we performed functional magnetic resonance imaging (fMRI) in 62 young, healthy individuals genotyped for DRD2 TaqIA and C957T variants. Participants performed an incentive delay task, followed by a recognition memory task 24 h later. We observed effects of both genotypes on the overall recognition performance with carriers of low-expressing variants, namely TaqIA A1 carriers and C957T C homozygotes, showing better performance than the other genotype groups. In addition to the better memory performance, C957T C homozygotes also exhibited a response bias for cues predicting monetary reward. At the neural level, the C957T polymorphism was associated with a genotype-related modulation of right hippocampal and striatal fMRI responses predictive of subsequent recognition confidence for reward-predicting items. Our results indicate that genetic variations associated with DRD2 expression affect explicit memory, specifically for rewarded stimuli. We suggest that the relatively better memory for rewarded stimuli in carriers of low-expressing DRD2 variants may reflect an intermediate phenotype of addiction memory. (shrink)

According to the reward-prediction error hypothesis (RPEH) of dopamine, the phasic activity of dopaminergic neurons in the midbrain signals a discrepancy between the predicted and currently experienced reward of a particular event. It can be claimed that this hypothesis is deep, elegant and beautiful, representing one of the largest successes of computational neuroscience. This paper examines this claim, making two contributions to existing literature. First, it draws a comprehensive historical account of the main steps that led to the formulation (...) and subsequent success of the RPEH. Second, in light of this historical account, it explains in which sense the RPEH is explanatory and under which conditions it can be justifiably deemed deeper than the incentive salience hypothesis of dopamine, which is arguably the most prominent contemporary alternative to the RPEH. (shrink)

According to the reward-prediction error hypothesis of dopamine, the phasic activity of dopaminergic neurons in the midbrain signals a discrepancy between the predicted and currently experienced reward of a particular event. It can be claimed that this hypothesis is deep, elegant and beautiful, representing one of the largest successes of computational neuroscience. This paper examines this claim, making two contributions to existing literature. First, it draws a comprehensive historical account of the main steps that led to the formulation and (...) subsequent success of the RPEH. Second, in light of this historical account, it explains in which sense the RPEH is explanatory and under which conditions it can be justifiably deemed deeper than the incentive salience hypothesis of dopamine, which is arguably the most prominent contemporary alternative to the RPEH. (shrink)

Extraversion has two central characteristics: (1) interpersonalengagement, which consists of affiliation (enjoying and valuing close interpersonal bonds, being warm and affectionate) and agency (being socially dominant, enjoying leadership roles, being assertive, being exhibitionistic, and having a sense of potency in accomplishing goals) and (2) impulsivity, which emerges from the interaction of extraversion and a second, independent trait (constraint). Agency is a more general motivational disposition that includes dominance, ambition, mastery, efficacy, and achievement. Positive affect (a combination of positive feelings and (...) motivation) is closely associated with extraversion. Extraversion is accordingly based on positiveincentivemotivation. (shrink)