The interaction between social determinants of schizophrenia and brain dopamine circuitry

It is well established that dopamine plays an important role in the pathogenesis of schizophrenia. A recent meta-analysis confirmed that striatal dopamine synthesis capacity and stress- or amphetamine-induced dopamine release are substantially increased in this disorder, and that both measures correlate with the severity of positive symptoms1. Meta-analytic evidence points to several social risk factors for schizophrenia (or proxies for such factors): urban upbringing, childhood trauma, low academic achievement, a personal or parental history of migration from a developing country to Europe, African-American ancestry, hearing impairment, and the presence of autism2. An important question, therefore, is whether exposure to these risk factors can influence dopamine function before the onset of the disorder. Dopamine function in the living human brain can be assessed using single photon emission computed tomography (SPECT) or positron emission tomography (PET). We conducted a systematic review of SPECT and PET studies of the relationship between chronic social stressors and striatal dopamine functioning, and obtained fairly consistent evidence of an association between childhood trauma and increased striatal dopamine synthesis and release3. This finding suggests that the relationship between childhood trauma and schizophrenia may be mediated by dopamine dysregulation. In contrast, the results of six investigations of the relationship between educational attainment and dopamine D2/3 receptor availability were mainly negative (no association)3. A study of first- and second-generation immigrants (healthy volunteers, subjects at high risk of psychosis, and antipsychotic-naïve patients with schizophrenia) and non-immigrants (divided into the same three clinical groups) examined striatal dopamine release after exposure to a psychological stressor while in the scanner. The results showed an increased striatal dopamine release for immigrants in each clinical group4. The same researchers also examined striatal dopamine synthesis capacity in immigrants and non-immigrants, divided into healthy volunteers and subjects at high risk of psychosis. The synthesis capacity was higher in immigrants than in non-immigrants and this finding applied, again, to both clinical groups4. A study of non-psychotic young adults with severe hearing impairment revealed a greater amphetamine-induced striatal dopamine release, which constitutes evidence of a sensitized dopamine system. An investigation of non-psychotic individuals with autism found, instead, no increase in striatal dopamine synthesis capacity3. A PET study of healthy individuals in New York examined the relationship between genetic ancestry and striatal dopamine D2/3 receptor availability5. African and European ancestry differentially predicted this availability in the dorsal striatum (caudate nucleus and putamen). African ancestry predicted the availability negatively, while European ancestry predicted it positively. The results remained statistically significant after correction for age, sex, body mass index, level of education, smoking status, and estimated socio-economic status. The effects, of moderate size, were not driven by variation in dopaminergic candidate genes. The reduced dopamine D2/3 receptor availability in individuals of African ancestry probably means that more receptors are occupied by endogenous dopamine, reflecting a more active dopaminergic system. It is important to clarify whether this putatively greater dopaminergic activity in people of African ancestry is a direct genetic effect or a consequence of their social status. This is not a side issue, because social status (standing, rank, prestige) appears to be the most important single predictor of our health and lifespan, which remains strong after adjustment for behavioral habits such as diet, cigarette smoking, alcohol consumption, and exercise6. Social status and economic situation are correlated, but also different. This becomes clear if one considers the ups and downs of migrants from developing countries in Europe: migration improves their economic situation, but is often accompanied by a decline in their social status. Social status affects our health profoundly in that it determines to a large degree how autonomous we are and to what extent we participate socially. The suffering due to a subordinate position or outsider status damages health in ways that are as yet incompletely understood. Research into the relationship between social status and dopamine function is very interesting, but not easy. First, the phenomenon is complex, because humans belong to multiple hierarchies (e.g., appearance, intelligence, income, social and physical abilities). Second, the measurement of social status requires effort: in the absence of individual measures, one can use group membership as an approximation. This is the approach of the social defeat hypothesis of schizophrenia, which posits that low social status and repeated humiliation increase the risk of developing the disorder in the presence of a poor homeostatic control of dopamine neurons in the dorsal striatum2. The results of research in rodents provide strong encouragement to continue this work. The vast majority of this research has relied upon the chronic social defeat stress procedure7. This involves placing a male test mouse in the home cage of a larger, male breeder mouse, screened for a sufficient level of aggressive activity. Physical interaction is permitted for 5-10 min, after which the mice are separated for 24 hours by a plexiglass barrier. This is repeated every day for 10 consecutive days, with a different dominant mouse each time. Two out of three defeated mice develop social avoidance and anhedonia-like symptoms, while a third are resilient. The main findings in the brain of sensitive mice are an increase in phasic firing of mesolimbic dopamine neurons that project from the ventral tegmental area to the nucleus accumbens, and an opposite effect in dopamine neurons projecting from the ventral tegmental area to the prefrontal cortex. Resilient mice, in contrast, display normal firing activity after the procedure. Important for our story is the possibility that social defeat leads to destabilization of the mesolimbic dopamine system via synaptic pruning. Indeed, studies in rodents have shown that social stressors, including repeated exposure to dominant animals, activate microglia and lead to excessive synaptic pruning. The loss of synapses can then disrupt the function of pyramidal neurons in the cortex, disinhibit their projections to meso-striatal regions and destabilize the meso-striatal dopamine system8. Among primates, whether low- or high-ranking animals are most stressed is a function of their social organization. In some species, the physical demands of frequent fighting can make a dominant position stressful. In cynomolgus macaques, however, a higher rank is associated with less stress and with a greater amount or availability of striatal dopamine D2/3 receptors, which may reflect a lower level of synaptic striatal dopamine. Well-designed experiments have shown that these aspects of dopamine functioning are the consequence, rather than the cause, of place in the hierarchy9. Major problems for human studies in this area are the high refusal rates due to the use of radiotracers, the impossibility to assess several aspects of dopamine function in one session, and the high costs. New techniques such as neuromelanin-sensitive magnetic resonance imaging are emerging, and may help to expand this field of research. In conclusion, SPECT and PET studies provide preliminary evidence of increased synthesis of dopamine (childhood trauma, migration), increased dopamine release (childhood trauma, migration, hearing impairment) and diminished D2/3 receptor availability (African-American ancestry) in the striatum. This is likely to be relevant for the pathogenesis of schizophrenia and schizophrenia-related disorders. Further research on the relationship between social status and dopamine function, which can also be relevant to other mental health conditions, is needed.