In this study we have determined, for the first time to our knowledge, the relative influence of genetic inheritance and environmental factors over presynaptic striatal dopamine function in the living human brain. Our main finding is that overall striatal presynaptic dopaminergic function is determined by a combination of genetic factors, which accounted for 44% of the variance from the ROI analysis and 33% from the parametric analysis, and individual-specific environmental factors that accounted for 56% of the variance from both the ROI and parametric analyses. We found that shared familial environmental factors had very little influence over human presynaptic striatal dopamine function. Intriguingly, heritability estimates varied between functional striatal subdivisions with the highest heritability values found in the sensorimotor striatum and the lowest in the limbic striatum.
These results have a number of implications for the interpretation of variation in striatal dopaminergic function in both health and disease. Our finding that individual-specific environmental factors account for 56% of the variance of presynaptic striatal dopamine function is consistent with previous findings that striatal dopaminergic function is adaptive to environmental influences. For example in primates, striatal dopaminergic function can be altered by change in social hierarchy, and in humans striatal dopaminergic function is associated with social status and perceived social support (Martinez et al, 2010
; Morgan et al, 2002
). Interestingly, our results contrast to the heritability of the 5HT2A
receptor, the only other neurochemical system where heritability has been established in vivo
, in which the individual-specific environmental influences accounted for <10% of the variance of the cortical signal (Pinborg et al, 2008
). One explanation for this contrast could be due to differences in measurement error, which contributes to the individual environmental variance term, between the two tracers. However, as the test–retest variability of [18F]-DOPA uptake (4–6%) (Egerton et al, 2010a
) is similar to [18F]-altanserin variability (5–12%) (Haugbol et al, 2007
), this does not account for the large differences in the individual-specific environmental variance observed between the two systems. There would therefore seem to be a marked difference in the adaptability of these two neurochemical systems to non-shared individual-specific environmental influences.
We interpret the relatively greater influence of individual-specific environmental factors on limbic presynaptic striatal dopamine function as a reflection of the greater responsiveness of the limbic striatum to environmental factors when compared with other functional striatal areas. A number of studies support this interpretation; the greatest increases in striatal dopamine release produced by environmental stimuli such as stress, monetary reward and playing a video game occurs in the ventral striatum rather than more dorsal striatal functional subdivisions (Koepp et al, 1998
; Pappata et al, 2002
; Pruessner et al, 2004
; Schott et al, 2008
). Use of stimulants, such as amphetamine, may also act preferentially to increase limbic striatal dopamine release. This is supported by amphetamine challenge studies in healthy volunteers that report greater dopamine release in the ventral striatum in healthy volunteers compared with other striatal subregions (Martinez et al, 2003
; Willeit et al, 2008
). Indeed in modeling sensitization to stimulants in humans, Boileau et al (2006)
reported that sensitization of the striatal dopamine system is greatest in the ventral striatum and with repeated exposure progressively involves the dorsal caudate and putamen. This is exactly the pattern of sensitization we would predict based on our findings.
The influence of individual-specific environmental influences on presynaptic dopamine function also has implications for the interpretation of studies of dopaminergic function in neuropsychiatric conditions such as schizophrenia and addictions. We previously found no increases in [18F]-DOPA uptake in healthy DZ co-twins of patients with schizophrenia, at high genetic risk of developing the disorder, which supports the role that environmental factors may play in influencing increased [18F]-DOPA uptake found in schizophrenia (Shotbolt et al, 2011
). The findings from this present study indicate that disease alterations in the limbic striatum in both schizophrenia and addictions are more likely to reflect individual-specific environmental than inherited risk factors for these conditions and we would suggest that future environmental risk studies focus particularly on limbic striatal function.
There are several limitations to the present study. First, the number of volunteers imaged was small in comparison to epidemiological twin studies, restricting our statistical power. However, we have previously shown very good test–retest reliability (intraclass correlation coefficient >0.84) for striatal [18F]-DOPA PET imaging on the scanner used for this study with a smaller volunteer sample size (Egerton et al, 2010a
). Furthermore, our cohort of volunteers is larger than the 5HT2A
twin study (Pinborg et al, 2008
). Second, the reliability of [18F]-DOPA PET measurements varies between functional subdivisions studied, with the greatest variability occurring in the limbic striatum. Limbic heritability estimates may therefore be less reliable than other functional subdivisions that potentially could influence the heritability pattern between functional subdivisions. However, within subject variability in the limbic striatum, although greater than in sensorimotor striatum, is nevertheless low, <8% (Egerton et al, 2010a
), so this is unlikely to account for the ~40% difference we found in heritability between the limbic and sensorimotor striatal regions. Third, the zygosity status of one pair of MZ twins was not confirmed by genetic analysis as they declined to provide consent for zygosity testing. Although the possibility remains that this pair may have been DZ, this is unlikely given the physical similarity of the pair at the time of imaging and a previous study confirming zygosity status in over 95% of twins who reported that they were MZ (Reed et al, 2005
). Moreover, the pattern of our results did not change with the exclusion of this pair from our analysis.
In summary, we have demonstrated that overall presynaptic dopamine function is determined by a combination of genetic and individual-specific environmental factors and that heritability varies between functional striatal subdivisions. These findings underline the adaptability of the striatal dopaminergic system, and particularly the limbic striatum, to individual-specific environmental influences. We would suggest that it is important to explore whether similar patterns of heritability also occur in twin studies of striatal dopamine release and post-synaptic striatal dopamine D2/D3 receptor availability. Our findings also reinforce the importance of identifying the underlying neurochemical mechanisms that mediate the effects of unique environmental factors on striatal dopamine function.