Maturation of the human striatal dopamine system revealed by PET and quantitative MRI

Abstract

The development of the striatum dopamine (DA) system through human adolescence, a time of increased sensation seeking and vulnerability to the emergence of psychopathology, has been difficult to study due to pediatric restrictions on direct in vivo assessments of DA. Here, we applied neuroimaging in a longitudinal sample of n = 146 participants aged 12-30. R2', an MR measure of tissue iron which co-localizes with DA vesicles and is necessary for DA synthesis, was assessed across the sample. In the 18-30 year-olds (n = 79) we also performed PET using [11C]dihydrotetrabenazine (DTBZ), a measure of presynaptic vesicular DA storage, and [11C]raclopride (RAC), an indicator of D2/D3 receptor availability. We observed decreases in D2/D3 receptor availability with age, while presynaptic vesicular DA storage (as measured by DTBZ), which was significantly associated with R2' (standardized coefficient = 0.29, 95% CI = [0.11, 0.48]), was developmentally stable by age 18. Our results provide new evidence for maturational specialization of the striatal DA system through adolescence.

Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1. Developmental effects.

Age related-differences in Raclopride assessment of available D2/D3 receptor concentration (N = 78 individuals, 128 sessions; outlier removals: NAcc = 3, putamen = 1, caudate = 1), DTBZ assessment of VMAT2 concentration (N = 74 individuals, 119 sessions; outlier removals: NAcc = 1, putamen = 2, caudate = 0), and R2′ assessment of tissue iron content (N = 121 individuals, 180 sessions; outlier removals: NAcc = 2, putamen = 1, caudate = 2) in the striatum. All analyses were conducted using linear mixed-effects models. Model parameters can be found in Table 1.+p < 0.05 uncorrected, *p < 0.05, ***p < 0.001, ****p < 0.0001 Bonferroni corrected. DTBZ BP [11C]Dihydrotetrabenazine binding potential; Raclopride BP [11C]Raclopride binding potential.

Fig. 2. Association between R2′ and [11C]Dihydrotetrabenazine binding potential (DTBZ BP) in the nucleus accumbens.

a Tissue iron, assessed with R2′, is significantly positively associated with VMAT2 (N = 98 sessions), assessed with [11C]Dihydrotetrabenazine binding potential (DTBZ BP). Results are from a linear mixed-effects model (*p < 0.05 Bonferroni corrected). b This relationship remains after regressing age effects out of both variables (age corrected). c Cross-lagged structural equation model indicating within-subject residualized change in DTBZ BP and R2′ at visit two (bolded) are significantly positively correlated (N = 30 individuals, 60 sessions; *p < 0.05, **p < 0.01). d Visual depiction of the effect from c.

Fig. 3. Schematic depiction of PET imaging results and prior work from rodent models of dopamine system development in the striatum.

Results from the present study are indicated in dashed lines, and schematic representations of age trajectories from developmental rodent models are depicted in solid lines. DA dopamine; DTBZ [11C]Dihydrotetrabenazine binding potential, Raclopride [11C]Raclopride binding potential; C-Pu caudate-putamen; VS ventral striatum; NAcc nucleus accumbens.