Marked disparity between age‐related changes in dopamine and other presynaptic dopaminergic markers in human striatum

Abstract

Because age-related changes in brain dopaminergic innervation are assumed to influence human disorders involving dopamine (DA), we measured the levels of several presynpatic DAergic markers [DA, homovanillic acid, tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (AADC), vesicular monoamine transporter 2 (VMAT2), and dopamine transporter (DAT)] in post-mortem human striatum (caudate and putamen) from 56 neurologically normal subjects aged 1 day to 103 years. Striatal DA levels exhibited pronounced (2-to 3-fold) post-natal increases through adolescence and then decreases during aging. Similarly, TH and AADC increased almost 100% during the first 2 post-natal years; however, the levels of TH and, to a lesser extent, AADC then declined to adult levels by approximately 30 years of age. Although VMAT2 and DAT levels closely paralleled those of TH, resulting in relatively constant TH to transporter ratios during development and aging, a modest but significant decline (13%) in DAT levels was observed in only caudate during aging. This biphasic post-natal pattern of the presynaptic markers suggests that striatal DAergic innervation/ neuropil appears to continue to develop well past birth but appears to become overelaborated and undergo regressive remodeling during adolescence. However, during adulthood, a striking discrepancy was observed between the loss of DA and the relative preservation of proteins involved in its biosynthesis and compartmentation. This suggests that declines in DA-related function during adulthood and senescence may be explained by losses in DA per se as opposed to DAergic neuropil.

Distribution of Vesicular Monoamine Transporter 2 Protein in Human Brain: Implications for Brain Imaging Studies

“…The lack of an aging change of VMAT2 protein in the nigrostriatal system in our limited sample size and within a limited age span is nonetheless consistent with a previous Western blotting study (Haycock et al, 2003) and a recent PET VMAT2 imaging report (Troiano et al, 2010) although the question of the influence of aging on striatal VMAT2 in the human is still controversial (cf. Troiano et al, 2010).…”

“…As expected (Haycock et al, 2003), the antibody detected in human striatal samples a total of four broad protein bands with an MW of B75 (I), 55 (IIa), 45 (III), and 35 kDa (IV), respectively ( Figure 1A). The B75 kDa VMAT2 I was the predominant band, accounting for 53% ± 2% (n = 10) and 56% ± 3% (n = 10) of the total VMAT2 immunoreactivity in putamen and caudate, respectively.…”

“…The intensity of the smaller bands decreased along with their sizes in the putamen (28% ± 1%, 14% ± 1%, and 5% ± 1% of total, respectively; see Figure 2B) and caudate (26%±2%, 14%±1%, and 5%±1% of total, respectively). The B35 kDa band IV was either ignored (Haycock et al, 2003;Jassen et al, 2005) or not reported (Miller et al, 1999) in previous studies due to its weak staining.…”

Gonadal steroids mediate the opposite changes in cocaine-induced locomotion across adolescence in male and female rats

“…These observations are not surprising as the presence or absence of sex hormones is only one factor that could affect behavioral responsiveness to stimulants across adolescence. Forebrain dopamine systems continue to mature and reorganize across adolescence (Haycock et al 2003;Montague et al 1999;Teicher et al 1995;reviewed in Spear 2000). For example, it has been shown that there is an overproduction and regressive pruning of striatal dopamine receptors during adolescence (Teicher et al 1995).…”

Response bias and aging on a recognition memory task

“…The multiple factor framework proposes "distinct age-associated cascades that target different brain systems and may independently vary in their level of progression across individuals" (in Buckner, 2004, p. 196). Investigators have given particular attention to frontalstriatal white matter changes (Salat et al, 2005), frontal gray (Raz et al, 1997;Salat et al, 1999) and striatal volume loss (Raz et al, 2003), and neuro-chemical changes such as reduction of dopamine (Haycock et al, 2003). Typically, researchers refer to age ranges starting at 65 and older as a particularly vulnerable period for expression of specifically age associated pathophysiological changes (Buckner, 2004).…”