Age‐dependent differences in dopamine transporter and vesicular monoamine transporter‐2 function and their implications for methamphetamine neurotoxicity

Abstract

The abuse of methamphetamine (METH) is a serious public health problem because METH can cause persistent dopaminergic deficits in the brains of both animal models and humans. Surprisingly, adolescent postnatal day (PND)40 rats are resistant to these METH-induced deficits, whereas young adult PND90 rats are not. Studies described in this report used rotating disk electrode voltammetry and western blotting techniques to investigate whether there are age-dependent differences in monoamine transporter function in PND38-42 and PND88-92 rats that could contribute to this phenomenon. The initial velocities of dopamine (DA) transport into, METH-induced DA efflux from, and DA transporter (DAT) immunoreactivity in striatal suspensions are greater in PND38-42 rats than in PND88-92 rats. DA transport velocities into vesicles that cofractionate with synaptosomal membranes after osmotic lysis are also greater in PND38-42 rats. However, there is no difference in vesicular monoamine transporter-2 (VMAT-2) immunoreactivity between the two age groups in this fraction. This suggests that younger rats have a greater capacity to sequester cytoplasmic DA into membrane-associated vesicles due to kinetically upregulated VMAT-2 and also have increased levels of functionally active DAT. In the presence of METH, these may provide additional routes of cellular efflux for DA that is released from vesicles into the cytoplasm and thereby prevent cytoplasmic DA concentrations in younger rats from rising to neurotoxic levels after drug administration. These findings provide novel insight into the age-dependent physiological regulation of neuronal DA sequestration and may advance the treatment of disorders involving abnormal DA disposition including substance abuse and Parkinson's disease. The abuse of methamphetamine (METH) is a serious public health problem with 7.3% of young adults (19-30 years of age) in the United States reporting lifetime illicit use of METH (Johnston et al., 2007b). By way of comparison, the percentages of adolescent 8th, 10th, and 12th graders in the United States reporting lifetime illicit use of METH are 2.7, 3.2, and 4.4%, respectively, (Johnston et al., 2007a). This prevalence of use is concerning because the behavioral consequences of METH differ as a function of age (Vorhees et al., 2005). METH and related stimulants can also cause long-term decreases in markers for monoaminergic neurons (Brown and Yamamoto, 2003). Specifically, multiple high-dose METH administrations cause long-term reductions in striatal dopamine (DA) content, tyrosine hydroxylase activity, and DA transporter (DAT) density in rodents (Hotchkiss et al.,

Analysis of synaptic proteins in the cerebrospinal fluid as a new tool in the study of inborn errors of neurotransmission

“…For DAT, D2R and GABA VT, it was possible to establish a statistically significant relationship, particularly in the group of children under 6 months of age from whom most of our sample was drawn. Age-related changes in DAT functionally active protein have been described in rats (Volz et al 2009), showing a decrease between young adolescent rat levels and adult levels. Interestingly, in the same report, no difference between VMAT 2 immunoreactivity in the two groups was found, although conflicting data had previously been published (Volz et al 2006).…”

“…In the case of dopaminergic transmission, the vesicular monoamine transporter-2 (VMAT2) is responsible for the loading of dopamine (DA) and other monoamines into synaptic vesicles (Cartier et al 2010). The DA transporter (DAT) carries DA across the plasmalemmal membrane from the synaptic cleft into the cytoplasm (Volz et al 2009). The central actions of DA are mediated by five distinct receptors that belong to the G-protein receptor family.…”

Reduced sensitivity to reinforcement in adolescent compared to adult Sprague-Dawley rats of both sexes

“…Based on the extensive changes occurring in the brain during adolescence (Andersen et al 1997(Andersen et al , 2000Dagher et al 2001;Koss et al 2014;Juraska and Willing 2017), another possibility is that differences in pharmacodynamics (e.g. dopamine transporter function; Volz et al, 2009) contribute to our findings. Further studies will be required to determine the impact of pharmacokinetics and pharmacodynamics on age-and sex-differences in drug seeking.…”

Perturbed Development of Striatal Dopamine Transporters in Fatty Versus Lean Zucker Rats: a Follow-up Small Animal PET Study

“…However, other studies in rat striatal membranes showed that the B max of [ 3 H]GBR-12935 binding peaked at 2 months [19] or 3 months of age [20] and declined substantially in the subsequent 9 months. Furthermore, the uptake rate of [ 3 H]dopamine in rat striatal synaptosomes, which is mediated by DAT, decreased between 1 and 3 months [21]. Similarly, striatal DAT protein concentrations decreased in post-mortem human material between preadolescents and young adults [22].…”