The dopamine transporter mediates the reinforcing effects of cocaine, thus playing a central role in human cocaine addiction, and perhaps providing the mechanism for inducing the effects of prenatal cocaine exposure. This possibility has stimulated growing interest in the normal and abnormal development of this transporter. [3H]WIN 35,428 is a cocaine analog that is useful for studying the distribution and density of the dopamine transporter in striatum and other brain regions. The postnatal development of the dopamine transporter in the rat striatum was measured by quantitative autoradiography with [3H]WIN 35,428. Dopamine transporter levels were low at birth, increased through day 15, followed by much more rapid growth in late postnatal development. The majority of the transporter sites appeared after day 15. Lateral to medial and anterior to posterior gradients in transporter density were established early during development, and there was also an early concentration of transporter in striosomes that became difficult to identify by day 15. Differences between the developmental patterns described here and studies using other ligands for the dopamine transporter suggest there are significant differences in the transporter binding sites for these drugs. These differences in transporter ligand binding characteristics may reflect developmental changes in post-translational modification of the transporter and/or changes in the functional activity rather than simply the presence of the transporter.
"All monoamine, metabolite, and turnover ratio endpoints measured here indicated significant effects of age. This is consistent with previous findings describing rapidly increasing DAT and SERT proteins from PND 0 through PND 21-35 (Coulter, Happe et al. 1997, Tarazi, Tomasini et al. 1998). Further, the majority of striatal development may be complete by PND 45 A C C E P T E D M A N U S C R I P T "
[Show abstract][Hide abstract] ABSTRACT: Attention Deficit Hyperactivity Disorder (ADHD) is estimated to affect 4–5% of the adult human population (Kessler et al., 2006; Willcutt, 2012). Often prescribed to attenuate ADHD symptoms (Nair and Moss, 2009), methylphenidate hydrochloride (MPH) can have substantial positive effects. However, there is a paucity of literature regarding its use during pregnancy. Thus, adult women with ADHD face a difficult decision when contemplating pregnancy. In this study, pregnant Sprague–Dawley rats were orally treated a total of 0 (water), 6 (low), 18 (medium), or 42 (high) mg MPH/kg body weight/day (divided into three doses) on gestational days 6–21 (i.e., the low dose received 2 mg MPH/kg body weight 3 ×/day). Offspring were orally treated with the same daily dose as their dam (divided into two doses) on postnatal days (PNDs) 1–21. One offspring/sex/litter was sacrificed at PND 22 or PND 104 (n = 6–7/age/sex/treatment group) and the striatum was quickly dissected and frozen. High Performance Liquid Chromatography (HPLC) coupled to a Photo Diode Array detector (PDA) was used to analyze monoamine content in the striatum of one side while a sandwich ELISA was used to analyze tyrosine hydroxylase (TH) from the other side. Age significantly affected monoamine and metabolite content as well as turnover ratios (i.e., DA, DOPAC, HVA, DOPAC/DA, HVA/DA, 5-HT and 5-HIAA); however, there were no significant effects of sex. Adult rats of the low MPH group had higher DA levels than control adults (p < 0.05). At both ages, subjects of the low MPH group had higher TH levels than controls (p < 0.05), although neither effect (i.e., higher DA or TH levels) exhibited an apparent dose–response. PND 22 subjects of the high MPH treatment group had higher ratios of HVA/DA and DOPAC/DA than same-age control subjects (p < 0.05). The increased TH levels of the low MPH group may be related to the increased DA levels of adult rats. While developmental MPH treatment appears to have some effects on monoamine system development, further studies are required to determine if these alterations manifest as functional changes in behavior.
Neurotoxicology and Teratology 08/2014; DOI:10.1016/j.ntt.2014.08.001 · 2.76 Impact Factor
"All molecular markers of dopaminergic neurons are expressed at significant levels before birth, but the explosive growth of dopamine innervation of the forebrain occurs after birth in the rat. From PN5 to PN40, most markers including dopamine content, tyrosine hydroxylase, D1 and D2 receptors and dopamine transporter increase markedly in striatum, n. accumbens and frontal cortex (Coyle and Axelrod 1972; Porcher and Heller 1972; Nomura et al. 1976; Kirksey and Slotkin 1979; Giorgi et al. 1987; Gelbard et al. 1989; Broaddus and Bennett 1990; Broaddus and Bennett 1990; Rao et al. 1991; Coulter et al. 1997; Tarazi et al. 1999). A dramatic rise in all of these dopaminergic markers occurs between two to three weeks postnatally, just before adolescence, but maturation continues until at least PN60. "
[Show abstract][Hide abstract] ABSTRACT: Adolescence is the developmental epoch during which children become adults—intellectually, physically, hormonally and socially. Brain development in critical areas is ongoing. Adolescents are risk-taking and novelty-seeking and they weigh positive experiences more heavily and negative experiences less than adults. This inherent behavioral bias can lead to risky behaviors like drug taking. Most drug addictions start during adolescence and early drug-taking is associated with an increased rate of drug abuse and dependence.The hormonal changes of puberty contribute to physical, emotional, intellectual and social changes during adolescence. These hormonal events do not just cause maturation of reproductive function and the emergence of secondary sex characteristics. They contribute to the appearance of sex differences in non-reproductive behaviors as well. Sex differences in drug use behaviors are among the latter. The male predominance in overall drug use appears by the end of adolescence, while girls develop the rapid progression from first use to dependence (telescoping) that represent a female-biased vulnerability. Sex differences in many behaviors including drug use have been attributed to social and cultural factors. A narrowing gap in drug use between adolescent boys and girls supports this thesis. However, some sex differences in addiction vulnerability reflect biologic differences in brain circuits involved in addiction. The purpose of this review is to summarize the contribution of sex differences in the function of ascending dopamine systems that are critical to reinforcement, to briefly summarize the behavioral, neurochemical and anatomical changes in brain dopaminergic functions related to addiction that occur during adolescence and to present new findings about the emergence of sex differences in dopaminergic function during adolescence.
Hormones and Behavior 11/2009; 58(1-58):122-137. DOI:10.1016/j.yhbeh.2009.10.015 · 4.63 Impact Factor
"Our laboratory and others have shown that low (15-20 mg/kg) dose cocaine produces similar extracellular dopamine levels in the striatum and nucleus accumbens in adolescents and adults (Frantz et al. 2007; Walker and Kuhn 2008). This is surprising, considering that most markers of presynaptic dopamine terminal density in the striatum, such as dopamine transporter binding, dopamine content, and vesicular monoamine transporter, reach maximal levels somewhere between PN 50 and PN 70 in rats (Coulter et al. 1997; Coyle and Campochiaro 1976, Galineau et al., 2004, Giorge et al. 1987; Nomura et al. 1976; Porcher and Heller 1972; Slotkin et al. 2002; Tarazi et al. 1998; Trauth et al. 2001). Modeling of dopamine uptake and release kinetics suggests that differences in transporter function (a higher affinity for dopamine) might enhance uptake in adolescents despite the lower transporter density (Walker et al. 2008). "
[Show abstract][Hide abstract] ABSTRACT: Adolescence may be a critical period for drug addiction. Young adolescent male rats have greater locomotor responses than adults after acute low dose cocaine administration. Further, repeated cocaine administration produces as much or more conditioned place preference but reduced locomotor sensitization in adolescents compared to adults. Acute activation of neurons by cocaine induces long-term changes in behavior by activating transcriptional complexes. The purpose of the present study was to correlate cocaine-induced locomotor activity with neuronal activation in subregions of the striatum and cortex by acute cocaine in young adolescent (postnatal (PN) 28) and adult (PN 65) male rats by measuring the induction of the plasticity-associated immediate early genes (IEGs) c-fos and zif268 using in situ hybridization. Animals were treated with saline, low (10 mg/kg), or high (40 mg/kg) dose cocaine in locomotor activity chambers and killed 30 min later. Low dose cocaine induced more locomotor activity and striatal c-fos expression in adolescents than adults whereas high dose cocaine induced more locomotor activity, striatal c-fos, and striatal zif268 expression in adults. Locomotor activity correlated with the expression of both genes in adults but correlated with striatal c-fos only in adolescents. Finally, there was a significant correlation between the expression of c-fos and zif268 in the adult striatum but not in adolescents. Our results suggest that the coordinated expression of transcription factors by cocaine continues to develop during adolescence. The immature regulation of transcription factors by cocaine could explain why adolescents show unique sensitivity to specific long-term behavioral alterations following cocaine treatment.
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