Neonatal 6-hydroxydopamine (6-OHDA) treatment of rats is associated with supersensitization of the dopamine (DA) D1 agonist induction of stereotyped and locomotor behaviors. The present study was conducted to determine whether ontogenetic treatments of these rats with the DA D1 receptor agonist, SKF 38393, would produce a maximal DA D1 receptor supersensitivity, as measured by locomotor behavior in adulthood. Rat pups were treated daily with SKF 38393-HCl (3.0 mg/kg per day, i.p.) or saline vehicle for 28 consecutive days from birth. These animals were additionally treated at 3 days after birth with 6-OHDA-HBr (100 μg, in each lateral ventricle, salt form) or its vehicle. Between 6 and 9 weeks locomotor activity or stereotyped behaviors were observed after weekly challenge doses of SKF 38393-HCl (3.0 mg/kg, i.p.). In the neonatal 6-OHDA group, successive SKF 38393 treatments produced progressively greater locomotor activity. In the group of rats treated during postnatal ontogeny with both 6-OHDA and SKF 38393 daily treatments, the first adult challenge dose of SKF 38393 produced an enhanced locomotor response, greater than that seen in other groups (P < 0.01). Subsequent SKF 38393 treatments of this group produced increasingly greater locomotor responses. SKF 38393-induced stereotyped behavioral effects were greater in the 6-OHDA-lesioned groups, whether or not SKF 38393 was administered ontogenetically. Profound reductions (> 99%) of DA and its metabolites were found in the striatum of neonatal 6-OHDA treated rats, regardless of whether SKF 38393 was co-administered ontogenetically. A marked elevation in striatal 5-HT (> 50%) accompanied the DA depletion in the striatum. These findings indicate that neonatal 6-OHDA treatment produces the expected destruction of striatal DA fibers with associated sprouting of 5-HT fibers, while repeated ontogenetic treatments of these rats with a D1 agonist produces partial sensitization of the DA D1 receptors in adulthood.

The effect of chronic postnatal treatment of rats with selective D1- and/or D2-receptor antagonists on the development of D1- and D2-receptors in the striatum was studied. When neonatal rats were treated postnatally from the day of birth for 32 successive days with the D1-receptor antagonist, SCH-23390 (0.30 mg/kg i.p.), the development of striatal dopamine D1-receptors was markedly impaired, and the development of striatal D2-receptors was slightly impaired. Alternatively, chronic treatment with the D2-receptor antagonist, spiroperidol (1.0 mg/kg i.p.), resulted in a markedly impaired development of striatal dopamine D2-receptors, and a slightly impaired development of striatal D1-receptors. Scatchard analysis revealed that chronic SCH-23390 treatment during development resulted in a 78% decrease in the Bmax for in vitro binding of [3H]SCH-23390 to striatal homogenates, while the Kd was unaltered. Similarly, chronic postnatal treatment with spiroperidol was associated with a 74% reduction in the Bmax, while the Kd for in vitro binding of [3H]spiroperidol to striatal homogenates was unchanged. These findings demonstrate that chronic selective dopamine receptor antagonism affects development of both striatal D1- and D2-receptor types. The critical period during which striatal dopamine receptor ontogeny can be altered is not restricted to prenatal periods, since suitable postnatal challenge will alter striatal dopamine-receptor development.

Long-term postnatal treatment of rats with the dopamine D2 receptor antagonist, spiroperidol, results in the impaired development of striatal D2 receptors. Because the tripeptide prolyl-leucyl-glycinamide (MIF-1) attenuates haloperidol-induced up-regulation of striatal dopamine D2 receptors in adult rats, we studied the effect of MIF-1 on the spiroperidol-induced alteration of striatal D2 ontogeny. Postnatal treatment of rats with spiroperidol (1.0 mg/kg/day, IP, ×32 days from birth) resulted in a 74% decrease in the Bmax for [3H]spiroperidol binding with no change in the Kd at 5 weeks. When rats were studied at 8 weeks, in the absence of additional treatment, total specific [3H]spiroperidol binding was reduced by 59%. While MIF-1 alone (1.0 mg/kg/day, IP, ×32 days from birth) had no effect on [3H]spiroperidol binding, MIF-1 completely attenuated the ontogenic impairment of striatal D2 receptors that was produced by spiroperidol treatment. At 5 weeks the Bmax for [3H]spiroperidol binding was at the saline control level in the group of rats cotreated with spiroperidol and MIF-1. At 8 weeks, with no additional treatments, the specific binding of [3H]spiroperidol to striatum was also at control levels in the group cotreated with spiroperidol and MIF-1. These findings demonstrate that MIF-1 attenuates spiroperidol-induced impairment of development of striatal dopamine D2 receptors in rats.

Proton-coupled and sodium-dependent monocarboxylate transporters are encoded by the SLC16A and SLC5A gene family of solute carriers, and are responsible for the transport of essential nutrients such as L-lactate, pyruvate, and ketone bodies. Basigin, or CD147, acts as an ancillary protein for MCT1 and MCT4, and is involved in membrane surface expression of transporters. MCT's are also involved in the shuttling of monocarboxylic xenobiotics across cell membranes, including the drugs valproate and gamma hydroxybutyrate. MCT’s are also important for normal mammalian development, particularly during embryogenesis and early neonatal life. Previous studies have shown that ketogenic diets increase MCT expression in the brain, and the obesity biomarker leptin increases MCT1 and CD147 expression and colocalization in colonocytes. Clinical studies in post-mortem tissue demonstrated that hepatic MCT1 expression changes nonlinearly from birth to adulthood. We hypothesize that age and high fat dietary intake regulate monocarboxylate transporter and ancillary protein expression in the liver, and other organs of drug disposition during childhood obesity. The purpose of this study was to elucidate just how diet and ontogeny regulate MCT1, MCT4, CD147, and SMCT1 mRNA and protein expression in the liver, kidney, and ileum. Timed-pregnant rats were fed either normal or high fat diet, and tissue was harvested from the progeny of both cohorts at predetermined postnatal timepoints. Serum leptin levels were measured, and MCT1, MCT4, CD147, and SMCT1 transcripts were evaluated using real time quantitative PCR. Whole cell and total membrane proteins were extracted and transporter expression was analyzed via western blot. In summary, we have demonstrated age, diet, and sex dependent regulation of MCT1, MCT4, CD147, and SMCT1 expression in the liver, kidneys, and intestine, and that these effects are tissue specific. Pediatric drug-dosing is both a pressing and understudied clinical field, with the possibility of altered pharmacokinetics in obese children. Changes in hepatic, renal, and intestinal monocarboxylate transporter expressions during mammalian development may affect functional activity of these transporters and lead to altered metabolism and drug disposition. Further studies of this animal model can shine new light on the dynamic and highly-variable nature of drug pharmacokinetics in pediatric obesity.

京都大学 / 0048 / 新制・課程博士 / 博士(理学) / 甲第20557号 / 理博第4315号 / 新制||理||1620(附属図書館) / 京都大学大学院理学研究科生物科学専攻 / (主査)教授 友永 雅己, 准教授 後藤 幸織, 教授 平井 啓久 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

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The preservation and quantity of fossil tapirs (Tapirus polkensis) from the Gray Fossil Site in northeastern Tennessee provides a unique opportunity for comparison and analysis of skeletal characters. Intraspecifically, modern tapirs show little to no variation in the morphology of the sagittal crest. However, several different morphologies exist within the sample at Gray. No osteological evidence of sexual dimorphism exists for tapirs, and no correlation between crest shape and sex was observed. Several juveniles display well defined crests, while some adults have only minor thickening of the temporal ridges; therefore, no distinct correlation between age and crest state could be established. Three different patterns of wear exist within the sample, but there is no correlation between these and crest morphology. No cranial pathologies were found to be associated with a crest type. Despite some correlations the sagittal crest could simply be a variable character due to intraspecific variation.

Excavations of ACb-3 Cave have uncovered the remains of at least seven individual Megalonyx jeffersonii, providing the most complete ontogenetic sequence of the taxon from one locality. Four individuals representing four distinct age classifications (infant, juvenile, subadult, and adult) were described and examined for pathologies. Cranial and major forelimb elements depict a change in morphology (trending from robust and stout to gracile and elongate) through ontogeny. Pathologies on the scapula and radius of the adult ground sloth indicate a potential attack from fighting or mating. The presence of infant and juvenile sloths suggests this cave may have been used as a maternity den. The nearly complete adult (RMM 5353) was compared to Megalonyx from other North American localities. Bivariate plots, created using linear measurements, showed that RMM 5353 was within the size range of M. jeffersonii and further supports the concept of Megalonyx chronospecies.