The behavioral sensitization produced by repeated amphetamine treatment may represent the neural adaptations underlying some of the features of psychosis and addiction in humans. Chromatin modification (specifically histone hyperacetylation) was recently recognized as an important regulator of psychostimulant-induced plasticity. We have investigated the effects of treatment with the histone deacetylase (HDAC) inhibitors butyric acid (BA, 630 mg/kg, i.p) and valproic acid (VPA, 175 mg/kg, i.p.) on the psyhcostimulant locomotor sensitization induced by amphetamine (AMPH, 2.0 mg/kg, i.p.). Neither BA nor VPA had locomotor effects alone, but both significantly potentiated the amphetamine-induced behavioral sensitization in mice. At the molecular level, VPA and amphetamine produced an increase of histone H4 acetylation in the striatum as detected by Western blot analysis, while co-treatment with VPA and AMPH produced an additive effect on histone H4 acetylation. We then administered the HDAC inhibitors after treatment with amphetamine for 8 days to establish locomotor sensitization. We found that repeated administration of VPA or BA for 6 days inhibited the expression of sensitized response following amphetamine challenge. Finally, in a context-specific model we studied the effect of HDAC inhibitors on amphetamine-induced association of the treatment environment (associative learning). We found that VPA and BA enhance the context-specificity of expression of amphetamine sensitization. Thus, HDAC inhibitors differentially modulate the induction and expression of amphetamine-induced effects. Together, these results suggest that dynamic changes in chromatin modification may be an important mechanism underlying amphetamine-induced neuronal plasticity and associative learning.

The effects of developmental lead exposure on the emotional reactivity, contextual fear conditioning and neurogenesis in the dentate gyrus of 60-80 days-old rats were studied. Wistar rat pups were exposed to 0.2% lead acetate via their dams' drinking water from postnatal day (PND) 1 to PND 21 and directly via drinking water from weaning until PND 30. At PND 60 and 80 the level of anxiety and contextual fear conditioning were studied, respectively. At PND 80 all animals received injections of BrdU to determine the effects of Pb on the generation of new cells in the dentate gyrus of hippocampus and on their survival and differentiation patterns. The results of the present study demonstrate that developmental lead exposure induces persistent increase in the level of anxiety and inhibition of contextual fear conditioning. Developmental lead exposure reduced generation of new cells in the dentate gyrus and altered the pattern of differentiation of BrdU-positive cells into mature neurons. A lower proportion of BrdU-positive cells co-expressed with the marker for mature neurons, calbindin. In contrast, the proportions of young not fully differentiated neurons and proportions of astroglial cells, generated from newly born cells, were increased in lead-exposed animals. Our results demonstrate that developmental lead exposure induces persistent inhibition of neurogenesis and alters the pattern of differentiation of newly born cells in the dentate gyrus of rat hippocampus, which could, at least partly, contribute to behavioral and cognitive impairments observed in adulthood.

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Background: The amount of blood that can be safely drawn from a preterm neonate for scientific purposes is poorly established. Objectives: To provide scientific evidence on the amount of blood that can be drawn from very low birth weight (VLBW) neonates for study purposes. Methods: We performed a post-hoc analysis of a pharmacokinetic (PK) study of penicillin-G, enrolling 18 neonates with a birth weight of <1,200 g, gestational age of <28 weeks and postnatal age of <5 days, with a risk of early onset sepsis. A median of 2.3 ml/kg of blood was collected from each neonate for the PK analysis. Hemoglobin (Hgb), hematocrit (Ht), basic hemodynamic parameters, total fluid intake, number of blood component transfusions and number of blood analysis for clinical indications were recorded. The control group consisted of 35 gestational age-, postnatal age- and birth weight-matched neonates who had not participated in a PK study. Results: We did not observe significant differences in any studied safety parameter, including Hgb and Ht values, between the two groups. Median number of blood component transfusions (n = 2 in both groups), median volume of transfused red blood cells (22 vs. 24 ml/kg in study vs. control group) and total daily fluid requirement were similar. The median calculated blood loss on clinical indications was 1.9 ml/24 h in the control group and 1.66 ml/24 h in the study group. Conclusions: In VLBW neonates, up to 2.3 ml/kg of blood (corresponding to 2.4% of calculated circulating blood volume) can be drawn for scientific purposes without compromising basic hemodynamic parameters, Hgb and Ht values, blood component transfusions or fluid requirements.