PMID- 25010656 OWN - NLM STAT- MEDLINE DCOM- 20150527 LR - 20211021 IS - 1872-9711 (Electronic) IS - 0161-813X (Print) IS - 0161-813X (Linking) VI - 44 DP - 2014 Sep TI - Sex-dependent impacts of low-level lead exposure and prenatal stress on impulsive choice behavior and associated biochemical and neurochemical manifestations. PG - 169-83 LID - S0161-813X(14)00104-1 [pii] LID - 10.1016/j.neuro.2014.06.013 [doi] AB - A prior study demonstrated increased overall response rates on a fixed interval (FI) schedule of reward in female offspring that had been subjected to maternal lead (Pb) exposure, prenatal stress (PS) and offspring stress challenge relative to control, prenatal stress alone, lead alone and lead+prenatal stress alone (Virgolini et al., 2008). Response rates on FI schedules have been shown to directly relate to measures of self-control (impulsivity) in children and in infants (Darcheville et al., 1992, 1993). The current study sought to determine whether enhanced effects of Pb+/-PS would therefore be seen in a more direct measure of impulsive choice behavior, i.e., a delay discounting paradigm. Offspring of dams exposed to 0 or 50ppm Pb acetate from 2 to 3 months prior to breeding through lactation, with or without immobilization restraint stress (PS) on gestational days 16 and 17, were trained on a delay discounting paradigm that offered a choice between a large reward (three 45mg food pellets) after a long delay or a small reward (one 45mg food pellet) after a short delay, with the long delay value increased from 0s to 30s across sessions. Alterations in extinction of this performance, and its subsequent re-acquisition after reinforcement delivery was reinstated were also examined. Brains of littermates of behaviorally-trained offspring were utilized to examine corresponding changes in monoamines and in levels of brain derived neurotrophic factor (BDNF), the serotonin transporter (SERT) and the N-methyl-d-aspartate receptor (NMDAR) 2A in brain regions associated with impulsive choice behavior. Results showed that Pb+/-PS-induced changes in delay discounting occurred almost exclusively in males. In addition to increasing percent long delay responding at the indifference point (i.e., reduced impulsive choice behavior), Pb+/-PS slowed acquisition of delayed discounting performance, and increased numbers of both failures to and latencies to initiate trials. Overall, the profile of these alterations were more consistent with impaired learning/behavioral flexibility and/or with enhanced sensitivity to the downshift in reward opportunities imposed by the transition from delay discounting training conditions to delay discounting choice response contingencies. Consistent with these behavioral changes, Pb+/-PS treated males also showed reductions in brain serotonin function in all mesocorticolimbic regions, broad monoamine changes in nucleus accumbens, and reductions in both BDNF and NMDAR 2A levels and increases in SERT in frontal cortex, i.e., in regions and neurotransmitter systems known to mediate learning/behavioral flexibility, and which were of greater impact in males. The current findings do not fully support a generality of the enhancement of Pb effects by PS, as previously seen with FI performance in females (Virgolini et al., 2008), and suggest a dissociation of the behaviors controlled by FI and delay discounting paradigms, at least in response to Pb+/-PS in rats. Collectively, however, the findings remain consistent with sex-dependent differences in the impacts of both Pb and PS and with the need to understand both the role of contingencies of reinforcement and underlying neurobiological effects in these sex differences. CI - Copyright (c) 2014 Elsevier Inc. All rights reserved. FAU - Weston, Hiromi I AU - Weston HI AD - Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA. FAU - Weston, Douglas D AU - Weston DD AD - Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA. FAU - Allen, Joshua L AU - Allen JL AD - Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA. FAU - Cory-Slechta, Deborah A AU - Cory-Slechta DA AD - Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA. Electronic address: deborah_cory-slechta@urmc.rochester.edu. LA - eng GR - P30 ES001247/ES/NIEHS NIH HHS/United States GR - P30 ES005022/ES/NIEHS NIH HHS/United States GR - R01 ES012712/ES/NIEHS NIH HHS/United States GR - ES P30 ES001247/ES/NIEHS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20140707 PL - Netherlands TA - Neurotoxicology JT - Neurotoxicology JID - 7905589 RN - 0 (Biogenic Monoamines) RN - 0 (Brain-Derived Neurotrophic Factor) RN - 0 (RNA-Binding Proteins) RN - 0 (Receptors, N-Methyl-D-Aspartate) RN - 0 (Sert1 protein, rat) RN - 2P299V784P (Lead) RN - VH92ICR8HX (N-methyl D-aspartate receptor subtype 2A) SB - IM MH - Animals MH - Biogenic Monoamines/metabolism MH - Brain/*metabolism MH - Brain Chemistry MH - Brain-Derived Neurotrophic Factor/metabolism MH - Delay Discounting/drug effects MH - Female MH - Impulsive Behavior/*drug effects MH - Lead/analysis/*toxicity MH - Male MH - Pregnancy MH - Prenatal Exposure Delayed Effects/metabolism/*physiopathology MH - RNA-Binding Proteins/metabolism MH - Rats MH - Rats, Long-Evans MH - Receptors, N-Methyl-D-Aspartate/metabolism MH - Restraint, Physical MH - Sex Factors MH - Stress, Psychological/metabolism/*physiopathology PMC - PMC4175053 MID - NIHMS615740 OTO - NOTNLM OT - Delay of reward OT - Impulsivity OT - Lead OT - Prenatal stress OT - Serotonin EDAT- 2014/07/11 06:00 MHDA- 2015/05/28 06:00 PMCR- 2015/09/01 CRDT- 2014/07/11 06:00 PHST- 2014/01/28 00:00 [received] PHST- 2014/06/23 00:00 [revised] PHST- 2014/06/27 00:00 [accepted] PHST- 2014/07/11 06:00 [entrez] PHST- 2014/07/11 06:00 [pubmed] PHST- 2015/05/28 06:00 [medline] PHST- 2015/09/01 00:00 [pmc-release] AID - S0161-813X(14)00104-1 [pii] AID - 10.1016/j.neuro.2014.06.013 [doi] PST - ppublish SO - Neurotoxicology. 2014 Sep;44:169-83. doi: 10.1016/j.neuro.2014.06.013. Epub 2014 Jul 7.