A chronic iron-deficient/high-manganese diet in rodents results in increased brain oxidative stress and behavioral deficits in the morris water maze.

Iron deficiency (ID) is especially common in pregnant women and may even persist following childbirth. This is of concern in light of reports demonstrating that ID may be sufficient to produce homeostatic dysregulation of other metals, including manganese (Mn). These results are particularly important considering the potential introduction of the Mn-containing gas additive, methyl cyclopentadienyl manganese tricarbonyl (MMT), in various countries around the world. In order to model this potentially vulnerable population, we fed female rats fed either control (35 mg Fe/kg chow; 10 mg Mn/kg chow) or low iron/high-manganese (IDMn; 3.5 mg Fe/kg chow; 100 mg Mn/kg chow) diet, and examined whether these changes had any long-term behavioral effects on the animals' spatial abilities, as tested by the Morris water maze (MWM). We also analyzed behavioral performance on auditory sensorimotor gating utilizing prepulse inhibition (PPI), which may be related to overall cognitive performance. Furthermore, brain and blood metal levels were assessed, as well as regional brain isoprostane production. We found that treated animals were slightly ID, with statistically significant increases in both iron (Fe) and Mn in the hippocampus, but statistically significantly less Fe in the cerebellum. Additionally, isoprostane levels, markers of oxidative stress, were increased in the brain stem of IDMn animals. Although treated animals were indistinguishable from controls in the PPI experiments, they performed less well than controls in the MWM. Taken together, our data suggest that vulnerable ID populations exposed to high levels of Mn may indeed be at risk of potentially dangerous alterations in brain metal levels which could also lead to behavioral deficits.

Nicotine sensitization and analysis of brain-derived neurotrophic factor in adolescent beta-arrestin-2 knockout mice.

Nicotine sensitization and levels of brain-derived neurotrophic factor (BDNF) were analyzed in adolescent beta-arrestin-2 knockout (betaA-2 KO) and wild type (WT) mice. The beta-arrestin-2 protein has been shown to be important in G-protein hydrolysis and receptor internalization. Four- to five-week-old adolescent betaA-2 KO and WT C57/Bl6 mice were administered either nicotine (0.5 mg/kg free base) or saline 10 min before being placed into a locomotor arena on each of 7 (Experiment 1) or 14 (Experiment 2) consecutive days. A nicotine challenge was given 7 days after sensitization was complete. In Experiment 1, betaA-2 KO mice administered nicotine or saline and WT mice administered nicotine demonstrated significant hypoactivity during early in testing, and neither WT nor betaA-2 KO mice administered nicotine demonstrated sensitization. On the nicotine challenge, WT mice administered nicotine demonstrated significantly higher activity levels compared to all groups, and this same group demonstrated significantly higher levels of accumbal BDNF compared to all groups. In Experiment 2, betaA-2 KO mice were again hypoactive compared to WT mice, whereas WT mice administered nicotine demonstrated significant hypoactivity during initial testing and significantly higher levels of activity compared to all other groups late in testing. On the nicotine challenge, WT mice that received nicotine demonstrated a significant increase in activity compared to all groups, and showed increased accumbal BDNF compared to all groups. These results show that the beta-arrestin-2 protein is important in induction and expression of nicotine sensitization as well as nicotine's effects on accumbal BDNF.

The effects of eticlopride on Morris water task performance in male and female rats neonatally treated with quinpirole.

RATIONALE: Previous studies have shown that neonatal quinpirole treatment which results in long-term dopamine D2 receptor supersensitization (D2 receptor priming) produces cognitive deficits in preweanling and adult rats behaviorally tested on the Morris water task (MWT). OBJECTIVE: This study was designed to analyze whether pretraining administration of the D2 antagonist eticlopride alleviates cognitive deficits produced by neonatal quinpirole treatment. METHODS: Both male and female Sprague-Dawley rats were treated with quinpirole HCl (1 mg/kg) or saline from postnatal days 1 to 21. From P22 to P24, rats were tested on the place version of the MWT in which a hidden platform remains stationary throughout training. From P25 to P28, rats were tested on the match-to-place version of the MWT, and rats are given a pair of daily training trials to locate the hidden platform that was moved to a new location each day. Fifteen minutes before each training session, rats were intraperitoneally administered with eticlopride (0.01 or 0.02 mg/kg) or saline. RESULTS: Pretraining eticlopride treatment alleviated cognitive deficits produced by neonatal quinpirole treatment in both male and female rats on the place version of the MWT, as well as in males tested on the match-to-place version of the MWT. However, there were no significant deficits produced by neonatal quinpirole treatment in females tested on the match-to-place version of the MWT, and control males demonstrated superiority over control females on this version of the task. CONCLUSIONS: Pretraining administration of the dopamine D2 antagonist eticlopride alleviated cognitive deficits produced by neonatal quinpirole treatment. However, it appears that the dopamine D2 receptor may have a more important influence on cognitive performance in males than in females, which may be related to increased sensitivity of the D2 receptor in males.

Neonatal quinpirole treatment impairs Morris water task performance in early postweanling rats: relationship to increases in corticosterone and decreases in neurotrophic factors.

BACKGROUND: Past studies from this laboratory have shown that quinpirole administration from postnatal day (P) 1-21 produces persistent supersensitization of the dopamine D2 receptor that persists throughout the animal's lifetime. METHODS: In Experiment 1, both male and female rats were treated with quinpirole or saline from P1-21 and tested on the place and match-to-place versions of the Morris water task (MWT) from P22-28. In Experiment 2, both male and female rats were administered either acute or chronic injections of quinpirole (1 mg/kg) or saline beginning on P1 until analysis for corticosterone (CORT) on P7, 14, or 21. RESULTS: Neonatal quinpirole treatment produced deficits on both versions of the MWT compared with saline control. One day after behavioral testing, brain tissue was harvested, and the hippocampus was analyzed for nerve growth factor (NGF) and brain-derived nerve growth factor (BDNF); NGF was found to be significantly decreased by neonatal quinpirole treatment. Acute or chronic quinpirole treatment on P14 produced a larger increase in CORT than controls and produced larger increases in CORT than control rats on P21. CONCLUSIONS: These results demonstrate that neonatal quinpirole treatment produces cognitive deficits that could be related to decreases in hippocampal NGF and increases in CORT, resulting in abnormalities in hippocampal development.

Adulthood nicotine treatment alleviates behavioural impairments in rats neonatally treated with quinpirole: possible roles of acetylcholine function and neurotrophic factor expression.

Increases in dopamine D(2) receptor sensitivity are known to be common in drug abuse and neurological disorders. Past data from this laboratory have shown that long-term increases in D(2) sensitivity can be produced by quinpirole treatment (a D(2)/D(3) agonist) during early development. The present investigation was designed to test the hypothesis that nicotine administration in adulthood would reduce both cognitive and skilled reaching impairments produced by increases in D(2) sensitivity. Female Sprague-Dawley rats were treated with quinpirole (1 mg/kg) or saline from postnatal day 1 (PD 1) to PD 21. Beginning in adulthood (PD 61), rats were treated with nicotine (0.3 mg/kg free base) or saline twice daily for 14 consecutive days before behavioural testing commenced. Animals neonatally treated with quinpirole demonstrated performance deficits on the Morris water task and a skilled reaching task compared to controls. Deficits on both tasks were completely alleviated by adulthood nicotine treatment. Animals neonatally treated with quinpirole demonstrated a significant 36% decrease of ChAT in the hippocampus compared to saline controls that was partially eliminated by nicotine. Additionally, neonatal quinpirole produced a significant decrease in hippocampal NGF content compared to controls, however, nicotine failed to alleviate this decrease in NGF. The results of this investigation demonstrate that long-term increases in dopamine D(2) receptor sensitivity produce significant decreases in hippocampal cholinergic and NGF expression that may result in cognitive impairment. Nicotine alleviates both cognitive and skilled reaching impairments caused by increases in D(2) sensitivity, but the mechanism through which nicotine is acting is currently unknown.