Prenatal haloperidol exposure: Effects on brain weights and caudate neurotransmitter levels in rats

Monoamines may exert a trophic effect on early brain development. To assess the role of dopamine in prenatal neurological development of the rat, haloperidol (HAL) was given in daily 2.5 or 5 mg/kg SC doses to dams over gestational days 6 to 20. This treatment regime did not enhance fetal mortality, but did produce reliable, if modest, stunting of the body and brain weight of offspring. The 5 mg/kg HAL dose consistently reduced offspring brain weight to roughly 90% of controls. This effect was probably permanent, in that it was seen throughout maturation and in adults as late as 140 days of postnatal age. Appropriate controls showed that this effect was not due to drug-induced reductions in food intake, to the presence of HAL in maternal milk, or to behavioral abnormalities in HAL-exposed dams. These effects had, at best, modest regional specificity, in that most brain regions were affected, independently of degree of dopaminergic innervation. Closer investigation of HAL effects on the striatum suggested that this permanent weight reduction was not accompanied by alterations in striatal concentrations of monoamines, monoamine metabolites, amino acids, choline, acetylcholine, DNA, protein, or water. It is concluded that prenatal HAL does stunt growth, but that this effect may not involve a direct drug influence restricted to the fetal dopamine system in the brain.     

Changed central and peripheral catecholamines and indoleamines in one-way crossed-intestine rats: Relationship to changes in feeding behavior and metabolism

The involvement of central and peripheral catecholamines and serotonin (5-HT) in regulation of feeding and energy metabolism was examined in one-way crossed intestine rats that show large and sustained changes in daily food intake. Five to six weeks after the crossed-intestinal surgery, catecholamines and indoleamines in dissected major brain regions and in the heart, intrascapular brown adipose tissue (IntBAT), pancreas, and serum were determined using HPLC with electrochemical detection. The food-losing rats increased daily food intake from 70.8 to 126.3 g, whereas their partners decreased daily food intake from 67.1 to 38.7 g (p < .001). Compared with the partners and sham-operated controls, the food-gaining rats had increased 5-hydroxy-indoleacetic acid (5-HIAA) throughout the brain [hypothalamus, 442.8 vs. 383.5 (p < .05) and 404.2 ng/ g (p < .05), Lateral cortex plus amygdala (LC + A), 236.6 vs. 216.8 (p < .05) and 212.0 ng/g (p < .05), brain stem, 282.8 vs. 238.7 (p > .05) and 245.1 ng/g (p = .05), cerebellum, 56.7 vs. 49.6 (p < .05) and 44.4 ng/g (p < .05). Higher 5-HIAA in food-gaining rats that were undereating are consistent with serotonin's role in inhibiting food intake. Peripherally, the rats gaining food showed significantly lower NE, 5-HT, and 5-HIAA in IntBAT compared with their partners (NE, 994.2 vs. 1236 ng/g, 5-HT 338.0 vs. 527 ng/g, and 5-HIAA, 39 vs. 51 ng/g). Because NE and 5-HT have been shown to exert stimulating effects on BAT-mediated thermogenesis, lower levels of NE, 5-HT, and 5-HIAA In IntBAT of food gaining rats are compatible with the lower metabolic rate observed in these animals. The results show that both central and peripheral catecholamines and serotonin are involved in regulation of food intake and energy metabolism.     

Early iron deficiency enhances stimulus-response learning of adult rats in the context of competing spatial information

Iron deficiency early in life results in neurocognitive deficits that persist into adulthood despite iron treatment. The hippocampus is particularly vulnerable to iron deficiency during the fetal and neonatal periods as evidenced by poorer hippocampus-mediated spatial recognition learning. However, the extent to which early iron deficiency alters interactions between hippocampus-based and extra-hippocampus based learning systems remains undetermined. The present study used an ambiguous maze-learning task to examine the learning process in iron sufficient young adult rats that had recovered from iron deficiency in the fetal and neonatal period. Animals were presented with a stimulus response-learning task in the context of spatial information; a procedure designed to elicit competition between dorsal striatum- and hippocampus-based systems respectively. Formerly iron deficient adult rats showed enhanced stimulus-response learning in the context of competing spatial/distal cue information, a finding suggestive of reduced hippocampal functional influence. The study provides evidence that early iron deficiency alters how different learning systems develop and ultimately interact in adulthood. The potential unbalancing of activity among major memory systems during early life has been postulated by others as a relevant factor underlying the developmental origins of certain psychiatric disorders.     

Impact of experimental hypothyroidism on monoamines level in discrete brain regions and other peripheral tissues of young and adult male rats

The levels of dopamine (DA), norepinephrine (NE) and serotonin (5-HT) in different brain regions as well as in blood plasma, cardiac muscle and adrenal gland of young and adult male albino rats were measured following experimentally induced hypothyroidism. Hypothyroidism induced by daily oral administration of propylthiouracil (PTU, 5 mg/kg body wt) caused a significant reduction in DA levels in most of the tissues examined of both young and adult rats after 21 and 28 days, in NE levels after all the time intervals studied in young rats, and after 21 and 28 days in adult rats. 5-HT exhibited a significant reduction in the selected brain regions and blood plasma after 21 and 28 days and in cardiac muscle after all the time intervals in the two age groups of animals. It may be suggested that the changes in monoamine levels induced by hypothyroidism may be due to disturbance in the synthesis and release of these amines through the neurons impairment or may be due to an alteration pattern of their synthesizing and/or degradative enzymes.     

Nocturnal rotational behavior in rats: Further neurochemical support for a two-population model

The relationship between circling behavior and the concentrations of dopamine (DA), serotonin, and their metabolites in corpus striatum was investigated in rats. We have previously reported evidence indicating that in both sexes there are two kinds, or populations, of rats: those with their turning biases directed away from (Contra greater than Ipsi rats), and those with their turning biases directed towards (Ipsi greater than Contra rats), the side containing the striatum with the greater dopaminergic innervation. In the present experiment rats were classified according to whether the contralateral or ipsilateral striatum contained the greater dopamine concentration. Whereas the ipsilateral striata were found to contain the same concentrations of dopamine, the contralateral sides were found to differ significantly; and the difference between the contralateral and ipsilateral dopamine concentrations was significantly correlated with the contralateral, but not the ipsilateral, dopamine concentration. These results are identical to those we previously reported using the Vmax for dopamine uptake in vitro as the measure for striatal dopaminergic innervation. As an initial attempt to determine what neurochemical mechanisms might underlie the differences between the "Contra greater than Ipsi" and "Ipsi greater than Contra" rats, it was found that dopamine turnover, as measured by the ratios of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid to DA, was higher in the striata of the latter group than in the former group. The present results are discussed in terms of their support for the two-population model, and in relation to previous work on behavioral and neurochemical asymmetry in rats.     

Prenatal exposure to organomercury,thimerosal, persistently impairs the serotonergic and dopaminergic systems in the rat brain: Implications for association with developmental disorders

Thimerosal, an organomercury compound, has been widely used as a preservative. Therefore, concerns have been raised about its neurotoxicity. We recently demonstrated perturbation of early serotonergic development by prenatal exposure to thimerosal (Ida-Eto et al. (2011) [11]). Here, we investigated whether prenatal thimerosal exposure causes persistent impairment after birth. Analysis on postnatal day 50 showed significant increase in hippocampal serotonin following thimerosal administration on embryonic day 9. Furthermore, not only serotonin, striatal dopamine was significantly increased. These results indicate that embryonic exposure to thimerosal produces lasting impairment of brain monoaminergic system, and thus every effort should be made to avoid the use of thimerosal.     

Effects of enucleation on postnatal development of catecholamines and serotonin metabolism in the superior colliculus of the rat

We have measured the level of catecholamines and serotonin and their principal metabolites, and the activities of tyrosine hydroxylase, tryptophan hydroxylase and monoamine oxidase-A and -B in the rat superior colliculus during postnatal development after bilateral removal of the eyes. The visual deprivation has different effects on the catecholamines and serotonin metabolism. The major changes in both amines were at day 15. Tyrosine hydroxylase and tryptophan hydroxylase activities increased during postnatal development but this increase was higher in enucleated compared with controls. An increase of the MAO-B to MAO-A ratio during postnatal development was found. The significance of these changes has been discussed.     

Iron-deficiency and dopaminergic treatment effects on RLS-Like behaviors of an animal model with the brain iron deficiency pattern of the restless legs syndrome

BackgroundBrain iron deficiency (BID), especially for the substantia nigra (SN), without peripheral iron deficiency (ID) has been well documented as a ubiquitous finding for restless legs syndrome (RLS) patients. This close association suggests the biology of RLS BID can produce RLS symptoms. Association, however, cannot establish such a direct relationship. Instead, the BID of RLS could be experimentally produced to determine if it then produces significant RLS-like biological or behavioral features. Forward genetics approach led to identification from the BXD strains the BXD40 females (BXD40f) as a putative animal model for the RLS BID. The BXD40f on an iron-sufficient diet have a lower iron in the VMB (containing the SN) during the active but not inactive period. This was not found for the other BXD strains evaluated. The BXD40f on an ID diet uniquely have even greater reduced VMB but not peripheral iron, matching the RLS BID pathophysiology. A prior report found that the BXD40f on an iron-sufficient diet had an RLS-like behavior of increased activity occurring only in the last part of the active period that was not present in the other strains without the low VMB iron. This increased activity matches the circadian pattern of symptoms in RLS patients with increased urge or drive to move in the last part of the day. This study asks first: if you decrease the VMB iron by an iron deficient diet do the RLS-like behaviors worsen; and second will the dopaminergic treatments effective for RLS also reduce the worsened RLSlike behaviors.MethodsIn sum, 13 BXD40f mice post weaning were randomly assigned for 100 days to either a iron-sufficient diet (n = 6) or an ID diet (N = 7). They were then evaluated for 24-h activity in their home cage using implanted G2 EMitter telemetry device. At 3 h before the end of the active period IP doses were given every other day of either: saline (vehicle only), 12.5 mg levodopa, 25 mg levodopa, 0.5 mg quinpirole, or 1 0.0 mg quinpirole.ResultsThe ID compared to irons-sufficient diet produced earlier onset of the RLS-like behavior matching the earlier onset of symptoms with increasing severity of RLS. The dopaminergic treatments significantly reduced the RLS-like behavior. Added analyses of the RLS-like behaviors as decreased resting times showed similar results to activity increases.ConclusionsThese data demonstrate both that The BXD40f provide a useful animal model of RLS and also strongly support the hypothesis that the biology of RLS BID can produce RLS symptoms.     

The detection and prevalence of iron deficiency in long-stay psychogeriatric patients

The prevalence and clinical diagnosis of iron deficiency was studied in 55 long-stay psychogeriatric patients. Iron deficiency was found in 29% of the sample and there was a trend for iron deficiency to be more common among patients with functional as opposed to organic psychiatric conditions. There were no clinical signs that could reliably detect iron deficiency and neither serum ferritin nor iron saturation studies detected more than 63% of iron-deficient patients. The importance and cost of detecting iron deficiency is discussed together with the need for attention to patients' dietary intake and physical state.     

Catecholamines and serotonin in rat frontal cortex after PCPA and 6-OHDA: Absolute amounts and ratios

The catecholamines dopamine, epinephrine and norepinephrine, as well as the indoleamine serotonin were measured using radioenzymatic assays, in the frontal cortex of normal rats and of rats in which serotonin synthesis had been inhibited with p-chlorophenylalanine. Besides serotonin, norepinephrine levels were significantly reduced, thus changing the monoamine ratios. To further evaluate these changes, two models of catecholaminergic deafferentation were analyzed, i.e., the massive catecholamine depletion induced by intraventricular 6-OHDA and the more selective norepinephrine deafferentation, obtained by microinjecting 6-OHDA in the dorsal noradrenergic bundle. The results are interpreted in relation to the functional interactions between the catecholamines and between the catecholamines and serotonin.     

Early-postnatal iron deficiency impacts plasticity in the dorsal and ventral hippocampus in piglets

In this study, we investigated whether alterations in plasticity markers such as brain-derived neurotrophic factor (BDNF), p75 neurotrophin receptor (p75^NTR) and tyrosine receptor kinase B (TrkB) are underlying iron deficiency (ID)-induced cognitive impairments in iron depleted piglets. Newborn piglets were either fed an iron-depleted diet (21 mg Fe/kg) or an iron-sufficient diet (88 mg Fe/kg) for four weeks. Subsequently, eight weeks after iron repletion (190–240 mg Fe/kg) we found a significant decrease in mature BDNF (14 kDa) and proBDNF (18 kDa and 24 kDa) protein levels in the ventral hippocampus, whereas we found increases in the dorsal hippocampus. The phosphorylation of cAMP response element binding protein (CREB) follows the mature BDNF protein level pattern. No effects were found on BDNF and CREB protein levels in the prefrontal cortex. The protein levels of the high affinity BDNF receptor, TrkB, was significantly decreased in both dorsal and ventral hippocampus of ID piglets, whereas it was increased in the prefrontal cortex. Together, our data suggest a disrupted hippocampal plasticity upon postnatal ID.     

Developmental stress and lead (Pb): Effects of maternal separation and/or Pb on corticosterone,monoamines, and blood Pb in rats

The level of lead (Pb) exposure in children has decreased dramatically since restrictions on its use were implemented. However, even with restrictions, children are exposed to Pb and still present with cognitive and behavioral deficits. One prominent aspect of the exposome of these children is that many come from low social economic status (SES) conditions, and low SES is associated with stress. In order to compare the combined effects of early stress and Pb, Sprague-Dawley rats were exposed to vehicle or Pb either alone or in combination with maternal separation stress during brain development (i.e., postnatal day (P)4–P11, P19, or P28). Maternally separated/isolated pups had lower body and thymus weights during exposure and had increased levels of blood Pb compared with vehicle controls. Isolation, but not Pb, affected the response to an acute stressor (standing in shallow water) when assessed on P19 and P29, but not earlier on P11. Interactions of Pb and isolation were found on monoamines in the neostriatum, hippocampus, and hypothalamus on turnover but not on levels, and most changes were on dopamine turnover. Isolation had greater short-term effects than Pb. Interactions were dependent on age, sex, and acute stress.     

Ferric carboxymaltose in patients with restless legs syndrome and nonanemic iron deficiency: A randomized trial

Background : Compromised iron status is important in restless legs syndrome pathophysiology. We compared the efficacy and tolerability of ferric carboxymaltose (single intravenous dose) versus placebo for restless legs syndrome treatment in iron‐deficient nonanemic patients. Methods : Patients with moderate to severe restless legs syndrome and serum ferritin < 75 μg/L (or serum ferritin 75‐300 μg/L and transferrin saturation < 20%) were randomized to ferric carboxymaltose (1000 mg iron) or placebo. Mean change difference between ferric carboxymaltose and placebo in International Restless Legs Syndrome Severity Scale score from baseline to week 4 was the primary end point; week 12 was a secondary end point. Results : Ferric carboxymaltose treatment (n = 59) led to nonsignificant improvement over placebo (n = 51) in International Restless Legs Syndrome Severity Scale score at week 4 (difference [95% confidence interval], ‐2.5 [‐5.93 to 1.02], P = 0.163), reaching significance by week 12 (‐4.66 [‐8.59 to ‐0.73], P = 0.021). Conclusions : In patients who responded to treatment, ferric carboxymaltose may require more time to stabilize restless legs syndrome than previously assumed. © 2017 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.     

d-MDMA during vitamin E deficiency: effects on dopaminergic neurotoxicity and hepatotoxicity

The mechanism of 3,4-methylenedioxymethamphetamine (d-MDMA)-induced neurotoxicity may involve formation of toxic radical species. Endogenous defenses against toxic radical species include tissue stores of vitamin E, and thiols. We examined whether vitamin E deficiency could alter d-MDMA-induced neurotoxicity by administration of the drug to animals with diet induced vitamin E deficiency. Brain vitamin E levels in deficient mice were reduced 75% compared to sufficient animals. Animals received d-MDMA 5 or 10 mg/kg or saline (delivered every 2 hx4, s.c.). Diet slightly altered d-MDMA-induced temperature modulation. In brain, MDMA treatment reduced vitamin E, total antioxidant reserve and protein thiols 72 h after the first dose. In liver, MDMA treatment reduced glutathione and total antioxidant reserve at the same time point. The vitamin E-deficient group, treated with the low dose of d-MDMA, exhibited neurotoxic responses, including reduced striatal dopamine (47%) and elevated GFAP protein (3-fold): while the sufficient diet group was not altered. The higher d-MDMA dose caused neurotoxic responses in both diet groups. Liver toxicity was determined by histopathologic examination. d-MDMA caused hepatic necrosis that was more severe in vitamin E deficient than sufficient mice. These data indicate that (1) d-MDMA administration reduces antioxidant measures at a time coincident with d-MDMA-induced neuronal damage and (2) vitamin E deficiency increases susceptibility to d-MDMA-induced neurotoxicity and hepatic necrosis.     

Similar properties of fetal and adult amine transporters in the rat brain

A variety of drug classes, including psychomotor stimulants and antidepressants, interact with monoamine transporters in order to exert their effects. Although these transporters have been extensively characterized in the adult brain, little is known about uptake mechanisms in the fetal system. High affinity dopamine (DA) and serotonin (5-HT) uptake in the striatum and frontal cortex, respectively, were examined in rat fetuses (embryonic day 20; E-20). These results were then compared to uptake in adult rat synaptosomal preparations of the same regions. The data indicate that the fetal (E-20) uptake mechanism is sodium-dependent. Furthermore, the potency of various agents to inhibit transporter function was assessed. These drugs produced a concentration-dependent inhibition of uptake, and the resulting IC₅₀ values were not significantly different from those obtained in the adult preparations. Our results provide evidence that the affinity of monoamine uptake inhibitors for fetal (E-20) DA and 5-HT transporters is similar to that observed with adult transporters. This observation has broad implications when considering neuronal development and in utero exposure to drugs that exert their effects through these transporters.     

Serotonin and dopamine in the parabrachial nucleus of rats during conditioned taste aversion learning

A microdialysis technique was used to monitor changes in serotonin (5-HT), 5-hydroxyindole acetic acid (5-HIAA) and dopamine (DA) in the extracellular space of the parabrachial nucleus (PBN) of rats to estimate the contribution of these neurotransmitter systems to the acquisition of conditioned taste aversion (CTA). A significant (280%) enhancement of 5-HT was found immediately after saccharin drinking (CS). I.p. injection of unconditioned stimulus LiCl alone (after water drinking) also increased level of 5-HT (200%). However, when saccharin intake was followed by injection of LiCl (CS–US pairing), no change in 5-HT was observed. 5-HIAA and DA were unaffected by any of the above treatments.

Thus in spite of elevation of 5-HT in PBN following saccharin consumption alone (CS) or LiCl administration alone (US) no changes in 5-HT occurred after pairing of both stimuli (CS–US). Our work demonstrates that participation of 5-HT in acquisition of CTA appears to be unlikely, and also DA appears not to be engaged in this acquisition at all. At the level of the PBN 5-HT participates mainly in CS and/or US stimuli processing, where this phenomenon has close relationship to other important physiological mechanisms, involved in behavioral control. Such as anxiety, alimentation intake.     

海洛因成瘾大鼠伏隔核毁损术前后觅药行为及多巴胺神经递质的变化

目的研究海洛因成瘾大鼠毁损伏隔核前后觅药行为及多巴胺神经递质的变化。方法建立海洛因成瘾大鼠模型，毁损大鼠双侧伏隔核，利用条件性位置偏好实验测定成瘾前、后，术前、术后成瘾大鼠觅药行为的变化，利用高效液相方法测定边缘系统多巴胺神经递质的变化。结果毁损大鼠双侧伏隔核能够完全消除条件性地点偏好。成瘾大鼠边缘系统多巴胺含量较对照组明显增高。毁损前后大鼠边缘系统多巴胺含量无明显变化。结论伏隔核是调节强化作用的重要位置，长期使用海洛因可使大鼠边缘系统多巴胺含量明显增高，但毁损前后无明显变化，与条件性位置偏好表现不同步。     

Impact of restless legs syndrome and iron deficiency on attention-deficit/hyperactivity disorder in children

OBJECTIVE: Increasing evidence suggests a significant comorbidity between attention-deficit/hyperactivity disorder (ADHD) and restless legs syndrome (RLS). Iron deficiency may underlie common pathophysiological mechanisms in subjects with ADHD plus RLS (ADHD+RLS). To date, the impact of iron deficiency, RLS and familial history of RLS on ADHD severity has been scarcely examined in children. These issues are addressed in the present study. METHODS: Serum ferritin levels, familial history of RLS (diagnosed using National Institutes of Health (NIH) criteria) and previous iron supplementation in infancy were assessed in 12 ADHD+RLS children, 10 ADHD children and 10 controls. RLS was diagnosed using NIH-specific pediatric criteria, and ADHD severity was assessed using the Conners' Parent Rating scale. RESULTS: ADHD symptom severity was higher, although not significantly, in children with ADHD+RLS compared to ADHD. The mean serum ferritin levels were significantly lower in children with ADHD than in the control group (p<0.0005). There was a trend for lower ferritin levels in ADHD+RLS subjects versus ADHD. Both a positive family history of RLS and previous iron supplementation in infancy were associated with more severe ADHD scores. CONCLUSIONS: Children with ADHD and a positive family history of RLS appear to represent a subgroup particularly at risk for severe ADHD symptoms. Iron deficiency may contribute to the severity of symptoms. We suggest that clinicians consider assessing children with ADHD for RLS, a family history of RLS, and iron deficiency.     

Vasopressin and oxytocin gene expression in intact rats and under catecholamine deficiency during ontogenesis

The development of the hypothalamic vasopressin (VP) and oxytocin (OT) systems has been studied in rats from the 16th embryonic day (E16) until the 11th postnatal day (P11). The VP and OT mRNA-producing neurons were identified on cryostat sections by in situ hybridization using oligonucleotide probes Iabeled by [³⁵S], [³H] or digoxigenin. Moreover, VP and OT gene expressions were evaluated either at E21 or at P11 following chronic depletion of catecholamines (CA). For this purpose, pregnant rats were daily injected with α-methyl-m(p)-tyrosine from gestational day 13 to 20, while neonates were daily injected with a-methyl-m(p)-tyrosine and neurotoxin 6-hydroxydopamine from postnatal day 2 to 10. No VP mRNA- or OT mRNA-expressing cells were observed in the hypothalamus of intact fetuses at E16, while 2 days later rather numerous VP and OT neurons occupied the anterior hypothalamus. One major bilateral group of VP and OT neurons was located in the supreoptic nucleus (SON). Less numerous labeled cab were found in the developing paraventricular nucleus (PVN). Some VP and OT neurons were also spread along the ventrolateral surface of the hypothalamus from the level of the median eminence, caudally, to the level of the optic nerves, rostrally. From E18 until birth, the OT neurons were localized in the dorsal portion of the SON, while its ventral portion was occupied by the VP neurons. The VP mRNA- and OT mRNA-expressing cells seemed to increase both in size and in number over the perinatal period. Frequent relatively long neuronal processes contained VP and OT mRNAs in fetuses and in newborns. When performed during the second half of the fetal life, the chronic depletion of CA did not cause any change in the VP and OT mRNA concentrations in the SON and PVN of fetuses. By contrast, similar treatment of neonates resulted in a significant increase of both mRNA levels in the SON. These data suggest that at least in the SON VP and OT gene expressions might be under the inhibitory control of CA during the neonatal period.     

Effect of pyridoxine deficiency in young rats on high-affinity serotonin and dopamine receptors

The high-affinity bindings of [3H]-5-hydroxytryptamine to serotonin S-1 receptors, [3H]-ketanserin to serotonin S-2 receptors in the cerebral cortex, [3H]-fluphenazine to dopamine D-1 receptors, and [3H]-spiroperidol to dopamine D-2 receptors in the corpus striatum were studied in pyridoxine-deficient rats and compared to pyridoxine-supplemented controls. There was a significant increase in the maximal binding (Bmax) of serotonin S-1 and S-2 receptors with a significant decrease in their binding affinities (Kd). However, there were no significant changes either in the maximal binding or binding affinity of striatal dopamine D-1 and D-2 receptors. Receptor sensitivity seems to correlate negatively with the corresponding neurotransmitter concentrations in the pyridoxine-deficient rats.