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PubMed2004

A 5-HT(2C) receptor-mediated interaction between 2,5-dimethoxy-4-methylamphetamine and citalopram in the rat.

Previous studies conducted in our laboratory have shown that acute administration of the selective serotonin re-uptake inhibitor (SSRI), citalopram, potentiates the stimulus effects of the phenethylamine hallucinogen [-]-2,5-dimethoxy-4-methylamphetamine (DOM) in the rat while neither substituting for the DOM stimulus when administered alone nor altering brain levels of DOM. The present investigation was designed to determine the mechanism by which citalopram acts on DOM-induced stimulus control. To that end, we tested the following hypotheses: (a) citalopram blocks the transport of DOM by the serotonin transporter, (b) citalopram acts via the 5-HT(1A) receptor, and (c) citalopram acts via the 5-HT(2C) receptor. Hypothesis (a) was rejected on the basis of equilibrium saturation studies of [3H]citalopram binding, which revealed no significant affinity of DOM for the 5-HT transporter of rat brain membranes. Hypotheses (b) and (c) were tested in a group of 20 rats in which stimulus control was established with DOM (0.6 mg/kg; 75 min pretreatment time). A two-lever, fixed ratio 10 (FR10), positively reinforced task with saline controls was employed. Hypothesis (b), a role for the 5-HT(1A) receptor, was rejected on the basis of an absence of antagonism of the effects of citalopram on DOM by the selective 5-HT(1A) receptor antagonist, WAY-100635. In contrast, Hypothesis (c), a role for the 5-HT(2C) receptor, gained support from the observation of significant antagonism of the effects of citalopram on DOM by the selective 5-HT(2C) receptor antagonist, SB-242084.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗

PubMed2000

The paradox of 5-methoxy-N,N-dimethyltryptamine: an indoleamine hallucinogen that induces stimulus control via 5-HT1A receptors.

Stimulus control was established in rats trained to discriminate either 5-methoxy-N,N-dimethyltryptamine (3 mg/kg) or (-)-2,5-dimethoxy-4-methylamphetamine (0.56 mg/kg) from saline. Tests of antagonism of stimulus control were conducted using the 5-HT1A antagonists (+/-)-pindolol and WAY-100635, and the 5-HT2 receptor antagonist pirenperone. In rats trained with 5-MeO-DMT, pindolol and WAY-100635 both produced a significant degree of antagonism of stimulus control, but pirenperone was much less effective. Likewise, the full generalization of 5-MeO-DMT to the selective 5-HT1A agonist [+/-]-8-hydroxy-dipropylaminotetralin was blocked by WAY-100635, but unaffected by pirenperone. In contrast, the partial generalization of 5-MeO-DMT to the 5-HT2 agonist DOM was completely antagonized by pirenperone, but was unaffected by WAY-100635. Similarly, in rats trained with (-)-DOM, pirenperone completely blocked stimulus control, but WAY-100635 was inactive. The results obtained in rats trained with (-)-DOM and tested with 5-MeO-DMT were more complex. Although the intraperitoneal route had been used for both training drugs, a significant degree of generalization of (-)-DOM to 5-MeO-DMT was seen only when the latter drug was administered subcutaneously. Furthermore, when the previously effective dose of pirenperone was given in combination with 5-MeO-DMT (s.c.), complete suppression of responding resulted. However, the combination of pirenperone and WAY-100635 given prior to 5-MeO-DMT restored responding in (-)-DOM-trained rats, and provided evidence of antagonism of the partial substitution of 5-MeO-DMT for (-)-DOM. The present data indicate that 5-MeO-DMT-induced stimulus control is mediated primarily by interactions with 5-HT1A receptors. In addition, however, the present findings suggest that 5-MeO-DMT induces a compound stimulus that includes an element mediated by interactions with a 5-HT2 receptors. The latter component is not essential for 5-MeO-DMT-induced stimulus control, but is revealed in animals tested or trained with a 5-HT2-selective agonist such as (-)-DOM. Based upon the present data, we conclude that 5-MeO-DMT differs from DOM with respect to the serotonergic element that mediates stimulus control in the rat, but that it shares with DOM a functionally significant interaction with 5-HT2 receptors.

DOM 2,5-Dimethoxy-4-Methylamphetamine↗

PubMed1990

Domoic acid: a dementia-inducing excitotoxic food poison with kainic acid receptor specificity.

Domoic acid (Dom), a rigid analog of the excitotoxic amino acids, glutamate and kainic acid, is believed to be the mussel neurotoxin responsible for a recent food poisoning incident in Canada that killed some people and left others with memory impairment. Since the literature contains very little information pertaining to Dom excitotoxicity, we have systematically evaluated the neuroexcitatory properties of Dom in vitro (cultured hippocampal neurons) and its neurotoxic properties both in vitro (chick embryo retina) and in vivo (adult rat). In the in vitro experiments, the properties of Dom were compared with those of kainic acid, N-methyl-D-aspartate (NMDA) and quisqualate, each of which is a prototypic agonist at a different subtype of glutamate receptor. Currents induced in hippocampal neurons by Dom and kainic acid were identical and displayed a linear current/voltage relationship (in contrast to NMDA currents) and were nondesensitizing (in contrast to quisqualate currents). Dom currents were not blocked by NMDA antagonists but were blocked by CNQX, an antagonist of non-NMDA receptors. In the chick embryo retina, Dom induced a lesion pattern having the same distinctive characteristics as a kainic acid lesion which differs from that induced by either NMDA or quisqualate, and the Dom lesion was blocked by CNQX but not by NMDA antagonists. Subcutaneous administration of Dom (2.5-3 mg/kg) to adult rats resulted in an acute seizure-brain damage syndrome almost identical to that induced in rats by KA (12 mg/kg) and having important features analogous to the neurotoxic syndrome observed in the human food poison victims.

Animals↗

PubMed2005

The emerging role of free radicals in delayed onset muscle soreness and contraction-induced muscle injury.

The first reported reference to delayed onset muscle soreness (DOMS) was that by Theodore Hough in 1902. Hough stated that when an untrained skeletal muscle performed exercise, it often resulted in discomfort that did not manifest until 8-10 h post-exercise, and concluded that this could not be solely attributed to fatigue. Since Hough's initial observation there has been a proliferation in research into DOMS, and despite this, the exact aetiology remains unclear. This review explores the concept of DOMS in relation to the likely causative factors and also discusses possible reasons for the equivocal findings in the literature. Free radicals are unquestionably produced during and following various forms of contractile activity and are known to result in skeletal muscle damage. Given the link between DOMS and contraction-induced muscle damage, post-exercise free radical production has been associated with DOMS; however, the precise nature of this relationship remains unsubstantiated. This review will address free radical production during and following exercise, discuss methods of assessing their generation, and critically evaluate their relationship with DOMS. There is increasing literature to suggest that free radicals act as signalling molecules, specifically activating redox sensitive transcription factors, which are necessary for muscle regeneration and adaptation following damage. Consequently free radicals may play a key physiological role in the aetiology of DOMS as opposed to a pathological role. Evidence for and against free radicals causing DOMS will be presented, and finally a suggested role of free radicals in DOMS will be proposed.

Exercise↗

PubMed2002

Probing reactivity of dissolved organic matter for disinfection by-product formation using XAD-8 resin adsorption and ultrafiltration fractionation.

The disinfection by-product (DBP) reactivity (yield and speciation upon reaction with chlorine) of dissolved organic matter (DOM) isolated from two surface waters was investigated. The source waters, each having significantly different specific ultraviolet absorbance (SUVA254), molecular weight (MW) distribution and polarity, were fractionated using XAD-8 resin adsorption and ultrafiltration (UF), with good DOM mass balance closures (based on dissolved organic carbon). It was found that such fractionation preserved both the SUVA and the reactivity of the source waters, as demonstrated by statistically similar DBP formation and speciation from chlorinated source water and source waters reconstituted from XAD-8 or UF fractions. In addition, there was no evidence of synergistic effects among DOM components when reacting with chlorine. Consistent trends between DBP yields and MW were not found. Hydrophobic fractions of DOM (isolated by XAD-8) were the most reactive DOM components; however, hydrophilic components also showed appreciable DBP yields, contributing up to 50% of total DBP formation. In contrast, strong and unique correlations were observed between the SUVA of individual fractions and their trihalomethane (THM) and haloacetic acid (HAA9) yields, confirming that the aromaticity of DOM components is more directly related to reactivity than other physicochemical properties. The finding of a single correlation independent of the fractionation process employed is notable because XAD-8 adsorption and UF fractionate DOM by significantly different mechanisms. These results confirm that SUVA is a distributed parameter that reflects DOM heterogeneity. Therefore, the SUVA distribution within natural water represents an important property that can be used as a reliable predictor of DBP formation. Finally, bromine appears to be more effectively incorporated into low UV-absorbing (i.e., low SUVA), low MW and hydrophilic DOM fractions.

Adsorption↗

PubMed2001

Bioavailability of atrazine, pyrene and benzo[a]pyrene in European river waters.

Thirteen river waters and one humic lake water were characterized. The effects of dissolved organic matter (DOM) on the bioavailability of atrazine, pyrene and benzo[a]pyrene (B[a]P) was evaluated. Binding of the chemicals by DOM was analyzed with the equilibrium dialysis technique. For each of the water samples, 24 h bioconcentration factors (BCFs) of the chemicals were measured in Daphnia magna. The relationship between DOM and other water characteristics (including conductivity, water hardness and pH), and bioavailability of the chemicals was studied by performing several statistical analyses, including multiple regression analyses, to determine how much of the variation of BCF values could be explained by the quantity and quality of DOM. The bioavailability of atrazine was not affected by DOM or any other water characteristics. Although equilibrium dialysis showed binding of pyrene to DOM, the bioavailability of pyrene was not significantly affected by DOM. The bioavailability of B[a]P was significantly affected by both the quality and quantity of DOM. Multiple regression analyses, using the quality (ABS270 and HbA%) and quantity of DOM as variables, explained up to 70% of the variation in BCF of B[a]P in the waters studied.

Animals↗

PubMed2003

Characterization and copper binding of humic and nonhumic organic matter isolated from the South Platte River: evidence for the presence of nitrogenous binding site.

Humic substances typically constitute 40-60% of the dissolved organic matter (DOM) in surface waters. However, little information is available regarding the metal binding properties of the nonhumic hydrophilic portion of the DOM. In this study, humic and nonhumic DOM samples were isolated from the South Platte River (Colorado, DOC = 2.6 mg x L(-1), SUVA254 = 2.4 L/mg x m) using a two-column array of XAD-8 and XAD-4 resins. The three major isolated fractions of DOM, which accounted for 57% of the bulk DOM,were characterized using a variety of analytical tools. Proton and copper binding properties were studied for each fraction. The main objective of this work was to compare the structural and chemical characteristics of the isolated fractions and test models describing DOM reactivity toward metal ions. The characterization work showed significant structural differences between the three isolated fractions of DOM. The hydrophobic acid fraction (i.e., humic substances isolated from the XAD-8 resin) gave the largest C/H, C/O, and C/N ratios and aromatic carbon content among the three isolated fractions. The transphilic acid (TPHA) fraction ("transphilic" meaning fraction of intermediate polarity isolated from the XAD-4 resin) was found to incorporate the highest proportion of polysaccharides, whereas the transphilic neutral (TPHN) fraction was almost entirely proteinaceous. The gradual increase of the charge with pH for the three DOM fractions is most likely caused by a large distribution of proton affinity constants for the carboxylic groups, as well as a second type of group more generally considered to be phenolic. In the case of the DOM fraction enriched in proteinaceous material (i.e., TPHN fraction), the results showed that the amino groups are responsible for the charge reversal. For low copper concentrations, nitrogen-containing functional groups similar to those of amino acids are likely to be involved in complexation, in agreement with previously published data.

Amino Acids↗

PubMed2003

Role of dissolved organic matter composition on the photoreduction of Cr(VI) to Cr(III) in the presence of iron.

The photochemical reduction of Cr(VI) by iron and aquatic dissolved organic matter (DOM) was investigated. DOM sampled from a number of surface waters (a eutrophic wetland, a blackwater stream, and river water from a mix-use watershed) was used in this study. Moreover, a fulvic acid from Lake Fryxell, Antarctica, was also used to represent a DOM derived from a strictly autochthonous source. Cr(VI) reduction to Cr(III) at pH 5.5 was observed for all target DOMs used in this study, but rates varied widely. In general, photoreduction rates increased with increasing iron concentrations, but the type of DOM appeared to influence the kinetics to a larger degree. The rate of reduction was significantly greater for DOM derived from terrestrial systems than from predominantly autochthonous materials even if additional iron was added to the later. A positive correlation was observed between rates of Cr(VI) photoreduction and properties of the isolated DOM samples whereby faster reduction was observed for larger more aromatic substrates. On the basis of the fast rates reported for the dark reduction of Cr(VI) to Cr(III) by Fe(II)-organic ligands, we hypothesize that the rate-limiting step in these reactions is the photoreduction of Fe(III) to Fe(II) by a ligand-to-metal charge-transfer pathway after absorption of light by Fe(III)-DOM complexes or by reduction of Fe(III) by superoxide or other intermediates formed after light absorption by DOM. Thus, the rate of Cr(VI) photoreduction to Cr(III) in natural sunlit waters is dependent upon both the amount of iron present and the nature of the dissolved organic matter substrate.

Biodegradation, Environmental↗

PubMed2006

Effects of dissolved organic matter on permethrin bioavailability to Daphnia species.

Synthetic pyrethroids are widely used insecticides in both agricultural and urban environments. Recent studies show frequent appearances of pyrethroid residues in runoff effluents and sediments, which stimulated concerns over the potential ecotoxicological implications. Pyrethroids are known to have two contrasting characteristics, high aquatic toxicity and strong affinity for the solid phase, that may negate the actual toxicity in a multiphased system. This study evaluated the effect of dissolved organic matter (DOM) on the pyrethroid uptake by and acute toxicity to water-column invertebrates using permethrin as a model compound. During the bioassays, the freely dissolved permethrin concentration was simultaneously measured using poly(dimethylsiloxane) (PDMS) fibers as a biomimetic surrogate. The presence of DOM consistently decreased permethrin uptake and increased its LC(50). For instance, compared to the DOM-free treatment, the LC(50) of permethrin to Ceriodaphnia dubia in a pond water containing DOM at 10 mg L(-)(1) increased from 0.56 to 1.03 microg L(-)(1), whereas the bioaccumulation factor by Daphnia magna decreased by 56%. Permethrin accumulation on the PDMS fiber closely mimicked permethrin uptake by D. magna. Statistical analyses suggest that permethrin associated with DOM was completely unavailable to D. magna or C. dubia. The effect of DOM on permethrin bioavailability appeared to depend also on the source of the DOM. These results indicate that the inhibitory role of DOM should be considered in the development of toxicologically relevant water quality limits and in monitoring protocols for permethrin and other pyrethroids in runoff effluents and surface streams that ubiquitously contain DOM.

Animals↗

PubMed2000

The marine toxin domoic acid may affect the developing brain by activation of neonatal brain microglia and subsequent neurotoxic mediator generation.

Amnesic shellfish poisoning, one of the shellfish poisoning syndromes, is caused by the marine diatom toxin domoic acid (DOM). While in adult rats, mice, monkeys and humans DOM poorly penetrates the blood-brain barrier, DOM has been shown to be very toxic to fetal in newborn mice, because the blood-brain barrier is incomplete during neurodevelopment. This fact may explain why neonates show a higher sensitivity to neurotoxins like DOM as compared to adult animals. Mechanistic studies on DOM's neurotoxicity have mainly concentrated on the investigation of DOM's effect on neuronal tissue. Recent studies have shown that glia is also involved in DOM's neurotoxicity to the adult as well as the developing nervous system. The scientific literature strongly supports the hypothesis that the microglia may play a critical role in mediating DOM's neurotoxic effects. However, the effect of DOM on microglia has not been systematically investigated. The literature supporting our hypothesis is presented and discussed.

Animals↗

PubMed1995

Effects of domoic acid on serum levels of TSH and thyroid hormones.

The actions of Domoic Acid (Dom), a marine toxin, on the levels of serum TSH and thyroid hormones (T4 and T3) has been studied to determine if these actions could be mediated by the serotoninergic system. In all the experiments, adult male Wistar rats were used. The Dom dissolved in saline was administered via i.p. in doses of 0.5 and 1 mg/kg. The T4 and T3 concentrations were determined by enzimoinmunoassay and TSH concentration was determined by radioinmunoassay. The results show that Dom 1 mg/kg increases the serum T4 levels one hour after treatment and decreases these levels 2 and 3 hr after treatment. Dom 0.5 mg/kg decreased the serum T4 levels 2 and 3 hr after treatment. The concentrations of T3 in serum were unchanged by both doses of Dom. The concentration of TSH was increased by Dom. In order to study the possible mediation of the serotoninergic system in the effect of Dom on the hormone levels, PCPA, a tryptophan hydroxylase inhibitor, was administered i.p. 90 min before blood sampling. In this case, with both doses of Dom a decrease in the levels of both hormones occurred with respect to the PCPA group. These results indicate that the serotoninergic system could affect the actions of Dom on TSH and thyroid hormone secretion.

Animals↗

PubMed2000

Systemic administration of domoic acid-induced spinal cord lesions in neonatal rats.

Domoic acid (Dom) is a glutamate analog and a seafood toxin that has caused neurological disturbance and death in humans. Brain lesions caused by Dom have been documented in the literature, but the effect of Dom on the spinal cord has not been investigated as extensively. Systemic administration of glutamate agonists (i.e., homocysteate, kainate, and a-amino-3-hydroxy-5-methylisoxazole-4-propionic acid) caused spinal cord lesions in infant rats. In the present study, the toxic effects of Dom on the developing spinal cord are examined. Neonatal rats on Postnatal Day 7 were administered Dom subcutaneously at doses of 0.10, 0.17, 0.25, 0.33, 0.42, and 0.50 mg/kg, respectively. Motor seizures characterized by scratching, tail flicking, and swimming-like movement were induced by Dom at all doses. High doses of Dom (> or = 0.33 mg/kg) further induced a hindlimb paralysis, a forelimb tremor, and death that occurred in less than 2 hours. The percentages of death and paralysis induced by 0.33 mg/kg Dom were 47% and 65%, respectively (n = 17). At this dose, electrocorticogram was recorded and synchronized interrupted electrical activities in brains of these animals were detected. However, no brain damage was detected in these rats. Spinal cord lesions characterized by focal hemorrhage, neuronal swelling, and neuronal vacuolization were found in 73% of the animals that had shown the paralysis/tremor in their extremities, as examined 1 to 2 hours after Dom injection. These lesions were seen at all spinal cord levels. Neuronal degeneration was mainly found in the ventral and intermediate gray matter, whereas cells in the dorsal portion of the spinal cord were relatively spared. Data suggest that observed behavioral changes were due to spinal cord damage rather than seizures or brain lesions.

Animals↗

PubMed1992

Domoic acid toxicity in rats and mice after intracerebroventricular administration: comparison with excitatory amino acid agonists.

A behavioural study of the domoic acid (DOM)-induced convulsive behaviour after intracerebroventricular administration was carried out in rats and mice. DOM-induced behaviours were compared to those elicited by other excitatory amino acid (EAA) agonists N-methyl-D-aspartate (NMDA), alpha-amino-3- hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and kainic acid (KA), in such a way as to assess the possible similarities between DOM-induced effects and EAA subtype receptor activation in vivo. In rat, DOM (0.03-3 nmol/rat) caused a complex pattern of convulsive behaviour, quantified by means of a 15-point rating scale. DOM-induced behavioural profile was characterized at the lower doses by "preconvulsive" behaviours as wet dog shakes, hypermotility, mild facial clonus. At higher doses, DOM caused clonic convulsions followed by the "status epilepticus" syndrome (wet dog shakes, forelimb clonus, rearing, salivation). Rats treated with KA (0.3-10 nmol/rat) showed an almost identical behavioural profile. AMPA (1-10 nmol/rat)-induced convulsive behaviour was similar to DOM and KA only at the higher doses. NMDA (0.25-10 nmol/rat) caused clonic convulsions but not "status epilepticus". In mice, similar results were obtained: all the tested drugs induced generalized seizures, but only animals treated with DOM, KA and AMPA showed a prolonged sequence of seizures with forelimb clonus. Our results confirm the findings reported in the literature and support the hypothesis that DOM and KA act at the same EAA receptor.

Animals↗

PubMed1980

Prolactin-releasing effect of domperidone in normoprolactinemic and hyperprolactinemic subjects.

The prolactin (PRL)-releasing effect of domperidone (DOM), a novel antidopaminergic drug which does not cross the blood-brain barrier, was investigated in normoprolactinemic subjects, in subjects with physiologic puerperal hyperprolactinemia or pathological hyperprolactinemia. DOM (4 mg i.v.), administered to 8 normoprolactinemic women, induced a clear-cut and sustained rise in plasma PRL, with peak levels occurring 15-30 min postinjection; the effect of the drug was also evident in 3 normoprolactinemic women at the dose of 0.25 mg i.v. Also in 8 puerperal women (postpartum day 2) intravenous administration of 4 mg DOM was followed by an increase in plasma PRL (51-517% of baseline levels, 15-45 min postinjection). Administration of DOM (4 mg i.v.) to 16 subjects with pathological hyperprolactinemia, evidenced the presence of 14 DOM-nonresponder (maximum percent increase of baseline PRL 48%) and 2 DOM-responder subjects. In 8 of the DOM-nonresponder subjects the existence of a pituitary tumor was established at surgery by selective removal of an adenoma (7 subjects) or a teratoma (1 subject): of the 6 subjects who did not undergo surgery, 3 had biochemical and/or radiologic evidence suggestive of a PRL-secreting tumor and 1 was acromegalic. These results indicate that DOM is capable of releasing PRL both in normoprolactinemic subjects and subjects with puerperal hyperprolactinemia. In contrast, DOM is unable to modify PRL levels in most subjects with pathological hyperprolactinemia, with proven or suspected pituitary tumors.

Adenoma↗

PubMed1987

Role of aging on growth hormone and prolactin release after growth hormone-releasing hormone and domperidone in man.

Growth hormone (GH) and prolactin (PRL) secretion after GH-releasing hormone (GHRH) and domperidone (DOM), an antidopaminergic drug which does not cross the blood-brain barrier (BBB), was evaluated in 8 healthy elderly men (65-91 years) and in 7 young adults (23-40 years). All received in random order at 2-day intervals: GHRH(1-40) (50 micrograms i.v.) bolus, DOM (5 mg/h) infusion, GHRH(1-40) (50 micrograms i.v.) plus DOM (5 mg/h i.v.), saline solution. In elderly men GH increase after GHRH was significantly lower than in young men. DOM alone did not change GH secretion in either of these groups, whereas it increased the GH response to GHRH only in young adults. PRL levels increased in both young and elderly men during both DOM and GHRH plus DOM, but the PRL release was more marked in young than in elderly men. Both integrated secretion of GH after GHRH and of PRL after DOM were inversely correlated to chronological age. Our data show an impairment of GH rise after GHRH and of PRL after DOM in elderly adults. It is also stressed that peripheral blockade of dopamine receptors by DOM is unable to amplify the GH response to GHRH only in elderly men. A reduction in GH release after GHRH might be related to aging, perhaps through a reduction of dopaminergic tonus.

Adult↗

PubMed2006

[Vertical fractionation of dissolved organic matter and its effect on the transport of Cu in Cu-contaminated soils].

The vertical fractionation of DOM and its effect on Cu transport in acidic and calcareous Cu-contaminated soils were studied in column experiments. The results showed that the polarities of DOM derived from green manure and pig manure were obviously decreased by 11.4% and 10.72%, respectively, when they were leached through soil columns, especially in the calcareous soil. Dissolved organic matter can increase the dissolution of copper from the two copper-contaminated soils, but the dissolution effect was influenced by the properties of DOM and soils. For example, the ability of DOM derived from green manure to increase copper dissolution was stronger than that of DOM from pig manure. On average, the amounts of copper into effluent leached by green manure DOM or pig manure DOM in the column packed with a calcareous soil are 4.37 and 3.03 times higher than that in the column packed with an acidic red soil, respectively. In addition, it was observed that Cu dissolution from soils facilitated by DOM was decreased due to microbial degradation of DOM in soils.

Adsorption↗

PubMed2003

Potentiation of domperidone-induced catalepsy by a P-glycoprotein inhibitor, cyclosporin A.

The distribution of domperidone (DOM), a peripheral dopamine D(2) receptor antagonist, to the brain is restricted by P-glycoprotein (P-gp) at the blood-brain barrier (BBB) and for this reason, DOM rarely causes parkinsonian symptoms, such as extrapyramidal side effects (EPS), unlike other dopamine D(2) antagonists. In this study, we aimed to investigate whether cyclosporin A (CsA), a P-gp inhibitor, potentiates EPS induced by DOM. The intensity of EPS was assessed in terms of the duration of catalepsy in mice. D(1), D(2) and mACh receptor occupancies at the striatum were measured in vivo and in vitro. Moreover, the distribution of DOM to the brain was investigated by using an in situ brain perfusion technique. The intensity of DOM-induced catalepsy was significantly potentiated by the coadministration of CsA. The in vivo occupancies of D(1), D(2) and mACh receptors, as well as the brain distribution of DOM, were increased by CsA. These results suggest that CsA increases the brain distribution of DOM by inhibiting P-gp at the BBB, and potentiates catalepsy by increasing the occupancies of the D(1) and D(2) receptors. The risk of DOM-induced parkinsonism may be enhanced by the coadministration of CsA.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1985

Prolactin and thyrotropin response to blockade of dopamine synthesis by monoiodotyrosine in subjects with postpartum and pathological hyperprolactinemia.

To better understand the state of dopamine (DA) neurotransmission in the tuberoinfundibular DA system (TIDA), monoiodotyrosine (3-iodo-L-tyrosine, MIT), a potent inhibitor of DA synthesis, was acutely administered to 8 normal women, 7 postpartum women, 8 women with pathological hyperprolactinemia and 5 women after successful removal of a prolactinoma. The effects on plasma prolactin (PRL) and thyrotropin (TSH) were compared to those induced in the same subjects by the DA receptor antagonist domperidone (DOM). MIT (1 gpo) and DOM (10 mg iv) induced qualitatively similar hormonal responses, although the PRL- and TSH-releasing effects of DOM were always greater than those of MIT. In control subjects, MIT treatment induced a consistent rise in plasma PRL (peak increment 45.2 +/- 13 ng/ml at 120 min); in the same subjects DOM induced a prompter and higher PRL response, (peak increment 147.8 +/- 26 ng/ml at 30 min). MIT failed to alter plasma TSH levels, while DOM induced a significant rise in plasma TSH. In postpartum women MIT induced a prompter and higher PRL rise than that occurring in controls (peak increment 180.3 +/- 20 ng/ml at 90 min), though also in this instance DOM proved to be a more potent PRL releaser (peak increment 345.7 +/- 88 ng/ml at 30 min) than MIT. MIT was unable to stimulate TSH secretion, while DOM induced a significant rise in plasma TSH. In women with pathological hyperprolactinemia MIT failed to alter baseline PRL levels while DOM slightly increased them (peak increment 14.7 +/- 3 ng/ml at 30 min).(ABSTRACT TRUNCATED AT 250 WORDS)

Adenoma↗