Determination of dopamine and two of its acidic metabolites by high-performance liquid chromatography with electrochemical detection: a retrospective article.
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Animals↗
Biomedical subjects
O Magnusson
Publications and source records attributed to O Magnusson.
Temporal studies of the inhibition of voluntary ethanol intake in the rat induced by intermittent ethanol treatment and some long term neurochemical consequences.
Male rats were injected with ethanol (groups 3 and 5; 2.0 g/kg i.p.) or saline (groups 2 and 4) once a week for 52 weeks. The rats had access to ethanol as a voluntary choice for 24 h either once 6 days after the injection (groups 2 and 3) or twice 3 and 6 days after the injection (groups 4 and 5). At the beginning of the treatment ethanol injections inhibited voluntary ethanol intake if tested 6 days later (groups 3 and 5), but a tolerance developed to this inhibition. During tolerance development the rats in group 5 also drank less ethanol on day 3 than on day 6. No corresponding behaviour was seen in group 4. Thus part of the tolerance was a gradual reduction of the duration of inhibition. During the evaluation period (25 weeks) after the treatment, ethanol exposure (20 weeks) consisted of a continuous choice between ethanol and water. Of different ethanol concentrations both ethanol-injected groups (3 and 5) took the same voluntary dose of ethanol independent of the offered concentration. After 5 weeks without ethanol all rats were killed and a number of neurochemical variables were determined. Compared with almost unexposed rats (group 1) changes were seen in inositol phospholipid breakdown, muscarinic binding sites in hippocampus, noradrenaline concentrations in frontal cortex, hippocampus and hypothalamus, dopamine concentration in frontal cortex and 5-hydroxytryptamine concentration in hypothalamus. In most cases the largest changes were seen in group 5. None of the variables had a constant relation to ethanol intake in the total population. However, significant correlations were found in some of the groups.
3,4-Dihydroxyphenylacetic Acid↗
Suppression of conditioned avoidance behavior by the local application of (-)sulpiride into the ventral, but not the dorsal, striatum of the rat.
The local application of (-)sulpiride, 200 ng side-1, into the nucleus accumbens produced a suppression of conditioned avoidance behavior in male rats, 10 and 90 min after injection. The decrease in avoidance behavior was accompanied by a decrease in motor activity, as evidenced by changes in the number of intertrial crosses. When injected into the dorsolateral neostriatum, or the amygdala, (-)sulpiride produced a suppression of conditioned avoidance behavior at the 90-min time interval only. Considering diffusion from the injection site, as indicated by an increase in local dopamine turnover [(DO-PAC + HVA) DA-1], the effects obtained in the dorsolateral neostriatum, and possibly also the amygdala, 90 min after injection could be due to diffusion to the nucleus accumbens. The local application of (-)sulpiride into the posterior neostriatum, or into the prefrontal cortex, produced no statistically significant effect on conditioned avoidance behavior 10 or 90 min after injection. It is concluded that the performance of conditioned avoidance behavior in the rat is critically dependent on an intact dopaminergic neurotransmission in the nucleus accumbens or adjacent areas of the ventral striatum.
Amygdala↗
Diffusion and absorption of (-)sulpiride and raclopride after intracerebral administration in the rat.
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Absorption↗
Gynaecological problems related to anatomical changes after conventional proctocolectomy and ileostomy.
Seventy-one women who had a proctocolectomy for ulcerative colitis (n = 41) or Crohn's disease (n = 30) were interviewed in the follow-up clinic about gynaecological problems and fertility. All women were examined by an independent gynaecologist and abnormalities of the internal genital tract were registered. Forty-nine per cent (35/71) of the women had a distressing vaginal discharge after proctocolectomy, compared with 9% (6/71) before surgery. At the gynaecological examination 45% (32/71) had a heavy vaginal secretion with- out any signs of an acute vaginal infection. In 68% (30/44) fluid retention in the vagina was associated with a caudally firmly fixed and dilated posterior vaginal fornix. Twelve per cent (8/66) of the women reported dyspareunia before surgery. After surgery, 27% (18/66) complained of this symptom. Fertility was significantly reduced after surgery since only 37% (10/27) of the women who attempted to become pregnant succeeded within 5 years follow-up. The corresponding figure before surgery was 72% (39/54). Those who conceived went through pregnancy and parturition without any incident, 6 of 21 delivered by caesarean incision. In conclusion, conventional proctocolectomy in women will result in distressing vaginal discharge, and dyspareunia in a considerable proportion of the patients. The operation also seems to decrease their chances of becoming pregnant.
Adult↗
Behavioural deficits and serotonin depletion in adult rats after transient infant nasal viral infection.
Dysfunction of subcortical serotoninergic neurons has been implicated in some behaviour disturbances. The serotoninergic neurons in the dorsal and median raphe project widely in the brain. They innervate the olfactory bulbs and can be targets for exogenous agents attacking the olfactory epithelium and bulbs. We report here an injury to the serotoninergic neurons after intranasal infection in 12-day-old rats with a temperature-sensitive mutant of vesicular stomatitis virus. The brain infection was focal and transient. Viral antigens could no longer be detected 13-15 days after infection. In spite of this the animals, as adults, had a severe serotonin depletion in the cerebral cortex and hippocampus, and showed abnormal locomotor and explorative behaviour as well as learning deficits. The neocortex was histologically intact and parameters related to other neurotransmitters such as dopamine, noradrenaline, GABA and acetylcholine showed no marked changes. A relatively selective damage to serotoninergic nuclei as a result of virus neuroinvasion through a natural portal of entry, may constitute a new pathogenetic mechanism for cortical dysfunction and behavioural deficits.
3,4-Dihydroxyphenylacetic Acid↗
Neuropharmacological and behavioural properties of remoxipride in the rat.
Remoxipride blocks dopamine agonist-induced effects in the rat, mediated by dopamine D2 receptors with an in-vivo potency less than that of haloperidol but greater than that of chlorpromazine, thioridazine, and sulpiride. Unlike haloperidol and sulpiride, remoxipride has weaker antagonistic effects towards presynaptic dopamine activity compared to its effects on postsynaptically mediated activity. Remoxipride causes a preferential inhibition of dopamine agonist-induced locomotion as compared to stereotyped behaviour, suggesting that it may exert a preferential blockade of mesolimbic dopamine neurotransmission. The low tendency of remoxipride to cause catalepsy in the rat is indicative of a weak effect on striatal dopamine neurotransmission and predicts a low liability to induce extrapyramidal side effects in man. Remoxipride causes a smaller elevation of prolactin than sulpiride at doses producing central dopamine receptor blockade. The results suggest that remoxipride, unlike haloperidol, can discriminate between different types of dopamine mediated functions probably by having a preferential action on subpopulations of functionally coupled dopamine D2 receptors.
Animals↗
Biochemical pharmacology of the atypical neuroleptic remoxipride.
In vitro receptor ligand binding studies in the rat showed that remoxipride displaced different radioligands at the dopamine D2, but not the D1 receptor. Remoxipride did not block dopamine-stimulated adenylate cyclase activity in vitro suggesting that it did not directly interact with the dopamine D1 receptor. Like other antipsychotic compounds, it increased dopamine turnover in the dopamine-rich areas of the brain. It showed no affinity for a wide range of neurotransmitter receptors, with the exception of the opiate sigma receptor. The affinity of remoxipride for the D2 receptor was low in vitro, while in vivo, the affinity was relatively high. Remoxipride was far more potent in preventing [3H]raclopride-binding than [3H]spiperone-binding to the D2 receptor in vivo. When the D2 receptor was labelled with [3H]spiperone, remoxipride was shown to exert a preferential blockade of this binding in extrastriatal areas of the brain (for example, olfactory tubercle, septum, substantia nigra) in vivo. After the injection of high doses of remoxipride most if not all drug in the brain was identified as authentic remoxipride. After injection of [3H]remoxipride in smaller and larger doses, radioactivity was detected in all areas of brain examined, including cerebellum and neocortex. Most of the remoxipride-derived radioactivity was found in the choroid plexus and circumventricular organs, while smaller amounts were recovered in the striatum, olfactory tubercle, and substantia nigra. Taken together, these findings suggest that remoxipride acts at both the central D2 and sigma receptors and that its affinity for the D2 receptor is relatively low in vitro. A regional preference for D2 receptors can be observed in vivo depending upon the radioligand used.
Animals↗
Animal pharmacology of raclopride, a selective dopamine D2 antagonist.
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Animals↗
Comparison of the effects of the novel antipsychotic agent remoxipride on dopamine and noradrenaline turnover in the rat brain.
The ex vivo effects of the antipsychotic dopamine receptor antagonist remoxipride on dopamine and noradrenaline turnover in the rat brain have been compared. Remoxipride (5-125 mumol/kg intraperitoneally) produced large increases in striatal DOPAC and HVA concentrations with only maginal effects on striatal, hippocampal and hypothalamic MHPG concentrations. Both remoxipride (5.6 mumol/kg intraperitoneally) and haloperidol (0.23 mumol/kg intraperitoneally) increased the rate of striatal dopamine disappearance following inhibition of tyrosine hydroxylase by H 44/68 without corresponding effect on hypothalamic and frontal cortical noradrenaline disappearance. It is concluded that at doses of remoxipride producing compensatory increases in dopamine turnover, there is little or no effect on noradrenaline turnover, confirming the in vitro dopamine:noradrenaline selectivity of this compound.
3,4-Dihydroxyphenylacetic Acid↗
Comparison of the effects of haloperidol, remoxipride and raclopride on "pre"- and postsynaptic dopamine receptors in the rat brain.
The ability of the dopamine receptor antagonists haloperidol, raclopride and remoxipride to prevent the B-HT 920-induced decrease in striatal and limbic L-DOPA accumulation in gamma-butyrolactone (GBL)- and NSD 1015-treated rats (termed 'GBL-reversal') was used to define the effects of these compounds on "presynaptic" dopamine receptors. The doses of the dopamine antagonists producing antagonism of GBL-reversal were in each case roughly similar to the doses required to increase dopamine turnover in striatal and limbic areas. The potencies of haloperidol, raclopride and remoxipride in the GBL model were compared with their potencies in behavioural models for postsynaptic dopamine receptors. Haloperidol produced antagonism of GBL-reversal over a similar dose range to that required for antagonism of apomorphine-induced hyperactivity and stereotypy syndromes. Raclopride was effective in the order of potency: antagonism of apomorphine-induced hyperactivity greater than antagonism of GBL-reversal greater than antagonism of apomorphine-induced stereotypy. For remoxipride, the dose-response curve for antagonism of GBL-reversal was superimposable over that for antagonism of apomorphine-induced stereotypies, with an ED50 value about 12 times higher than that for antagonism of apomorphine-induced hyperactivity. Thus, the relative potencies of dopamine receptor antagonists at "pre-" and postsynaptic dopamine receptors vary considerably from compound to compound.
Adrenergic alpha-Agonists↗
Influence of age on effects induced by intermittent ethanol treatment on the ethanol drinking pattern and related neurochemical changes in the rat.
Male rats were treated with one ethanol (2.0 g/kg i.p.) or saline injections once a week for 50 weeks. During this treatment period the rats had in addition access to ethanol (10% in drinking fluid) as a choice against water for 24 h prior to the injection. During the following evaluation period, animals had a continuous choice between ethanol and water and the concentration of the ethanol solution increased every 3rd week from 5 to 10, 15 and 25%, with 10% as a reference tested between the other concentrations. The animals were killed after an abstinence of 4 weeks, whereupon the concentrations of noradrenaline (NA), dopamine (DA), serotonin (5-HT) and 5-hydroxyindole acetic acid (5-HIAA) were determined in the frontal cortex. In the remaining cerebral cortex, activity of monoamine oxidase, reuptake of NA and stimulated inositol phospholipid (PI) breakdown was also determined. Muscarinic binding sites were determined in the striatum. During treatment, saline injected rats had a constant voluntary 24 h ethanol intake. There was a decrease in the corresponding intake in the animals given the ethanol injections. The diminishing of the intake was more marked in rats starting treatment at an age of 19.4 weeks when compared to rats starting at an age of 5.4 weeks. In the evaluation period the ethanol intake was fairly constant for all groups. However, the regressions between intake of the reference concentration when plotted against the different tested concentrations were most marked in the group where ethanol injections started at an early age. In the total material there were significant F-values when concentrations of NA, 5-HIAA, 5-HT/5-HIAA in the cortex and muscarinic binding sites in the striatum were tested. Age could not be excluded as a contributing factor, but for muscarinic binding sites in the striatum, concentrations of DA and 5-HIAA in the cortex, and potassium stimulated PI breakdown in the cortex significant regressions with voluntary ethanol intake as dependent variable could be established. Since these intakes are stable, a causal relation with dependence may be involved.
Age Factors↗
Increased duration of dopamine receptor antagonist-induced effects on both behaviour and striatal dopamine turnover by repeated testing in rats.
The present results show that the effects on striatal dopamine (DA) turnover of a single dose of the DA receptor antagonists haloperidol or raclopride in the rat, are dependent on the activity level of the animal during treatment. Thus, animals tested for treadmill locomotion 30 and 60 min. after injection display an increased striatal DA turnover at 90 or 120 min. (raclopride and haloperidol, respectively) compared with control animals which were administered the same dose of the DA antagonist, but which did not have the treadmill tests. The relevance of these findings with respect to individual differences in clinical response and occurrence of side effects as well as the reported difficulties in obtaining good correlations between plasma levels and clinical response with DA-receptor blocking antipsychotic drugs are discussed.
Animals↗
Impaired performance of rats in the Morris swim-maize test late in abstinence following long-term sodium barbital treatment.
Rats were tested for place learning in the Morris swim maze on days 110-114 of abstinence following 48 weeks of treatment with sodium barbital. A retarded acquisition of the swim-maze task, that could not be ascribed to motor impairments, was found in the barbital-treated rats. There was a significant difference in brain weight, but there were no significant differences between the control and barbital-treated rats in the frontal cortical concentrations of noradrenaline (NA), dopamine (DA), 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA), nor in the intra- and extrasynaptosomal activities of cerebral cortical monoamine oxidase towards NA and 5-HT. Postsynaptically, neither the cerebral cortical inositol phospholipid breakdown responses to carbachol and NA (mediated by muscarinic and alpha 1-adrenergic receptors, respectively), nor the striatal and cortical densities of muscarinic receptors labelled by [3H]quinuclidinyl benzilate [( 3H]QNB) were found significantly to be altered in the barbital-treated rats. A strong correlation between the density of striatal and cortical [3H]QNB binding sites was seen for the barbital-treated (r = 0.91) but not for the control (r = -0.05) rats. It is suggested that the deficit in performance of the barbital-treated rats in the Morris maze may be related to a cholinergic dysfunction.
Animals↗
Suppression of exploratory locomotor activity and increase in dopamine turnover following the local application of cis-flupenthixol into limbic projection areas of the rat striatum.
Recent neuroanatomical tracer studies have demonstrated the topography of 'limbic' (A10) projections into the striatum of the rat (see Introduction). The target areas include the nucleus accumbens and the ventromedial part of the neostriatum, whereas the dorsolateral part of the neostriatum does not receive such afferents. Taking this topography into account, the present results show that local application of cis-flupenthixol (10-40 micrograms/side) into the nucleus accumbens or the ventromedial, but not the dorsolateral, neostriatum produces suppression of exploratory locomotor activity in the rat. trans-Flupenthixol (40 micrograms/side) was completely ineffective when locally applied into the nucleus accumbens. Measurements of the concentrations of the dopamine metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) at the site of injection, and in neighboring areas at different times after cis-flupenthixol administration, indicated that there was little or no diffusion of the drug from the injection sites. Much higher concentrations of DOPAC and HVA in a given area were found after systemic administration of cis-flupenthixol as compared with local application of the drug to the same area.
3,4-Dihydroxyphenylacetic Acid↗
Comparison of the effects of dopamine D1 and D2 receptor antagonists on rat striatal, limbic and nigral dopamine synthesis and utilisation.
The effects of dopamine (DA) antagonists upon DA synthesis and utilisation in the rat striatum, olfactory tubercle and substantia nigra have been studied. The concentrations of dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), the rate of depletion of DA after in vivo inhibition of tyrosine hydroxylase by H44/68, and the accumulation of L-DOPA after in vivo inhibition of l-aromatic amino acid decarboxylase by NSD 1015 were measured in the study. Haloperidol (0.23 mumol/kg i.p.), sulpiride (293 mumol/kg i.p.) and remoxipride (5.6 mumol/kg i.p.) increased both DA synthesis and utilisation in the striatum and olfactory tubercle. A lower dose of sulpiride (45 mumol/kg i.p.) increased DA synthesis and utilisation in the olfactory tubercle alone. None of the compounds, at the doses used, affected either DOPAC and HVA concentrations or the rate of utilisation of DA in the substantia nigra. Sulpiride (293 mumol/kg i.p.) and remoxipride, however, produced a modest rise in nigral DA synthesis. The dopamine D 1-selective antagonist SCH 23390 had only modest effects on striatal, limbic and nigral DA synthesis and utilisation at the doses tested (0.078 and 0.36 mumol/kg i.p.).
3,4-Dihydroxyphenylacetic Acid↗
Postoperative complications in colorectal surgery in relation to preoperative clinical and nutritional state and postoperative nutritional treatment.
The impact of the pre-operative nutritional and clinical state on post-operative morbidity and mortality is not fully known and the effect of total parenteral nutrition (TPN) on the postoperative complication rate has not been established. We have investigated the effects of postoperative TPN on the complication rate in 92 patients after major colorectal surgery for carcinoma of the large bowel or inflammatory bowel disease in a controlled, randomised study. The complication rate was analysed against seven commonly used nutritional (biochemical and anthropometric) variables and against the diagnosis, clinical inflammatory activity and presence of pre-operative septic complication. Patients were randomly allocated to postoperative TPN or conventional fluid and electrolyte support. The results show no correlation between the complication rate and the nutritional and clinical state of the patients as assessed pre-operatively. The complication rate was not significantly reduced by postoperative TPN. This study indicates that biochemical and anthropometric nutritional variables do not identify patients at risk to develop postoperative complications. The presence of pre-operative complications showed a marginal correlation with postoperative morbidity, in agreement with previous experience. The result of this study obviates the use of TPN in routine postoperative care.
Adult↗
The immediate and long-term effects of postoperative total parenteral nutrition on body composition.
The short and long-term effects of postoperative total parenteral nutrition (TPN) on body composition were studied in a randomised series of patients undergoing major colorectal surgery. Ninety-two patients (colorectal cancer: 50, ulcerative colitis or Crohn's disease: 42) were grouped according to diagnosis and clinical inflammatory activity. TPN was given for 9.7 +/- 1.1 days. The complication rate was not changed by the TPN. Nitrogen balance was studied during the first week. Body weight, total body potassium, triceps skinfold, serum albumin and body water were measured before and at intervals up to 24 weeks after the operation. Cumulative nitrogen balance in control patients at 7 days after surgery was -47.3 g. Patients given TPN balanced nitrogen intake and output (cancer patients and patients with quiescent inflammatory bowel disease, IBD) or were in positive balance (patients with active IBD). Weight loss at 1 week after surgery was less in TPN patients compared to controls and this difference remained statistically significant up to 6 months after termination of the nutritional treatment. A similar, although not statistically significant, difference was noted in total body potassium and triceps skinfold. Patients with active IBD regained pre-operative body composition earlier than cancer patients and patients with quiescent IBD. It is concluded that TPN after major colorectal surgery reduces postoperative weight loss and that this effect lasts after termination of the nutritional treatment. In the absence of increased body potassium and increased body water, we conclude that the long-term effect of TPN on body weight is most likely due to preservation of fat.(ABSTRACT TRUNCATED AT 250 WORDS)
Adolescent↗