Dopaminergic and serotonergic alterations in the rat brain during ethanol withdrawal: association with behavioral signs

Changes in dopaminergic and serotonergic levels and metabolites in cerebral cortex, corpus striatum and hippocampus were investigated during the first 6-h of withdrawal in ethanol-dependent Wistar rats. Ethanol was given by a liquid diet for 21 days. The concentration of ethanol was 7.2% (v/v) for the last 15 days of the exposure. After 2, 4 and 6 h of ethanol withdrawal, and after audiogenic stimulus (100 dB for 60 s) at 6 h of ethanol withdrawal, various brain regions were assayed for levels of dopamine (DA), DOPAC, HVA, serotonin (5-HT) and 5-HIAA. Behavioral signs of ethanol withdrawal and blood ethanol levels were also evaluated in other parallel groups of ethanol-dependent rats. Significant decreases in 5-HT levels and significant increases in HVA levels in striatum were found during the first 6 h of ethanol withdrawal and after the audiogenic seizures. In hippocampus, 5-HIAA levels were significantly reduced after 2 h of ethanol withdrawal and after the audiogenic seizures. 5-HIAA levels significantly increased after 2 h of ethanol withdrawal in cerebral cortex. Significant increases in both DA and 5-HT levels were also found in cerebral cortex after the audiogenic seizures. The results suggest that the levels of DA, 5-HT and their metabolites are altered by ethanol withdrawal. Furthermore, this may suggest that DA and 5-HT may be involved in the first 6 h of ethanol withdrawal syndrome in rats.     

Effects of acute ethanol administration on monoamine and metabolite content in forebrain regions of ethanol-tolerant and -nontolerant alcohol-preferring (P) rats

The contents of dopamine (DA), serotonin (5-HT) and their metabolites in the frontal cortex, anterior striatum, nucleus accumbens and hypothalamus of alcohol-tolerant and -nontolerant rats of the alcohol-preferring P line were determined one hour after the IP administration of 2.5 g ethanol/kg body wt. Compared with saline-injected controls, nontolerant P-rats injected with ethanol had (a) 60% higher levels of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the frontal cortex; (b) 30-60% higher levels of DOPAC and HVA in the anterior striatum and nucleus accumbens; and (c) 20% higher levels of 5-HIAA in all three forebrain regions. In the tolerant group, the effects of IP ethanol on DOPAC and HVA were markedly attenuated or completely eliminated in these three forebrain regions. However, in the case of 5-HIAA, an attenuated response was observed only in the nucleus accumbens of the tolerant group. The IP administration of ethanol had little effect on the contents of DA or 5-HT in any of these three forebrain regions, with the exception that 5-HT levels were elevated in the anterior striatum of both the tolerant and nontolerant groups. In the hypothalamus, there were no significant differences for the contents of DA, 5-HT or their metabolites between the nontolerant or tolerant P rats after IP ethanol. The data indicate that both acute ethanol administration and chronic alcohol intake by the P line of rats alters certain DA and 5-HT systems that may be involved in the brain reward circuitry and in DA pathways involved in motor functions.     

Monoamine and metabolite levels in CNS regions of the P line of alcohol-preferring rats after acute and chronic ethanol treatment

Levels of norepinephrine (NE), dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), serotonin (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were determined in 8 brain regions of the P line of alcohol-preferring rats following: (a) an IP injection of 2.5 g ethanol/kg body wt; (b) 8 and 15 weeks of chronic free-choice drinking of 10% ethanol; (c) 15 weeks of chronic free-choice drinking of 10% ethanol and 24 hours of withdrawal; and (d) 7 weeks of forced administration of 5% ethanol in liquid diet. One hour after IP injection of 2.5 g ethanol/kg body wt, the levels of DOPAC and HVA increased 209-45% in the cerebral cortex (CTX) and striatum (STR). A 209% lower content of NE in the CTX of the ethanol group was the only other statistically significant difference observed. Chronic free-choice drinking of 10% ethanol for 8 weeks (6.5 +/- 0.4 g ethanol/kg/day) or 15 weeks (7.8 +/- 0.2 g ethanol/kg/day) and the chronic forced administration of ethanol in liquid diets (up to 13.2 +/- 0.2 g ethanol/kg/day) did not produce any consistent pattern of alterations in the levels of the monoamines or their metabolites in the 8 CNS regions. After 15 weeks of chronic free-choice drinking of 10% ethanol, withdrawal from alcohol also did not produce alterations in the content of the monoamines or their metabolites. These data indicate that acute administration of hypnotic doses of ethanol increases the metabolism of specific dopaminergic neurons in the CNS of the P rat, but monoamine levels and metabolism are not altered after chronic (7-15 weeks) alcohol consumption.     

Brain concentrations of biogenic amine metabolites in acutely treated and ethanol-dependent rats.

1 Mass fragmentography was used to measure whole brain concentrations of some of the major metabolites of tyramine, octopamine, dopamine and noradrenaline in acutely treated and in ethanol-dependent rats. 2 Treatments with ethanol, either acutely or chronically, failed to alter significantly brain concentration of p-hydroxphenylacetic and p-hydroxymandelic acid (metabolites derived from tyramine and octopamine respectively). The effect on catecholamine metabolites was marked and therefore suggests that ethanol is selective in its effect on central metabolism of biogenic amines. 3 Acute ethanol treatment significantly increased brain concentration of homovanillic acid (HVA), 3,4-dihydroxyphenylacetic acid (DOPAC) and 3-methoxy-4-hydroxyphenylglycol (MHPG). Vanilmandelic acid (VMA) was not affected. All four metabolites (HVA, DOPAC, MHPG and VMA) were increased in the brains of rats rendered dependent on ethanol while still intoxicated (blood ethanol levels above 200 mg/dl). In ethanol-dependent rats undergoing ethanol withdrawal syndrome (no ethanol present in blood), the brain concentrations of HVA and DOPAC were normal while those of MHPG and VMA continued to be elevated. 4 From the decline in the concentrations of HVA and DOPAC after 50 mg pargyline/kg in control rats and rats acutely treated with ethanol, it was concluded that ethanol has no effect on the transport of phenolic acids across the blood brain barrier. 5 No reversal in the metabolism of catecholamines from an oxidative to a reductive pathway, analogous to that produced by ethanol in the periphery, could be established in the brain. 6 The increase in catecholamine metabolite concentrations after ethanol treatment, either acute or chronic, were interpreted as manifestations of increases catecholamine turnover.     

Dopamine in the basal ganglia and benzodiazepine-induced sedation

The effects of the anxiolytic benzodiazepine flurazepam on motor activity and the turnover of dopamine were measured in rats. Changes in motor activity were measured using a doppler-shift device; changes in extracellular homovanillic acid (HVA), monitored by linear sweep voltammetry with carbon paste electrodes implanted in the striatum and nucleus accumbens and ex vivo measurements of changes in 3,4-dihydroxyphenylacetic acid/dopamine (DOPAC/DA) ratios in the striatum and nucleus accumbens were used as indices of changes in the turnover of dopamine. Injection of vehicle increased the nocturnal rise in the concentration of HVA and the ex vivo DOPAC/DA ratio in the nucleus accumbens. Injection of flurazepam decreased the nocturnal rise in HVA and DOPAC/DA ratio in the nucleus accumbens below control levels. There was also a decrease in the nocturnal rise in motor activity. Neither injection of vehicle nor injection of flurazepam caused changes in either the concentration of HVA or the DOPAC/DA ratio in the striatum. The correlation coefficient for motor activity compared to concentration of HVA remained high for the nucleus accumbens but was reduced for the striatum after administration of flurazepam. The results suggest that the sedative effect of flurazepam may be due to an action on the mesolimbic but not the nigrostriatal dopaminergic pathway.     

The dynamics of dopamine metabolism in the rat superior cervical, coeliac and mesenteric ganglia

Dopamine (DA) metabolism was compared in rat superior cervical ganglion, coeliac ganglion, mesenteric ganglion and adrenal medulla. Substantial amounts of DA, 3-4 dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were found in all the above structures. The proportion of DA metabolites over total adrenergic compounds increased from the superior cervical (22 +/- 2.2%) to the mesenteric ganglia (37 +/- 1.4%) and was much higher in ganglia (30 +/- 1.6%) than in adrenal medulla (1.1 +/- 0.3%). The turnover rates of DOPAC and HVA were calculated in sympathetic ganglia after pargyline (75 mg/kg i.p.) or probenecid (200-500 mg/kg i.p.). After pargyline, the DOPAC levels decreased faster than HVA levels in all ganglia. The corresponding half-lives and calculated turnover rates were: about 4 and 10 min and 100 and 40 pmol/mg protein per h for DOPAC and HVA respectively. No differences were observed between the three ganglia. After probenecid, DOPAC accumulated in all the ganglia in a dose-dependent way; HVA accumulated in the superior cervical and coeliac ganglia but not in the mesenteric ganglion. As in central areas, the turnover rates of DOPAC and HVA calculated on the basis of the greatest accumulation of acidic levels after probenecid were much smaller than those obtained after pargyline. Probenecid increased DOPAC levels in adrenal medulla, but the concomitant changes in DA and epinephrine (E) amounts suggest that probenecid was able to enhance adrenomedullary activity.(ABSTRACT TRUNCATED AT 250 WORDS)     

Changes induced by sodium cromoglycate in brain catecholamine turnover in morphine dependent and abstinent mice

The effects of sodium cromoglycate (CRO) were studied in relation to the metabolism of brain catecholamines: dopamine (DA) and noradrenaline (NA), and their metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and 4-hydroxy-3-methoxyphenylethyleneglycol (MHPG). CRO was injected SC in control mice, morphine-tolerant mice (tolerance was induced by SC implantation of a 75 mg morphine pellet; CRO was administered on day 4 of addiction) and 30 min before abstinence (withdrawal was induced by SC injection of naloxone (1 mg/kg) on day 4 of addiction). Brain catecholamines and their metabolites were measured using high performance liquid chromatography coupled with electrochemical detection (HPLC-ECD), for DA, NA, DOPAC and HVA, and coupled with fluorescence detection for MHPG. The ratios of DOPAC + HVA/DA and MHPG/NA were kept as an index of DA and NA turnovers, respectively. CRO administered 30 min before naloxone-precipitated withdrawal diminished significantly NA levels in frontal cortex. CRO increased DA turnover in striatum and frontal cortex in naive animals and significantly diminished DA levels in frontal cortex and DOPAC levels in frontal cortex and midbrain in morphine-dependent mice. These findings are discussed in relation to the protective effects of CRO on opiate withdrawal and the effects of CRO on locomotor activity.This work was supported by a grant from the Fondo de Investigaciones Sanitarias de la Seguridad Social (FIS, programme no. 0166/93).     

Effects of phencyclidine on extracellular levels of dopamine, dihydroxyphenylacetic acid and homovanillic acid in conscious and anesthetized rats

Dose-dependent effects of phencyclidine on extracellular levels of dopamine (DA), dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in the neostriatum were studied in both urethane-anesthetized and conscious rats. In vivo microdialysis was used to collect 10 min samples that were analyzed for levels of DA, DOPAC and HVA, using high-performance liquid chromatography with electrochemical detection (HPLC-EC). In both the anesthetized and conscious preparations, 20 mg/kg of phencyclidine produced an increase in extracellular levels of DA, 10 mg/kg resulted in no change, while 1 mg/kg produced a slow decrease. In the anesthetized animals phencyclidine did not have a significant effect on levels of DOPAC or HVA, but in the conscious animals phencyclidine produced a dose-dependent decrease in levels of DOPAC and HVA. The increase in levels of DA could be the result of increased release of DA or inhibition of the uptake of DA. The decrease in levels of DOPAC and HVA, at the 1 mg/kg dose, could result from a decrease in the synthesis of DA that is offset at the 10 and 20 mg/kg doses by opposing mechanisms.     

Study of the turnover or the release of brain dopamine in rats after administration of N-linoleyl dopamine]

Wistar male rats received N-linoleyl dopamine (L-DA) at doses of 10, 50 or 100 mg/kg (i.p.). 2 h after these injections they were decapitated and dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), as well as the ratio DOPAC/DA, which could represent the DA turnover, were determined in the striatum, the frontal cortex or the hypothalamus, while homovanillic acid (HVA) as well as the ratio HVA/DA, which could represent the DA release, were determined in the striatum by high performance liquid chromatography (HPLC). Except a small rise of DA and DOPAC in the hypothalamus, at high L-DA doses, no significant modifications in DA, DOPAC, DOPAC/DA, HVA or HVA/DA were observed in the other brain areas studied. These results, in good agreement with the recent data obtained with other dopaminergic agonists, could show the absence of correlation between the hypomotility, on the one hand and the decreasing of the turnover or the release of the brain DA, on the other hand. Together with the data obtained recently by scandinavian and italian authors, they could raise questions about the position and the role of dopaminergic autoreceptors.     

Decrease in dopamine,its metabolites and noradrenaline in cerebrospinal fluid of schizophrenic patients after withdrawal of long-term neuroleptic treatment

Dopamine (DA), homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC), noradrenaline (NA), and 5-hydroxyindolacetic acid (5HIAA) were measured in cerebrospinal fluid (CSF) of 15 chronic schizophrenic patients before and 2 weeks after withdrawal of long-term neuroleptic treatment. Total neuroleptic-like activity in serum (NLA) was determined at the same times. Levels of DA and its metabolites (DOPAC and HVA) and NA were significantly reduced after the discontinuation of neuroleptic treatment. No change was observed in 5HIAA values. NLA was substantially reduced, but still remained detectable. The decrease in DA, DOPAC, and HVA all showed positive correlations with each other, and correlated negatively with NLA measured after 2 weeks. Our data implies that the decrease in DA turnover is the result of the discontinuance of DA receptor blockade, while the change in NA level is independent of it.This work was supported by the State Office for Technical Development, Hungary     

A biochemical study of cholinergic-dopaminergic interactions in the central nervous system

The effects of cholinergic (Ach) and anti-Ach drugs on striatal dopamine (DA) levels and turnover were studied. Treatment with both atropine sulfate and scopolamine hydrobromide increased striatal DA levels; scopolamine increased striatal DA turnover and decreased both striatal 3,4-dihydroxyphenylacetic acid (DOPAC) levels and DOPAC/homovanillic acid (HVA) relation. Oxotremorine decreased striatal DA levels but did not change striatal DA turnover or DA metabolites. Changes in striatal DA levels or turnover were not observed after atropine methyl nitrate or physostigmine. The data show the Ach-DA interactions in the striatum.     

Partial lesions of the nigrostriatal pathway in the rat. Acceleration of transmitter synthesis and release of surviving dopaminergic neurones by drugs

In rats with partial, unilateral lesions of the dopaminergic nigrostriatal pathway, synthesis of dopamine (DA) per surviving neurone was assessed by measuring the ratio of DOPA accumulated after inhibition of aromatic amino acid decarboxylase to dopamine (DOPA/DA ratio). Release of DA per surviving neurone was assessed by measuring the ratios of the concentrations of 3,4-dihydroxyphenylalanine (DOPAC) and homovanillic acid (HVA) to DA. In striata ipsilateral to the lesion, the DOPA/DA ratio was elevated 4-fold, and the DOPA/DA and HVA/DA ratios were elevated 2-fold as compared to values in contralateral striata. Administration of gamma-butyrolacetone (750 mg/kg, 30 min), i.e. of a drug which accelerates synthesis of DA, further increased the DOPA/DA ratio in lesioned striata to levels 37 times higher than those measured on the control side of saline-injected controls. Morphine (20 mg/kg, 30 min) and haloperidol (2.5 mg/kg, 60 min), i.e. drugs known to accelerate the turnover and release of DA, further elevated the DOPAC/DA and HVA/DA ratios in lesioned striata to levels approx. 5 times higher than the ratios measured on contralateral sides of saline-treated controls. The data indicate that dopaminergic neurones surviving partial lesions of the nigrostriatal pathway synthesize and release DA at an elevated but submaximal rate. Synthesis and release of DA can be further enhanced to a large extent by drugs.     

Simultaneous determination of homovanillic acid, 3,4-dihydroxyphenylacetic acid and 5-hydroxyindoleacetic acid in brain tissue, using a double-column procedure

A double-column procedure for simultaneous determination of homovanillic acid (HVA), 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA) in brain tissue was described. These compounds extracted with perchloric acid were adsorbed on Sephadex G-10 in the column. HVA and DOPAC were desorbed from Sephadex G-10 with 0.01 N HCl and then retained on QAE-Sephadex A-25 (acetate form) placed beneath the Sephadex G-10 column. HVA and DOPAC were eluted with small volume of 0.2 mol/l NaCl. 5-HIAA remaining on the Sephadex G-10 was eluted with 0.05 mol/l phosphate buffer at pH 7.5. Each substance was determined fluorometrically. The recovery rates of HVA, DOPAC and 5-HIAA were more than 80, 80 and 85%, respectively. Effects of oxypertine on dopamine (DA) neurons in the rat brain were investigated using the method described here. Oxypertine caused marked increases in the levels of HVA and DOPAC in cortex and striatum of the rat brain, without any obvious change in the level of 5-HIAA after the intraperitoneal administration of 10 mg/kg oxypertine. These findings suggest that the favorable antipsychotic action of oxypertine may be due not only to a marked reduction in brain norepinephrine level, but to a blockade of DA receptors.     

The role of dopamine in the facilitatory effect of angiotensin II on impaired learning in rats chronically treated with ethanol

Rats with impaired active avoidance induced by chronic (9 weeks) administration of ethanol were studied. Angiotensin II (ANG II) administered (ICV, 2.0 g) 12 h after the withdrawal of the alcohol not only neutralized the toxic effect of ethanol but also improved learning. When administered on the 5th day after ethanol withdrawal, the effect of ANG II was weaker. Tests of stereotypy and catalepsy were used to study the possible role of the dopaminergic system in this action of ANG II. It was shown that both chronic alcohol treatment and ANG II alone increased apomorphine (1 mg/kg) and amphetamine (7.5 mg/kg) stereotypy but the effects of ANG II were greater. ANG II did not change the stereotypy induced by amphetamine but increased the stereotypy induced by apomorphine in the group of animals chronically treated with alcohol. Haloperidol — induced catalepsy was reduced in these rats. ANG II alone intensified catalepsy and eliminated the effect of ethanol. Both ANG II and alcohol increased striatal dopamine (DA) concentration. This effect of ANG II was significantly greater in the animals chronically treated with alcohol. The above changes were not observed after the DA level had been reduced by alpha-methyl-p-tyrosine (250 mg/kg), nor were changes observed in the striatal DOPAC. The results suggest involvement of the central dopaminergic system in the effect of ANG II on the ethanol — induced impairment of acquisition of active avoidance but, however, the results of the biochemical determinations of DA turnover do not provide an explanation of these changes.     

Time course of bromocriptine induced excitation in the rat: behavioural and biochemical studies

The aim of the present study was to further investigate the behavioural and biochemical pharmacology of the directly acting dopamine (DA) receptor agonist bromocriptine (BRC).BRC produced an initial depression of locomotion followed after about an hour by a weak but significant locomotor stimulation. The stimulation was potentiated by concomitant administration of the D₁ agonist SKF38393.Ex vivo biochemical determinations indicated that reductions in dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels occurred in the striatum after BRC injection without a significant change in DA levels, indicating a reduced DA turnover. An increase in 5-hydroxytryptamine (5HT) and 5-hydroxyindoleacetic acid (5HIAA) levels occurred in the striatum leading to a significant increase in turnover (i.e. ratio of 5HIAA to 5HT). Noradrenaline concentrations increased in the striatum. In the cortex, sharp falls in HVA and DOPAC levels without a corresponding change in DA were observed. While there was no significant change in noradrenaline levels in this brain region, an increase in 5HIAA, but not in 5HT, levels occurred. These changes indicate an increase in 5HT turnover (ratio of 5HIAA to 5HT).In vivo dialysis indicated that extracellular levels of DA, DOPAC and HVA in the striata of freely moving rats were sharply reduced for at least 6 h after injection.In vitro binding studies showed that BRC exhibited high (K_i values in low nanomolar range) affinities for DA D_2A, D_2B, D₃, ₁ and ₂ adrenergic receptors together with unexpectedly high affinity (about 1 nM) for 5HT_1A receptors.The data indicate that the initial behavioural depression and later locomotor stimulation induced by BRC are accompanied by a sharp monophasic fall in striatal extracellular DA levels as indicated by dialysis studies. Since the behavioural stimulation was augmented by concomitant D₁ receptor stimulation, the data suggest that the reduced DA turnover is influencing the amount of DA available to stimulate postsynaptic D₁ receptors. However, the biochemical studies indicated that BRC has a high affinity for 5HT_1A receptors and affects the turnover of 5HT in the brain. Thus, the behavioural effects of BRC may depend not only on effects on the DA system but also on 5HT systems.[/p]     

Reduced metabolism and turnover rates of rat brain dopamine, norepinephrine and serotonin by chronic desipramine and zimelidine treatments

As part of of an ongoing effort to compare changes in whole body turnover of catecholamines and serotonin in man with those induced by antidepressants in the rat brain, we have evaluated the chronic effects of desipramine (DMI) and zimelidine (ZMI) on brain catecholamines and serotonin in the rat. The amines and metabolites measured include norepinephrine (NE), dopamine (DA) and their metabolites, 3-methoxy-4-hydroxyphenylglycol (MHPG), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). Three brain areas were analysed; the hypothalamus, caudate nucleus and frontal cortex. Chronic DMI and ZMI reduced hypothalamic MHPG and caudate nucleus DA metabolites, in particular HVA. Both drugs reduced NE and DA turnover rates (estimated after alpha-methyl-p-tyrosine injection) and the rate of MHPG formation in the hypothalamus (estimated after pargyline treatment). They did not change NE turnover rate, but reduced DA turnover rate and rate of HVA formation in the caudate nucleus. Chronic DMI but not ZMI reduced DOPAC rate of formation in the caudate nucleus. Apparently changes in DA turnover and metabolism produced by these antidepressants are better related to changes in HVA than DOPAC concentrations. Similar to their influence on hypothalamic and caudate nucleus catecholamines, both chronic DMI and ZMI produced changes in serotonin concentration in the caudate nucleus and frontal cortex serotonin that suggest a reduction in its turnover rate and metabolism. The reduction in NE turnover in hypothalamus is consistent with the effects of chronic DMI and ZMI on whole body NE turnover observed in man.(ABSTRACT TRUNCATED AT 250 WORDS)     

Modification of the striatal dopaminergic neuron system by carbon monoxide exposure in free-moving rats,as determined by in vivo brain microdialysis

Acute carbon monoxide (CO) intoxication in humans results in motor deficits, which resemble those in Parkinson's disease, suggesting possible disturbance of the central dopaminergic (DAergic) neuronal system by CO exposure. In the present study, therefore, we explored the effects of CO exposure on the DAergic neuronal system in the striatum of freely moving rats by means of in vivo brain microdialysis. Exposure of rats to CO (up to 0.3%) for 40 min caused an increase in extracellular dopamine (DA) levels and a decrease in extracellular levels of its major metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), in the striatum depending on the CO concentration. Reoxygenation following termination of the CO exposure resulted in a decline of DA to the control level and an overshoot in the recovery of DOPAC and HVA to levels higher than the control. A monoamine oxidase type A (MAO-A) inhibitor, clorgyline, significantly potentiated the CO-induced increase in DA and completely abolished the subsequent overshoot in the recovery of DOPAC and HVA. Tetrodotoxin, a Na(+) channel blocker, completely abolished both the CO-induced increase in DA and the overshoot of DOPAC and HVA. A DA uptake inhibitor, nomifensine, strongly potentiated the CO-induced increase in DA without affecting the subsequent overshoot of DOPAC and HVA. Clorgyline further potentiated the effect of nomifensine on the CO-induced increase in DA, although a slight overshoot of DOPAC and HVA appeared. These findings suggest that (1) CO exposure may stimulate Na(+)-dependent DA release in addition to suppressing DA metabolism, resulting in a marked increase in extracellular DA in rat striatum, and (2) CO withdrawal and subsequent reoxygenation may enhance the oxidative metabolism, preferentially mediated by MAO-A, of the increased extracellular DA. In the light of the neurotoxicity of DA per se and reactive substances, such as quinones and activated oxygen species, generated via DA oxidation, the significant modification of the striatal DAergic neuronal system by CO exposure might participate in the neurological outcome following acute CO intoxication.     

The influence of thiamine deficiency and ethanol on rat brain catecholamines

In rats treated with a thiamine deficient diet for 30 days the brain content of total thiamine decreased by 27-50%. Thiamine deficiency decreased the dopamine (DA) concentration of the striatum indicating a reduced synthesis of DA. In the hypothalamus the levels of the catecholamine metabolites homovanillic acid (HVA) and 4-hydroxy-3-methoxyphenyl glycol (HMPG) were reduced indicating a reduced DA and noradrenaline (NA) turnover. Animals on a diet containing 5% ethanol had increased concentrations of HVA and HMPG in rest brain indicating an increased DA and NA turnover. The concentration of 1-carboxysalsolinol (1-CSAL) and salsolinol (SAL) in the brain stem was increased in animals receiving ethanol. Thus, both thiamine deficiency and ethanol treatment influenced the catecholamine system in a complex region-dependent way. In the brain regions most susceptible to brain damage in thiamine deficiency, i.e., hypothalamus and brain stem, 1-CSAL and SAL increased most following thiamine deficiency combined with ethanol intake.     

Effects of trepelennamine on brain monoamine turnover in morphine dependent and abstinent mice

Previous studies have reported that the histamine H₁ receptor blocker tripelennamine potentiates morphine withdrawal. In this paper, the in vivo effects produced by tripelennamine on the turnover of serotonin (5-HT), dopamine (DA) and noradrenaline (NA) in the whole brain, excluding the cerebellum, were studied in control, morphine-dependent (by SC implantation of a 75 mg morphine pellet) and morphine-dependent male CD1 mice just before naloxone-precipitated withdrawal. Tripelennamine (1–10 mg/kg) was administered SC 45 min before the animals were killed. Serotonin, 5-hydroxyindole-3-acetic acid (5-HIAA), dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA) and noradrenaline were measured by high performance liquid chromatography coupled with electrochemical detection (HPLC-ECD) and 3-methoxy-4-hydroxyphenylethyl-eneglycol (MHPG) was measured by HPLC coupled with fluorimetric detection. Ratios 5-HIAA/5-HT, DOPAC + HVA/DA and MHPG/NA were taken as an index of serotonin, dopamine and noradrenaline turnovers, respectively. Tripelennamine (1 and 10 mg/kg) significantly reduced serotonin turnover in control and morphine-dependent mice, and potentiated the serotonin turnover reduction when it was administered 30 min before naloxone injection. The dopamine turnover was diminished by tripelennamine (1 and 10 mg/kg) in the morphine-dependent group. Tripelennamine (10 mg/kg) reduced noradrenaline turnover during abstinence. These results suggest that the potentiation of opiate abstinence by tripelennamine could be related to its antiserotonergic profile.     

Withdrawal from repeated morphine sensitises mice to the striatal dopamine release enhancing effect of acute morphine

The effects of morphine withdrawal and challenge on the a-methyl-p-tyrosine (MT)-induced depletion of dopamine (DA) as well as on DA metabolism and ³H-SCH 23390 and ³H-spiperone binding were studied in the striata of male mice. Morphine was given s.c. 3 times daily for 5 days followed by 1 to 3 days' withdrawal.The MT induced DA depletion was retarded in mice withdrawn for 1 day from repeated morphine. At this time point the striatal concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) fell, too. In mice withdrawn for 3 days from morphine neither DA depletion nor DOPAC or HVA concentrations differed from those of control mice. In control mice acute morphine challenge accelerated the DA depletion at the dose 10 mg/kg but not at the dose 30 mg/kg. Both doses elevated striatal DOPAC and HVA. In mice withdrawn from repeated morphine for 1 day acute morphine partially counteracted the withdrawal-induced retardation of DA depletion and elevated striatal DOPAC and HVA clearly less than in control mice. However, in mice withdrawn for 3 days 10 mg/kg of morphine clearly enhanced DA depletion and its effect on striatal HVA was significantly augmented. In these mice as in controls the 30 mg/kg dose did not alter striatal DA depletion and elevated HVA less than in controls. Acute morphine did not alter striatal 3-methoxytyramine (3-MT) concentration in control mice but at the dose 10 mg/kg increased it in mice withdrawn for 3 days. Morphine withdrawal did not significantly affect striatal 3H-SCH 23390 binding, but slightly decreased ³H-spiperone binding in mice withdrawn for 3 days indicating a down-regulation of D₂ receptors.Our results by using three different indices of DA release (DA depletion after aMT, HVA and 3-MT) show that long enough withdrawal from repeated morphine treatment augments the morphine-induced release of striatal DA in mice. We propose that the striatal DA release in mice is regulated by two opposite opioid sensitive mechanisms with different dose-dependencies and different tolerance development. Correspondence to: L. Ahtee at the above address