Effects of ethanol on the accumbal output of dopamine,GABA and glutamate in alcohol-tolerant and alcohol-nontolerant rats

Effects of ethanol on the accumbal extracellular concentrations of dopamine, as well as of the amino acid transmitters gamma-amino butyric acid (GABA), glutamate and taurine, were studied in the alcohol-insensitive (alcohol-tolerant, AT) and alcohol-sensitive (alcohol-nontolerant, ANT) rats selected for low and high sensitivity to ethanol-induced motor impairment. Ethanol (2 or 3 g/kg ip) enhanced the output of dopamine and its metabolites in freely moving rats of both lines as measured by in vivo microdialysis. The effect of ethanol on the metabolites of dopamine tended to be stronger in the ANT rats. The smaller dose of ethanol decreased the output of GABA only in the AT rats, whereas the larger dose of ethanol decreased the output of GABA in rats of both lines to a similar degree. Ethanol at the dose of 2 g/kg slightly, but statistically, significantly decreased the output of glutamate in rats of both lines, but the larger dose of ethanol decreased the output of glutamate only in the AT rats. Ethanol at the dose of 2 g/kg induced a small transient increase in the output of taurine within 2 h after its administration in rats of both lines, but the larger dose of ethanol was without significant effect. These results confirm the previous findings that ethanol suppresses the release of GABA more in the AT than ANT rats. Thus, among the neurotransmitter systems we studied, the effects of ethanol might be the most relevant on GABAergic transmission regarding the sensitivity towards ethanol. However, our findings suggest that glutamate is also involved in this respect.     

Plus-maze behavior and susceptibility to 3-mercaptopropionate-induced seizures in rat lines selected for high and low alcohol sensitivity

Selective outbreeding for high and low acute alcohol sensitivity has produced two rat lines (alcohol-sensitive ANT and alcohol-insensitive AT lines) that also differ in their sensitivity to GABAergic drugs, benzodiazepines and barbiturates. These rats were now compared in two behavioral tests believed to involve central GABAergic mechanisms, in elevated plus-maze test and in 3-mercaptopropionate-induced seizure test. The AT animals spent more time in the open arms of the plus-maze than the ANT rats, suggesting that the AT's behave less anxiously. The ANT's were more susceptible to seizures induced by 3-mercaptopropionate (50 mg/kg, IP) than the AT's, suggesting the ANT's having greater sensitivity to a decrease in brain GABA concentration. At the time of the first seizure signs, there was a tendency, though a nonsignificant one, to greater decreases in brain GABA in the ANT's than AT's. These results suggest that there are differences in GABA-related behaviors between ethanol-naive rats of the lines produced by selective outbreeding for differences in alcohol sensitivity. In theory, these behavioral line differences might physiologically counteract alcohol effects in the ANT's and enhance them in the AT's. In elevated plus-maze test, however, an acute dose of ethanol (1 g/kg, IP) significantly changed the behavior of the ANT animals, but only up to level of the AT rats. The apparent sensitivity to ethanol may thus be dependent on the naive behavior of the alcohol-insensitive AT and alcohol-sensitive ANT rats.     

Enhanced benzodiazepine and ethanol actions on cerebellar GABA(A) receptors mediating glutamate release in an alcohol-sensitive rat line.

Granule cell axon terminals of rat cerebellum possess benzodiazepine-insensitive GABA(A) receptors mediating glutamate release. We have investigated the ability of benzodiazepines, ethanol and furosemide to modulate the function of these receptors in the cerebellum of alcohol-tolerant (AT) and alcohol-nontolerant (ANT) rats. AT and ANT synaptosomes, prelabeled with [3H]D-aspartate, were superfused with GABA and various drugs during the K+ -depolarization. GABA similarly enhanced [3H]D-aspartate overflow in AT (EC50 = 1.7 microM) and ANT (EC50 = 3.9 microM) rats in a bicuculline-sensitive manner. Diazepam or zolpidem, at 0.1 microM, potentiated GABA at the GABA(A) receptor of ANT rats, but were ineffective at the AT receptor. Zolpidem acted with great potency (EC50 = 13.6 nM). Ethanol, added at 50 mM, potentiated GABA in ANT rats, but it was inactive at the GABA(A) receptor of the AT cerebellum. Furosemide significantly inhibited the effect of GABA in ANT, but not in AT synaptosomes. Our results show that one GABA(A) receptor (the receptor sited on granule cell terminals which mediates glutamate release) exhibits functional responses to diazepam and ethanol that differ between AT and ANT rats. However, the data with zolpidem and furosemide differ from previous results obtained with membranes of the granule cell layer suggesting that distinct GABA(A) receptor subtypes may exist on axon terminals versus soma/dendrites of granule cells.     

Effect of GABAergic drugs on motor impairment from ethanol, barbital and lorazepam in rat lines selected for differential sensitivity to ethanol

The effect of GABAergic drugs on the motor-impairing effects of ethanol, barbital, and lorazepam were studied in the ethanol-sensitive ANT (Alcohol Nontolerant) and ethanol-insensitive AT (Alcohol Tolerant) rat lines, selected for differential ethanol-induced motor impairment on the tilting plane. The basic population from which these rat lines were derived, the mixed (M) line, was also included in the study. The ANT rats were more sensitive to the intoxicating effects of ethanol, barbital, and lorazepam than the AT and M rats at the dose ranges tested. Picrotoxin antagonized motor impairment from all three drugs. Flumazenil (Ro 15-1788) antagonized only the effects of lorazepam, and isoniazid did not modify motor impairment induced by any of the three drugs. These results confirm that the selection of AT and ANT lines has not been specific to ethanol, and that it has increased sensitivity to ethanol, barbital, and lorazepam in the ANT rats rather than decreasing it in the AT rats relative to the M rats. The finding that picrotoxin counteracted motor impairment from ethanol, barbital, and lorazepam support the view that the GABAA receptor complex is important in mediating the intoxicating effects of these drugs. These results also suggest that the genetically-determined difference in sensitivity to ethanol between the rat lines involves GABAergic mechanisms, but it remains to be determined whether any part of the GABAA receptor itself has been affected by the selection program.     

Increased behavioral neurosteroid sensitivity in a rat line selectively bred for high alcohol sensitivity.

Acute administration of a neurosteroid 5beta-pregnan-3alpha-ol-20-one induced a greater impairment in motor performance of the selectively bred alcohol-sensitive (ANT) than alcohol-insensitive (AT) rats. This difference was not associated with the sensitivity of gamma-aminobutyrate type A (GABA(A)) receptors, as 5alpha-pregnan-3alpha-ol-20-one (allopregnanolone) decreased the autoradiographic signals of t-butylbicyclophosphoro[35S]thionate binding to GABA(A) receptor-associated ionophores more in the brain sections of AT than ANT rats. Nor was the difference associated with baseline levels of neuroactive progesterone metabolites, as 5alpha-pregnan-3,20-dione (5alpha-DHP) and 5alpha-pregnan-3alpha-ol-20-one were lower in the ANT rats. After ethanol (2 g/kg, i.p.) administration and the subsequent motor performance test, the increased brain concentrations of these metabolites were still lower in the ANT than AT rats, although especially in the cerebellum the relative increases were greater in the ANT than AT rats. The present data suggest that the mechanisms mediating neurosteroid-induced motor impairment are susceptible to genetic variation in rat lines selected for differences in ethanol intoxication.     

Diminished stress responses in the alcohol-sensitive ANT rat line.

During behavioral tests of alcohol sensitivity, rapid alcohol-opposing reactions may constitute an important mechanism in reducing the acute performance-impairing actions of alcohol. The alcohol-sensitive ANT (alcohol nontolerant) rats achieve lower plasma corticosterone concentrations after a tilting plane test of alcohol sensitivity (2 g ethanol/kg, IP) than the alcohol-insensitive AT (alcohol tolerant) rats, suggesting a dampening of activated stress mechanisms in the ANT rats. We have extended the comparison of these rat lines by examining central and peripheral stress responses to an acute 10-min swimming stress without ethanol administration. After the stress, plasma and adrenal corticosterone concentrations, adrenal dopamine concentrations, binding of [3H]Ro 5-4864 to adrenal membranes, and hypothalamic norepinephrine turnover were lower in the ANT than AT rats. Habituation to daily handling did not affect the stress effects or the differences between the rat lines. These results suggest that the alcohol-sensitive ANT rats have a diminished reaction to general stress, even in the absence of ethanol. This may impair their capacity to overcome the sedative and motor-impairing effects of moderate ethanol doses.     

Effect of the convulsive agent 3-mercaptopropionic acid on the levels of GABA, other amino acids and glutamate decarboxylase in different regions of the rat brain

Intraperitoneal injection of 3-mercaptopropionic acid into rats caused severe convulsions which started after about 7 min. Of the amino acids examined only the level of GABA changed after 4 min and immediately before (6.5–7 min) the convulsions started. The decrease in GABA concentration detected immediately before the onset of convulsions was about 35 per cent in the cerebral cortex, corpus striatum and cerebellum, 30 per cent in pons-medulla and 20% in hippocampus. Concomitant with the fall in GABA there was a large, reversible inhibition of glutamate decarboxylase activity in the brain. The uptake of GABA into synaptosomes isolated after injection of the convulsive agent was not reduced, and the uptake of GABA into synaptosomes was not inhibited by high concentrations of 3-mercaptopropionic acid added in vitro. During convulsions levels of aspartate and taurine decreased significantly in all the brain regions investigated. A small increase in glutamine was detected in pons-medulla and in cerebellum. Major changes in the concentrations of other amino acids such as glutamate, alanine, serine and glycine were found only in corpus striatum.     

Hormone responses to sedative drugs and cold exposure in two rat lines with high and low alcohol sensitivity.

Two rat lines bred for differences in motor impairment in the tilting plane test after a moderate dose of ethanol were compared for peripheral hormone responses. The alcohol-sensitive ANT rats had significantly lower plasma corticosterone concentrations than the alcohol-insensitive AT rats 30 min after an IP saline injection. Ethanol (2 g/kg, IP) and lorazepam (3 mg/kg, IP) injections increased the corticosterone concentration in ANT rats. Sodium barbital (160 mg/kg, IP) did not produce any increase in these rats; instead, it prevented any increase caused by a tilting plane test procedure 10 min before decapitation. Three trials on the tilting plane significantly elevated the corticosterone concentration in saline-treated ANT rats, but produced no additional increase in drug-treated ANT rats. In AT rats, drug injections caused no significant corticosterone increase but the tilting plane test procedure after barbital (lorazepam) treatment(s) elevated the corticosterone concentration. Cold exposure (+4 degrees C for 30 min) of the drug-naive animals elevated their concentrations of serum and adrenal corticosterone, thyrotropin, and growth hormone, but not of prolactin and luteinizing hormone. The increase in serum corticosterone was greater in AT than ANT rats, whereas the increase in serum thyrotropin was slightly greater in ANT rats. No differences between the rat lines were found in the growth hormone, prolactin, and luteinizing hormone levels. The results confirm and extend our earlier findings of the inability of ANT rats to produce additional stress responses to behavioral challenges when being intoxicated by sedative drugs, which may at least partly account for their increased sensitivity to sedative drugs.     

Cadmium chloride exposure modifies amino acid daily pattern in the mediobasal hypothalamus in adult male rat

The present study was conducted to investigate the possible effects of cadmium exposure on the daily pattern of aspartate, glutamate, glutamine, gamma‐aminobutyric acid (GABA) and taurine levels in the mediobasal hypothalamus of adult male rats. For this purpose, animals were treated with cadmium at two different exposure doses (25 and 50 mg l^?1 of cadmium chloride, CdCl₂) in the drinking water for 30 days. Control age‐matched rats received CdCl₂‐free water. After the treatment, rats were killed at six different time intervals throughout a 24 h cycle. CdCl₂ exposure modified the amino acid daily pattern, as it decreased aspartate, glutamate, GABA and taurine levels at 12:00 h with both exposure doses employed. In addition, the treatment with 25 mg l^?1 of CdCl₂ induced the appearance of minimal values at 16:00 h and maximal values between 04:00 and 08:00 h for glutamate, and a peak of glutamine content at 20:00 h. The heavy metal also decreased GABA medium levels around the clock in the mediobasal hypothalamus. However, CdCl₂ did not alter the metabolic correlation between glutamate, aspartate, glutamine and GABA observed in control animals. These results suggest that CdCl₂ induced several alterations in aspartate, glutamate, glutamine, GABA and taurine daily pattern in the mediobasal hypothalamus and those changes may be related to alterations in hypothalamic function. Copyright © 2009 John Wiley & Sons, Ltd.     

Taurine blocks the glutamate increase in the nucleus accumbens microdialysate of ethanol-dependent rats

During ethanol withdrawal, dramatic changes in the concentration of many neurotransmitters may be responsible for many of the adverse effects. In the present study, the technique of microdialysis was used to assay the changes in excitatory and inhibitory amino acids after withdrawal from chronic ethanol intoxication. Rats were made physically dependent on ethanol by vapor inhalation for 4 weeks. The basal concentrations of both arginine and GABA were significantly decreased in ethanol-dependent rats, although there were no significant changes in any of the other amino acid basal concentration assayed (i.e.. glutamate and taurine). During the first 12 h after withdrawal from ethanol, only glutamate increased significantly (p < 0.05) at 6 h, and for the duration of the study period of 12 h. To investigate whether either taurine and ethanol interact with amino acids during ethanol withdrawal, two other ethanol-dependent groups were injected with a single intraperitoneal injection of either taurine or ethanol 5 h after commencement of ethanol withdrawal. The IP injection of ethanol (2 g/kg) significantly increased taurine microdialysate content, and although this dose of ethanol was not able to block completely the increase of glutamate release after ethanol withdrawal, a delayed decrease in glutamate content was observed by the end of the period of the study (i.e., 11-12 h). However, IP injection of taurine (45 mg/kg) significantly blocked the increased glutamate release during ethanol withdrawal. This latter finding suggests that taurine may interact with glutamate, possibly by inducing a blockade of glutamate release during ethanol withdrawal.     

Effects of ethanol, barbital, and lorazepam on brain monoamines in rat lines selectively outbred for differential sensitivity to ethanol

The acute effects of ethanol, barbital, and lorazepam on the synthesis and metabolism of brain monoamines were studied in the AT (Alcohol Tolerant) and ANT (Alcohol Nontolerant) lines of rats, which have been selected for differential motor impairment after ethanol administration. The ethanol-sensitive ANT rats are also more sensitive than the ethanol-insensitive AT rats to the motor impairment caused by barbital and lorazepam. Ethanol increased, whereas barbital and lorazepam decreased, the synthesis of catecholamines in several regions of the brain. Ethanol did not affect the formation of DOPAC, whereas barbital and lorazepam reduced it. Similarly, the accumulation of 5-HTP was increased after administration of ethanol, but was decreased after administration of barbital or lorazepam. Ethanol, barbital and lorazepam decreased the formation of 5-HIAA. The rat lines did not differ in any of these responses. Some differences could, however, be demonstrated between the AT and ANT rats in the effects of the three drugs on the levels of the brain monoamines. Although the importance of these differences in the differential sensitivity to these drugs between the two lines is difficult to determine, the role of central monoaminergic mechanisms cannot be excluded. These findings also suggest that the motor impairment induced by ethanol, barbiturates, and benzodiazepines is probably not primarily based on the monoaminergic systems.     

Changes in cortical amino acids during electrical kindling in rats

The effect of kindling rats by electrical stimulation of the frontal cortex for approx. 3 months on the concentrations of amino acids (taurine, aspartate, glutamate, glutamine and GABA) in the cerebral cortex has been studied, as well as the release of endogenous amino acids from kindled slices of brain in vitro. In these kindled rats, killed 1 week after the last shock, there were no changes in any concentrations of amino acids. However, when cortical slices, prepared from either the control or kindled rats, were stimulated in vitro by exposure to veratrine, more endogenous glutamate and aspartate were released from the kindled tissue than from the control. The neurotransmitter amino acids, glutamate and aspartate, may be involved in the permanent effects of electrical kindling.     

Altered time course of changes in the hippocampal concentration of excitatory and inhibitory amino acids during kainate-induced epilepsy

The temporal sequence of electrophysiological and biochemical correlates of epilepsy induced by systemic injection of kainic acid (15 mg/kg i.p.) was investigated in male rats. A significant decrease in the hippocampal concentration of glutamate and aspartate was observed 20 min after the injection. These decreases preceded both electrographic and behavioral manifestations of epilepsy, thus suggesting a causal relationship between acidic amino acid changes and the genesis of kainate-induced hyperactivity. About 30-45 min after kainate injection, a decrease in glutamate, aspartate, glycine and taurine and no change in GABA concentration were observed. Bioelectrical activity, recorded in the regio inferior (CA3) of the hippocampus or in the fascia dentata revealed the presence of high frequency bursts separated by a long-lasting depression of discharge. About 55-75 min after the injection, the number of spikes in each burst increased and the duration and frequency of interictal pauses decreased. This stage was characterized by a decrease in glutamate and aspartate, restoration to normal of glutamine, glycine and taurine and a decrease in GABA.     

Differential effects of vigabatrin, γ-acetylenic GABA,aminooxyacetic acid,and valproate on levels of various amino acids in rat brain regions and plasma

Drugs which elevate brain levels of the inhibitory amino acid neurotransmitter GABA by inhibiting the GABA catabolizing enzyme GABA transaminase (GABA-T) have been developed for treatment of brain disease, such as epilepsy. Among all GABA-T inhibitors available, vigabatrin is thought to be the most selective compound, and this drug is the only GABA-T inhibitor in clinical use. However, some previous studies have indicated that vigabatrin might affect the metabolism of several amino acids not directly linked to the GABA shunt. In the present study, various amino acids, involving inhibitory and excitatory neurotransmitters, were determined in 12 brain regions and plasma of rats after treatment with anticonvulsant doses of vigabatrin and the less selective GABA-T inhibitors aminooxyacetic acid (AOAA) and -acetylenic GABA (GAG). Furthermore, the antiepileptic drug valproate, which is also thought to act via the GABA system, was included for comparison. The GABA-T inhibitors markedly enhanced GABA levels in all brain regions examined, while valproate induced only moderate increases in some regions. All drugs, including valproate, significantly decreased aspartate in the brain to a similar extent, and the GABA-T inhibitors but not valproate decreased levels of glutamate. The decreases in aspartate and glutamate levels were not correlated with the different magnitudes of GABA increase produced by GABA-T inhibitors, suggesting that these effects were not simply due to the altered GABA degradation. In addition to glutamate and aspartate, alanine levels were decreased by GABA-T inhibitors but not valproate in several regions. Brain levels of glutamine were decreased by GAG and vigabatrin but increased by valproate and partly also by AOAA. Additional alterations were found in levels of glycine, taurine, serine, arginine, asparagine and threonine in some discrete brain areas. In plasma, the most marked changes in amino acids were obtained with vigabatrin, while valproate did not change plasma amino acids in rats. The data substantiate that vigabatrin is less specific than generally thought but, similar to AOAA and GAG, apparently affects several other cerebral enzymes and/or interacts with other neurotransmitter systems as well. Correspondence to: W. Löscher at the above address     

Intoxicating effects of lorazepam and barbital in rat lines selected for differential sensitivity to ethanol

The motor impairing effects and plasma concentrations of barbital and lorazepam were studied in the alcohol tolerant (AT) and alcohol non-tolerant (ANT) rat lines developed for low and high sensitivity to motor impairment from ethanol. The mixed (M) line, from which the AT and ANT rats were derived, was also included in the study. Like ethanol, barbital and lorazepam impaired the performance of the ANT rats more than that of the AT rats. The motor performance of the M rats was relatively more impaired after barbital than after lorazepam administration at the same dose used in the AT and ANT rats. At the two latter time points (2.5 and 3.5 h) the sensitive ANT rats had significantly higher serum barbital concentrations than the AT rats. The serum barbital concentrations of the AT and ANT rats did not differ, however, at the two first time points (0.5 and 1.5 h) of the tilting plane tests, although the ANT rats were significantly more intoxicated. The concentrations of lorazepam in plasma do not explain the differential motor impairment either, since the sensitive ANT rats had lower plasma concentrations than the insensitive AT rats. The results, thus, suggest that the selection involved in the development of the AT and ANT lines has not been specific for ethanol. The results also support the idea that ethanol, barbiturates and benzodiazepines have some modes of action in common.     

Aminooxyacetic acid induced accumulation of GABA in the rat brain

The effect of aminooxyacetic acid (AOAA, 90 mg/kg i.v.) on bicuculline, picrotoxin and 3-mercaptopropionic acid (3-MPA) induced convulsions and on GABA concentrations in cerebellum, whole brain and a synaptosomal fraction of whole brain was investigated. At various intervals after AOAA the rats were either injected with one of the convulsive drugs or sacrificed for analysis of the GABA concentration. AOAA caused a rapid initial (0-30 min) and a later slower increase of GABA in cerebellum and whole brain. In the synaptosomal fraction the GABA accumulation was delayed and less pronounced when compared to the whole brain. The bicuculline induced convulsions were markedly potentiated during the first hour but completely blocked from 2-6 h after AOAA. Picrotoxin showed a somewhat different pattern to bicuculline in the interactions with AOAA. The initial strong potentiation was not observed but the later phase of protection was present. In the interactions with 3-MPA, the effect of AOAA was always protective. The time to onset of convulsions was gradually increased during the first 30 min after AOAA. This protective effect remained practically unchanged up to 6 h after AOAA. However, once started, the convulsions were generally of the same duration and intensity. The results can be interpreted as GABA accumulating after AOAA stimulates GABA receptors to a degree more or less proportional to the whole brain GABA concentration and further that GABA synthetized in neurons is liberated, stimulates inhibitory bicuculline sensitive (predominant) and excitatory bicuculline insensitive receptors and is captured to a large extent by non-neuronal cells.     

Hippocampal rhythmic slow activity in rat lines selected for differences in ethanol-induced motor impairment

Hippocampal rhythmic slow activity (RSA) was recorded during rotation and vibration stimulation after saline and ethanol (2 g/kg) administration in restrained alcohol-sensitive (ANT) and alcohol-insensitive (AT) rats implanted with chronic bipolar electrodes in the dorsal hippocampus. The saline-treated ANT rats had more high-frequency RSA than the AT rats, especially during the rotational stimulation of the optovestibular mechanisms. The difference was not found during ethanol sessions. Plasma corticosterone levels were significantly higher in the AT than the ANT rats after the recording sessions. This first electrophysiological demonstration of an alcohol-sensitivity difference in the brain between these rat lines is discussed in relation to behavioral tilting plane test used in the development of the lines, to the different innate responses of the lines to acute stress, and to the plausible line differences in brain GABAergic and serotonergic mechanisms that are known to modulate hippocampal EEG in rodents.     

全脑缺血诱导沙土鼠纹状体,海马和皮层氨基酸水平的改变(英文)

目的:研究全脑缺血时沙土鼠海马、纹状体和皮层谷氨酸、天冬氨酸、γ-氨基丁酸(GABA)、谷氨酰胺、甘氨酸和牛磺酸含量的变化及氯胺酮对上述氨基酸含量的影响.方法:采用结扎双侧颈总动脉的方法制备沙土鼠全脑缺血模型,应用HPLC和荧光检测器联用测定氨基酸的含量.结果:全脑缺血显著增加沙土鼠海马,纹状体和皮层的谷氨酸,天冬氨酸,谷氨酰胺,GABA,甘氨酸和牛磺酸含量;氯胺酮(120 mg/kg,ip)预处理能完全逆转缺血诱导的谷氨酸、天冬氨酸、甘氨酸和谷氨酰胺释放的增加,但不能完全逆转缺血诱导的GABA和牛磺酸释放增加.结论:脑缺血诱发的神经元损伤可能与其增加谷氨酸、天冬氨酸、甘氨酸、谷氨酰胺含量有关,而抑制性氨基酸GABA和牛磺酸释放增加则可能是机体一种重要的自身脑保护机制.氯胺酮逆转脑缺血诱导的兴奋性氨基酸释放增加可能是其抗兴奋性神经毒的生化基础.     

Effects of Aminooxyacetic Acid and Baclofen on the Catalepsy and on the Increase of Mesolimbic and Striatal Dopamine Turnover Induced by Haloperidol in Rats

Abstract Effects of aminooxyacetic acid (AOAA) and baclofen on the catalepsy and on the increase of mesolimbic and striatal dopamine turnover induced by haloperidol were studied in rats. AOAA (25 mg/kg intraperitoneally) which increases the cerebral concentration of δ–aminobutyric acid (GABA) and baclofen (10 mg/kg intraperitoneally), a structural analogue of GABA, did not induce catalepsy by themselves but potentiated the catalepsy caused by haloperidol (0.1 mg/kg subcutaneously). AOAA and baclofen did not alter the haloperidol–induced striatal homovanillic acid increase. AOAA and baclofen decelerated the dopamine disappearance caused by α–methyl–p–tyrosine (αMT) both in mesolimbic nuclei and striatum. Haloperidol accelerated the αMT–induced dopamine disappearance in these structures. AOAA and baclofen prevented this stimulatory effect of haloperidol on the dopamine turnover. These results support the earlier suggestions that GABAergic pathways have an inhibitory effect on the mesolimbic and striatal dopaminergic pathways.     

Effect of ethanol dose on amino acid and urea concentrations in the fed rat liver in vivo

In order to assess the role of ethanol oxidation in vivo on amino acid metabolism and urea synthesis, the changes in the concentrations of hepatic dicarboxylic amino acids, glutamine, alanine, carbamoylphosphate and urea were measured in fed rats at various times after the administration of 10 and 50 mmoles of ethanol/kg body wt, i.p. (1) The dose dependence of the acute effects of ethanol upon liver dicarboxylic amino acids in vivo has been demonstrated. The 10 mmoles/kg ethanol dose determines an accumulation by 30 per cent of aspartate and glutamate in the rat liver (30 and 60 min after ethanol injection) whereas the 50 mmoles/kg ethanol dose induces a 35 per cent fall in the aspartate level at the same time, and only a 20 per cent increase in glutamate concentration during the second hour following ethanol injection. (2) The dose-dependent effects of ethanol upon the hepatic level of urea are also shown. A significant decrease by 20 per cent in the liver content of urea is only observed 60 min after the administration of the 50 mmoles/kg ethanol dose. (3) On the contrary, the ethanol induced alterations in the hepatic alanine and glutamine concentrations are not dose-dependent. A 50 per cent decrease in alanine level and a rise (about 30 per cent) in glutamine concentration are observed 30 and 60 min after the administration of the two ethanol doses. The comparison between the effects of either 10 or 50 mmoles/kg ethanol doses leads to the conclusion that the rate of ethanol oxidation related to the malate-aspartate shuttle activity is directly connected with the glutamate (and aspartate) concentration. These findings suggest that ethanol reduces the hepatic urea concentration in vivo only when the ethanol dose injected to rats induces a rapid decrease in the aspartate/glutamate ratio (about 40 per cent within 15 min following the injection of the 50 mmoles/kg ethanol dose).