Tyrosine influence on amphetamine self-administration and brain catecholamines in the rat

Earlier work had shown that L-tyrosine administration, precursor to both dopamine (DA) and norepinephrine (NE), could increase brain DA metabolite concentrations after amphetamine treatment and restore amphetamine-induced decreases in whole brain NE. Both monoamines have been suggested to participate in some aspects of continued drug abuse. Rats trained to self-administer IV d-amphetamine were treated with IP tyrosine during test sessions to examine the behavioral and neurochemical response. In animals with less than 35 days of amphetamine exposure, L-tyrosine treatments did not alter amphetamine self-administration. Experiments using a computer-controlled injection apparatus which administered IV amphetamine to naive rats in patterns mimicking those of self-administration animals indicated tyrosine could antagonize amphetamine-induced NE depletions. The increases in DA metabolite dihydroxyphenylacetic acid (DOPAC) were found limited to the striatum, an area not involved in the positive reinforcing effects of amphetamine. Concentrations of DOPAC in nucleus accumbens septi were unchanged by the amphetamine or the amphetamine-tyrosine regimen. In rats with 4-6 months of chronic amphetamine exposure, however, L-tyrosine administration significantly reduced daily drug self-injection. While neurochemical responses to tyrosine could not be performed, it is speculated that chronic long-term amphetamine abuse might alter the tyrosine-induced changes in DA and/or NE synthesis and release compared to that in the acute or short-term amphetamine abuse animals. These data suggest that the success or failure of an experimental pharmacologic treatment strategy in psychomotor stimulant abusers might be dependent on the subjects history of drug abuse.     

Effect of ethanol on the metabolism of brain catecholamines

Ethanol, 7 g/kg, was given orally to mice. At various time intervals thereafter the animals received ³H-tyrosine and the net accumulation of ³H-noradrenaline and ³H-dopamine in the brain during 30 min was measured. In some of the experiments the animals were divided into two groups with different degrees of intoxication. In general the accumulation of ³H-catecholamines increased following ethanol, more markedly in the severely than in the less severely intoxicated group. The former group also showed a higher blood ethanol level than the latter. Furthermore, the ratio ³H-dopamine/³H-noradrenaline was significantly increased by ethanol. There were no certain changes in the specific activity of ³H-tyrosine in brain and plasma. The effect of ethanol on the ³H-dopamine accumulation was prevented by nialamide. Endogenous noradrenaline in the brain was reduced by about 15% by ethanol. The only effect of ethanol observed on brain dopamine was a slight and transient decrease.This research was supported by the Swedish State Medical Research Council under grant No. B72-14X-2157-06. The expert technical assistance of Mrs. Barbro AldÄng, Miss Ingrid Blume, Miss Barbro Jörblad and Mrs. Lena Löfberg is gratefully acknowledged.     

Effect of depletion of brain catecholamines on ethanol tolerance and dependence.

Brain catecholamines were depleted in rats by intraventricular injection with 6-hydroxydopamine, prior to feeding rats on a liquid diet containing ethanol. On withdrawal of ethanol, withdrawal reactions were significantly more severe in catecholamine-depleted rats than control rats. Sleeping times after a standard dose of ethanol or pentobarbitone were significantly reduced in catecholamine-depleted animals. However, after prolonged ethanol treatment, tolerance developed to a similar extent in catecholamine-depleted rats as in controls. The effects on sleeping time and withdrawal severity were most probably due to the depletion of noradrenaline as they were not observed after a specific depletion of dopamine. It was concluded that these effects were due to a non-specific increase in CNS excitability resulting from depletion of noradrenaline and that central catecholamines do not play a direct role in the development of ethanol tolerance and physical dependence.     

Interaction of catecholamines and ethanol on the kinetics of rat brain (Na+ + K+)-ATPase

The effects of catecholamines (CA) and ethanol (EtOH), singly and in combination, on the kinetics of rat brain (Na+ + K+)-ATPase were studied. Addition of 0.05 M EtOH alone did not change Vmax or Km for K+, Na+, Mg2+ and ATP. Addition of 0.1 mM dopamine (DA) or noradrenaline (NA) alone stimulated the enzyme activity in presence of vanadium-containing ATP as substrate, but not with vanadium-free ATP except in the presence of high Mg2+ : ATP ratios. CA alone decreased the Km slightly for K+ and by about 50% for ATP, increased it for Mg2+ and did not change it for Na+. However, the combination of DA or NA + EtOH produced a marked inhibition which was competitive for K+, and uncompetitive or mixed for Mg2+, Na+ and ATP. The inhibitory effect of NA + EtOH was abolished in 20 mM K+. These findings suggest that NA sensitizes the enzyme to EtOH inhibition at physiological K+ concentrations, by conformational change away from the outwardly facing K+-binding E2P for to the inwardly facing Na+-binding E1P form.     

The influence of pentifylline and theophylline on reaction kinetics on rat brain ATPase stimulatable by catecholamines (author's transl)]

The effects of 1-hexyl-3,7-dimethyl-xanthine (pentifylline, Cosaldon) and theophylline on rat brain Na+-, K+-, Mg2+ ATPase activities were investigated in in vitro experiments. It was established that pentifylline inhibits catecholamine sensitive ATPase in a dose dependent manner. Theophylline was without effect. Pentifylline also inhibited the Mg2+-dependent portion of Na+, K+-, Mg2+-ATPase. The effect of pentifylline on the kinetic parameters of Na+-, K+-, Mg2+-ATPase of synaptosomes was studied in detail. It was shown by a Lineweaver-Burk plot under the influence of pentifylline that the Michaelis constant (Km) increases from 1.0 x 10(-4) mol/l to 6.7 x 10(-4) mol/l. Km by norepinephrine stimulated ATPase decreases from 3.7 x 10(-4) mol/l to 2.9 x 10(-4) mol/l. In both experimental situations a decrease of maximal reaction velocity (Vmax) was observed. At high concentration of potassium in incubation medium the ATPase of synaptosomes was significantly more sensitive to pentifylline than at low concentration of potassium. The inhibition of ATPase by pentifylline was not influenced by the change in Na+/K+ ratio in the incubation medium. In all these experiments, theophylline used as a standard xanthine, was virtually without effect on the reaction kinetic of Na+-, K+-ATPase.     

Combined metabolic effects of ethanol and thiamine deficiency in the central nervous system

The acute effects of ethanol on central nervous system (CNS) metabolism in the presence of thiamine deficiency were investigated in mice. The objective was to determine whether ethanol produced metabolic changes in thiamine-deficient mice different from those seen in controls. Thiamine deficiency was induced by a combination of feeding a thiamine-deficient diet and injecting pyrithiamine daily for 9 days. The metabolic effects of an acute dose of ethanol (4 g/kg, intraperitoneally [i.p.]) were determined by killing the mice 15 min after the injection. The metabolites that were studied included adenosine triphosphate, γ-aminobutyric acid (GABA) glucose, 6-phospho-gluconate, pyruvate, lactate, α-oxoglutarate, glucose 6-phosphate and glutamate. Thiamine-deficient mice not treated with ethanol showed elevated levels of most of the above metabolites compared to controls; smaller increases were observed in the cerebellum than in thalamus-hypothalamus and medulla. However, GABA and glutamate levels were significantly decreased in thalamus-hypothalamus in thiamine-deficient mice. The changes induced by ethanol in metabolite levels of both control and thiamine-deficient mice were largely similar; thus the extent of the initially altered levels were still maintained. Differences in the responses to ethanol were seen in 6-phospho-gluconate and glutamate, which were decreased by ethanol in thiamine-deficient mice but unchanged in controls. It is concluded that acute ethanol treatment does not greatly alter the CNS metabolic states in thiamine-deficient mice.     

Pentazocine analgesia and regional rat brain catecholamines

In the rat, pentazocine produces a dose-dependent increase in the threshold for vocalisation and vocalisation afterdischarge (affective component of teh pain reactions); the threshold for a motor response is unchanged. Inhibition of tyrosine hydroxylase, dopamine β-hydroxylase or pretreatment with 1-Dopa showed that an increased dopamine concentration and a decreased noradrenaline concentration antagonized the antinociceptive actions of pentazocine.After inhibition of tyrosine hydroxylase or dopamine β-hydroxylase, pentazocine accelerated the depletion of noradrenaline and dopamine. The most pronounced effect was found on dopamine in regions including the diencephalon-mesencephalon. It is suggested that the pentazocine-induced increases of the threshold for vocalisation and vocalisation afterdischarge are related to a blockade of dopamine receptors and an increased turnover of noradrenaline.     

Lead induced thiamine deficiency in the brain decreased the threshold of electroshock seizure in rat.

Many neurological disorders that occur frequently in lead intoxicated animals, have also been observed in thiamine deficient animals. To test whether lead intoxication could decrease the thiamine status and thresholds of electroshock seizure in rats, 3-week-old Wistar rats were treated with lead or lead plus thiamine. For comparison, a thiamine deficient group was included. Thiamine contents and transketolase activity, one of the thiamine dependent enzymes in the brain regions were significantly lowered by lead intoxication and thiamine deficiency. In both cases, thresholds of the electroshock seizure were significantly decreased. Thiamine supplementation reversed these signs and decreased the brain lead concentration in the lead treated group. The results from the present study suggest that the increased seizure susceptibility induced by lead intoxication in rats may be mediated at least in part through the changes of thiamine status.     

The interaction between ethanol and manganese in rat brain

The effect of combined administration of ethanol and manganese on the brain tissue of rats was investigated to evaluate the role of alcohol ingestion in inducing susceptibility to manganese poisoning. Ethanol and manganese alone and the combination of the two were administered orally daily to the rats for 30 days. Almost identical increase in the brain contents of manganese in rats receiving the metal alone and in combination with ethanol indicates that ethanol administration does not influence the accumulation of manganese in that organ. The copper contents of brain also increased to almost the same extent in these two groups. Synergistic effect of ethanol and manganese was noticed on increasing the activity of ATPase and RNase while marked antagonistic effect was observed on the activity of MAO. The mechanism and the significance of these neurochemical alterations occurring after the administration of ethanol and manganese have been discussed.     

Lack of influence of brain catecholamines on acute effects of barbiturates

Rats with cerebral electrode implants were tested for sensitivity to EEG burst suppression by intravenously-infused sodium methohexital following manipulation of brain catecholamine function. Although depletion of both norepinephrine (NE) and dopamine (DA) with 6-hydroxydopamine resulted in a slight increase in methohexital sensitivity (MHS), similar depletion with α-methyltyrosine did not alter MHS. In addition, desipramine, an agent which selectively blocks uptake of NE did not affect MHS. The results indicate that brain NE and DA exert little, if any, effect on brain responsiveness to the acute effect of barbiturates.     

Inhibition of rat brain pyruvate dehydrogenase by thiamine analogs

The effects of thiamine thiazolone (TT) and thiamine thiazolone pyrophosphate (TTPP) on the in vitro and in vivo inhibition of pyruvate dehydrogenase complex (PDHC) from rat cortex and hippocampus were characterized. TTPP decreased PDHC activity in vitro but had no effect in vivo following its direct chronic administration via osmotic mini-pumps into the brains of behaving rats. In contrast, TT had no direct effect in vitro following a differential centrifugation purification of the mitochondrial PDHC fraction, but decreased PDHC activity in vivo. Additional experiments demonstrated that the cytosolic fraction converted TT to TTPP which, in turn, inhibited PDHC in vitro. A mechanism is proposed to explain these effects that is consistent with a non-competitive inhibition of brain PDHC by TTPP.     

Brain catecholamines during ethanol administration, effect of naloxone on brain dopamine and norepinephrine responses to withdrawal from ethanol

The variations in brain dopamine (DA) and norepinephrine (NE) levels after ethanol administration have been studied in rats. Acute ethanol administration significantly decreased brain DA and NE levels. After chronic ethanol intake no changes were observed in brain catecholamines. Ethanol withdrawal induced significant decreases in DA and NE concentrations in the brain. The administration of naloxone, antagonist of opiate receptors, blocked the effects of ethanol deprivation on brain catecholamines. These data suggest that endogenous opioids may be involved in the ethanol-withdrawal syndrome.     

The effect of LHRH on rat conditioned avoidance behavior: interaction with brain catecholamines

LHRH (100 micrograms/kg. SC) impairs the acquisition of two-way avoidance conditioning. This is partially potentiated by pretreatment with alpha-methyltyrosine (alpha-MT; 250 mg/kg IP) or fusaric acid (10 mg/kg IP). L-DOPA (100 mg/kg IP) administered 5 h after alpha-MT partially reversed its effects. The possible roles of brain catecholamines on the behavioral effects of LHRH are analysed. Other tentative mechanisms of action are also discussed.