Acetaminophen hepatotoxicity precipitated by short-term treatment of rats with ethanol and isopentanol: protection by triacetyloleandomycin

Ethanol and isopentanol are the predominant alcohols in alcoholic beverages. We have reported previously that pretreatment of rats with a liquid diet containing 6.3% ethanol plus 0.5% isopentanol for 7 days results in a synergistic increase in acetaminophen hepatotoxicity, compared with rats treated with either alcohol alone. Here, we investigated the role of CYP3A in acetaminophen hepatotoxicity associated with the combined alcohol treatment. Triacetyloleandomycin, a specific inhibitor of CYP3A, protected rats pretreated with ethanol along with isopentanol from acetaminophen hepatotoxicity. At both 0.25 and 0.5 g acetaminophen/kg, triacetyloleandomycin partially prevented elevations in serum levels of alanine aminotransferase. At 0.25 g acetaminophen/kg, triacetyloleandomycin completely protected 6 of 8 rats from histologically observed liver damage, and partially protected the remaining 2 rats. At 0.5 g acetaminophen/kg, triacetyloleandomycin decreased histologically observed liver damage in 7 of 15 rats. In rats pretreated with ethanol plus isopentanol, CYP3A, measured immunohistochemically, was decreased by acetaminophen treatment. This effect was prevented by triacetyloleandomycin. These results suggest that CYP3A has a major role in acetaminophen hepatotoxicity in animals administered the combined alcohol treatment. We also found that exposure to ethanol along with 0.1% isopentanol for only 3 days resulted in maximal increases in acetaminophen hepatotoxicity by the combined alcohol treatment, suggesting that short-term consumption of alcoholic beverages rich in isopentanol may be a risk for developing liver damage from acetaminophen.     

Motor disturbance induced by tremorine and oxotremorine

Summary The action of tremorine and oxotremorine on spinal motor activity was studied in the rat. Both tremorogenio agents increased a reflex activity and spontaneous activity. The increase in spontaneous activity consisted of rhythmic bursts of discharges. The increase in a reflex activity was accompanied by rigidity, which manifested itself by the appearance of tonic muscle activity.Tremorine and oxotremorine-induced tremor was depressed by the antitremor agents metixene and Kr 339, the antiparkinson drugs atropine and biperiden, and the adrenergic receptor blocking agents propranolol and pronethalol. The adrenergic. receptor blocking agents azapetine, dihydroergotamine, haloperidol, phenoxybenzamine and phentolamine failed to inhibit tremor activity. Chlorpromazine, however, as well as procaine, verapamil and DOPA, diminished the intensity of tremor activity without blocking the generation of tremor bursts.Drugs which depressed tremor activity also antagonized the effect of oxotremorine on and motor activity, whereas the drugs, which only diminished tremor intensity, depressed the increased reflex discharge without reducing spontaneous activity. Rigidity disappeared when reflex discharge was normalized.It is concluded that experimental parkinsonlike rigidity may be interpreted in terms of a disturbed balance between monoaminergic and cholinergic mechanisms in the brain.The authors are grateful to KnolI-Ludwigshafen for the support of the investigation.     

Amnesia attenuation specificity: Propranolol reverses norepinephrine but not cycloheximide-induced amnesia

Post-trial injections of norepinephrine (NE) or cycloheximide (CHX) into the amygdala produces a long-term retention deficit (amnesia) for a 1-trial footshock experience in rats. Concomitant post-trial injections of the adrenergic antagonist, propranolol, prevents NE-, but not CHX-induced amnesia. These results indicate separate mechanisms of action for amnesia produced by intracranial CHX and NE injections.     

Chronic treatment with antidepressant drugs and the analgesia induced by 5-methoxy-N,N-dimethyltryptamine: attenuation by desipramine

The effect of chronic and acute oral or intraperitoneal treatment with the antidepressant drugs, desipramine, amitriptyline, alaproclate and iprindole, upon pain thresholds in the tail flick, hot plate and shock titration tests of nociception in saline- and 5-MeODMT-treated rats was studied. Chronic desipramine treatment increased the pre-test tail flick latencies. In the saline-treated rats, chronic oral desipramine treatment increased tail flick latencies, whereas chronic oral amitriptyline treatment decreased tail flick latencies. In 5-MeODMT-treated rats, chronic oral desipramine treatment attenuated the effects of 5-MeODMT (1 mg/kg) in all three tests of nociception, whereas chronic amitriptyline caused a potentiation in the tail flick and hot plate tests. Chronic oral iprindole treatment attenuated 5-MeODMT-induced analgesia in the hot plate test. Chronic intraperitoneal desipramine treatment attenuated 5-MeODMT analgesia in the tail flick and shock titration tests. In a different chronic treatment experiment, oral desipramine treatment attenuated 5-MeODMT analgesia in the tail flick test and zimeldine did for both the tail flick and hot plate tests, whereas mianserin potentiated 5-MeODMT-induced analgesia in both the tail flick and hot plate tests. In the saline-treated rats, acute treatment with all four drugs, desipramine, amitriptyline, iprindole and alaproclate, elevated the shock thresholds, whereas in 5-MeODMT-treated rats, desipramine and amitriptyline elevated shock thresholds. Two main conclusions can be drawn: chronic desipramine caused a quite consistent attenuation of 5-MeODMT-induced analgesia and the effects of acute treatment differed strongly from that of the chronic treatment. The effects of chronic administration with these antidepressants were compared with other findings using different measures of behavioural and receptor function.     

Possible mechanism of action for the attenuation of ethanol intake induced by ritanserin in rats

The 5-HT₂ receptor antagonist, ritanserin, reduces alcohol intake in rats and the nucleus accumbens (NAC) has been proposed as a site of action for the drug. Recent microdialysis studies have shown that acute subcutaneous (SC) administration of ritanserin increases extracellular 5-HT levels in the NAC. The present study evaluated, in genetically heterogeneous rats with developed preference for 3% ethanol, whether the attenuation of ethanol intake induced by ritanserin might be related to its effect on the synaptic availability of 5-HT in the NAC. Damaging 5-HTergic neurons by intracerebroventricular infusion of 5,7-dihydroxytryptamine (5,7-DHT) abolished the effect of ritanserin on ethanol consumption. Injections of the 5-HT₃ receptor antagonist MDL 72222 into the NAC significantly reduced the inhibitory effect of SC injection of ritanserin, 1 mg/kg, and completely abolished the effect of ritanserin, 0.1 mg/kg. Subcutaneous injections of MDL 72222, 0.3 mg/kg 3times/day, suppressed the effect of SC ritanserin, 0.1 mg/kg. The present findings, together with those of previous experiments showing that the tryptophan hydroxylase inhibitor p-chlorophenylalanine abolishes the effect of ritanserin, support the hypothesis that its effect on ethanol intake may be due to increased synaptic availability of 5-HT into the NAC. Received: 22 March 1996/Final version: 10 July 1996     

Ethanol-ecstasy (MDMA) interactions in rats: preserved attenuation of hyperthermia and potentiation of hyperactivity by ethanol despite prior ethanol treatment

Recreational use of ecstasy, or (+/-)-3,4-methylenedioxymethamphetamine (MDMA), is often associated with other drugs, among which ethanol is one of the most common. Little is known, however, about the interaction between these two drugs. Using a daily ethanol and/or MDMA administration regimen, we recently showed that ethanol potentiated the hyperactivity (in the home cage), but attenuated the hyperthermia induced by MDMA. The prevention of hyperthermia occurred only on the first of four daily ethanol-MDMA treatments, indicating possible tolerance to ethanol. In order to test the tolerance hypothesis, we treated Long-Evans adult male rats with ethanol on 4 consecutive days prior to their first treatment with MDMA-ethanol. Our results first confirmed that ethanol (1.5 g/kg, i.p.) potentiates the psychomotor effects of MDMA (10 mg/kg, i.p.), while attenuating its pyretic effects (6.6 mg/kg, i.p.). The results also showed that both the potentiation of locomotor activity and the attenuation of hyperthermia by ethanol are not at all altered by prior ethanol treatment. This indicates that tolerance to ethanol per se does not account for what appears to be tolerance to the ethanol-MDMA combination, thus indicating that ethanol-MDMA combination likely has unique pharmacological effects.     

Amnesia induced by stimulation of the amygdala is attenuated by hexamethonium

Bilateral subseizure stimulation of the amygdala given immediately following training in an inhibitory avoidance task produced retrograde amnesia. Hexamethonium (3.0 and 10.0 mg/kg), a peripherally acting nicotinic cholinergic antagonist, attenuated the retention deficits induced by amygdala stimulation if the drug was given 30 min prior to, but not immediately following training. Hexamethonium had no effect in normal unoperated animals, but did produce a retention deficit in operated control (nonstimulated) animals if it was given immediately following training (3.0 and 10.0 mg/kg). The results suggest that memory deficits induced by electrical stimulation of the amygdala are associated with, or perhaps mediated in some way by peripheral autonomic function.     

Possible cholinergic-dopaminergic link in memory facilitation induced by oxotremorine in mice

The immediate post-trial injection of the centrally active muscarinic agonist oxotremorine (0.025, 0.050 and 0.100 mg/kg, IP) can facilitate the retention of a passive-avoidance response in mice, as indicated by performance on a retention test 24 h later. Injections given 10 min after training also significantly facilitated retention, but given 120 min after training did not affect retention. These findings suggest an action of oxotremorine on memory mechanisms. The enhanced retention was neither the result of a punishing effect of oxotremorine nor of a nonspecific proactive pharmacological action of the drug. The memory facilitation produced by oxotremorine (0.050 mg/kg, IP) was not antagonized by pretreatment with phentolamine (10 mg/kg, 30 min, IP), phenoxybenzamine (10 mg/kg, 120 min, IP) or piperoxane (20 mg/kg, 30 min, IP). The alpha-noradrenergic blocking agents had no effect by themselves. On the other hand, the immediate post-trial injection of oxotremorine (0.050 mg/kg, IP) did not enhance retention when mice were pretreated with haloperidol (0.5 mg/kg, 120 min, IP). Haloperidol injected either before training or before the retention test did not alter performance during the retention test. This suggests that haloperidol impairs neither acquisition of the avoidance response nor its retrieval. Thus, it is probable that haloperidol pretreatment impaired oxotremorine-induced memory facilitation. We suggest a possible participation of brain catecholamines in memory facilitation induced by oxotremorine in mice.     

Depression by amantadine of tremor induced by reserpine and oxotremorine in the rat

Summary Reserpine and oxotremorine tremor as well as the effect of amantadine on the tremor activity produced by both drugs were studied in rats with respect to changes in alpha and gamma motor activity.The tremor activity elicited by reserpine (10 mg/kg i.v.) is maintained by the alpha motoneurones, whereas the tremor activity developing during an infusion of oxotremorine (40 g/kg·min) is triggered by the gamma motoneurones. Amantadine (50 mg/kg i.v.), which itself elicited tremor activity, abolished the tremor produced by oxotremorine. The tremor activity resulting from an administration of reserpine was inhibited by amantadine in rats with their dorsal roots cut; in rats with intact dorsal roots, tremor activity persisted after reserpine and amantadine.It is concluded that the tremor resulting from reserpine and oxotremorine is brought about by an action of the two drugs on different structures of the central nervous system. The anti-tremor effect of amantadine is discussed.     

Power spectral analysis of tremor induced by TRH and oxotremorine in mice

Tremor induced by TRH and oxotremorine was recorded by a capacitance transducer, and its intensity and frequency were evaluated using power arrays. In mice treated with TRH (20 mg/kg, i.p.), the latency of tremor was 17.1 +/- 1.7 min (mean +/- S.E.) and the duration was 20.4 +/- 2.2 min, while the frequency was 13.7 +/- 0.3 Hz. In animals with oxotremorine (0.5 mg/kg, i.p.), the latency was 4.3 +/- 0.4 min and the duration was 18 +/- 2.2 min, while the frequency was 12.7 +/- 0.3 Hz. The latter frequency, however, was significantly shifted to a lower frequency as a function of time. In TRH-induced tremor, vertical movements appeared in the same degree as horizontal movements. In oxotremorine-induced tremor, the vertical movements were few, whereas the horizontal movements were observed in a degree similar to those of TRH. The TRH tremor was suppressed by haloperidol and propranolol, but not by atropine. On the contrary, the oxotremorine tremor was inhibited by atropine, but not by haloperidol or propranolol. These results suggest that mechanisms of tremor induced by TRH differ qualitatively from those by oxotremorine; dopaminergic and beta-adrenergic receptor mediated functions may be linked to the developments of tremor caused by TRH, while cholinergic systems have a little effect in mice. The apparatus used in this study and power spectral analysis with power arrays may provide a useful method for simultaneous evaluation of the latency, duration, intensity and frequency of tremors.     

Inhibitory effect of baicalein on mice tremor induced by oxotremorine and mechanisms

OBJECTIVE To investigate the anti-tremor effect and mechanism of baicalein on oxotremorine-induced muscle tremor in mice.METHODS The acute model of muscular tremor was induced by intraperitoneal injection of oxotremorine,and the latency,duration and frequency of muscle tremor in mice were measured immediately;the saliva of mice was measured to reflect the correlation between tremor and peripheral nerve function;the aim of this study was to determine the content of MDA and the activity of GSH-PX,and to investigate the anti-oxidation of mice with tremor model.The activity of acetylcholinesterase(AchE)and acetylcholine transferase(ChA T)can indirectly reflect the level of acetylcholine in the brain.The level of monoamine neurotransmitters in brain tissue was determined by high performance liquid chromatography(HPLC-ECD).RESULTS The animals in the model group appeared obvious tremoring,salivating and erecting and other symptoms.Compared to the model group,there was no obvious inhibitory effect on the administration of each dose.After 7,14,21 and 28 d of continuous administration,the latency,duration and tremor frequency of tremor mice were significantly shortened,the levels of acetylcholine were significantly decreased,the changes of DOPAC and DA neurotransmitters in the brain of model group were recovered,regulate the dynamic balance of acetylcholine and dopamine in the brain.CONCLUSION Long-term administration can improve the tremor behavior of mice,the mechanismmay be related to the regulation of neurotransmittersin brain.     

Regulation of ethanol intake by rats with an induced preference for ethanol.

This paper is an attempt to characterize the nature of ethanol preference acquired by male albino rats after 30 daily sessions of hypothalamic stimulation. It was observed that rats that acquired ethanol preference following hypothalamic stimulation continued to ingest significant amounts of ethanol even after it was adulterated with 0.05% quinine hydrochloride. None of the ethanol-preferring rats exhibited any signs of withdrawal when ethanol presentations were terminated following 73 days of ethanol ingestion. The ethanol preferring rats were extremely accurate in regulating the amount of absolute ethanol ingested when the concentration of solutions presented to them were systematically varied. The data is discussed in terms of the specificity of the phenomenon and possible shifts in preference-aversion taste function.     

Hypoglycemia and hypothermia induced by ethanol: antagonism by indomethacin

The influence of pretreatment with 5.0 or 10.0 mg/kg of indomethacin, a prostaglandin synthetase inhibitor, on the alterations in body temperature produced by 3.0 and 4.0 g/kg of ethanol, was studied in food-deprived and free-feeding rats. A partial antagonism of ethanol's hypothermic effect resulted from indomethacin pretreatments and this effect was found to be ethanol dose-dependent. This result could account for the conflicting reports in the literature on the effectiveness of indomethacin in antagonizing ethanol-induced hypothermia. Indomethacin (5.0 mg/kg) also antagonized ethanol-induced hypoglycemia in 48 hr starved rats. The relationship between two effects of ethanol, hypothermia and hypoglycemia, is discussed.     

Amnesia induced by beta-amyloid fragments is counteracted by cannabinoid CB1 receptor blockade

Administration of drugs activating cannabinoid CB(1) receptors in the brain induces memory deficit in rodents, and blockade of these receptors may restore memory capacity in these animals. Central administration of beta-amyloid or beta-amyloid fragments may also lead to memory disturbances. This study was undertaken to study the involvement of cannabinoid CB(1) receptors in amnesia induced by beta-amyloid fragments in mice tested in a step-through passive avoidance paradigm. Pre-training intracerebroventricular (i.c.v.) injection of beta-amyloid fragments, beta-amyloid peptide-(25-35) (4, 8 or 16 nmol/mouse) or beta-amyloid peptide-(1-42) (200, 400, 800 pmol/mouse) 7 days prior to the learning trial reduced in a dose-dependent manner the retention of passive avoidance response. This effect was observed in two retention tests, 1 and 7 days after the learning trial. The two beta-amyloid fragments showed similar potency in reducing retention of passive avoidance behavior. This effect was counteracted by a single intraperitoneal (i.p.) injection of the cannabinoid CB(1) receptor antagonist, N-(piperidin-l-yl)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide hydrochloride (SR141716A, 1 mg/kg), made 30 min prior to the second retention test. The injection of SR141716A per se did not affect memory capacity of mice. The i.c.v. administration of beta-amyloid peptide-(25-35) (8 nmol/mouse) or of beta-amyloid peptide-(1-42) (400 pmol/mouse) made 30 min prior to the learning trial failed to affect the retention capacity of mice as measured 1 and 7 days later. Also, the i.p. injection of SR 141716A (1 mg/kg) made 30 min prior to the learning trial did not influence the behavioral response of mice injected with beta-amyloid peptide-(25-35) (8 nmol/mouse) or of beta-amyloid peptide-(1-42) (400 pmol/mouse) 7 days prior to the learning trial. These results show that beta-amyloid fragments induce a dose-dependent memory deficit. Their effect on memory retention depends upon the time of administration and seems to involve cannabinoid CB(1) receptors in the brain.     

Amnesia induced by morphine in spatial memory retrieval inhibited in morphine-sensitized rats

The present study investigated the effect of morphine sensitization on the impairment of spatial memory retrieval induced by acute morphine in adult male rats. Spatial memory was assessed by 2-day Morris water maze task which included training and test day. On the training day, rats were trained by a single training session of 8 trials. On the test day, a probe trial consisting of 60s free swim period without a platform and the visible test were administered. Morphine sensitization was induced by subcutaneous (s.c.) injection of morphine, once daily for 3 days followed by 5 days without drug treatment before training. The results indicated that acute administration of morphine (7.5mg/kg, s.c.) before testing impaired spatial memory on the test day. Pre-test morphine-induced amnesia decreased in morphine-sensitized (15 and 20mg/kg, s.c.) rats. Improvement in spatial memory retrieval in morphine-sensitized rats was inhibited by once daily administration of naloxone (1 and 2mg/kg, s.c.) 30 min prior to the injection of morphine for three days. The results suggest that morphine sensitization reverses the impairment of spatial memory retrieval induced by acute morphine and it is implied that mu-opioid receptors may play an important role in this effect.     

Behavioral stimulation induced by ethanol withdrawal

A model for the study of an ethanol withdrawal syndrome on operant behavior is described. Rats maintained of 16% w/v solutions of ethanol for several months were trained to perform on a DRL-15 schedule. On withdrawal of ethanol the interresponse times were significantly shortened concomitant with an increase in the total number of responses.     

Changes in a hexobarbital anaesthesia threshold in rats induced by repeated long-term treatment with barbital or ethanol

The quantity of intravenously infused hexobarbital needed to produce a burst suppression of 1 sec or more in the EEG was determined in male rats after chronic barbital or ethanol treatments. The ensuing sleeping times were also recorded.At the end of the first treatment with barbital (200 mg/kg/day i.p. for 5 weeks) the hexobarbital thresholds had increased by approximately 45% compared with a pre-experimental average. The thresholds were back to normal after approximately a week. At the end of a second treatment with barbital there was a similar, slightly more prolonged, immediate increase in threshold. Three weeks after the second treatment there was also a new increase in threshold (Figs. 2 and 3). The ensuing sleeping times were unaffected.Ethanol treatment (10% W/V in the drinking water allowed twice 1 h each day for 16 weeks) caused a gradual increase in threshold which reached a maximum (20%) around day 9–10 after the end of the treatment (Fig.5). Two weeks after the ethanol treatment the thresholds were essentially normal. In an earlier barbital treated (200 mg/kg/day i.p. for 5 weeks) group a second slightly larger increase was also seen around 3 weeks after the end of the ethanol treatment. In this group an increase was also seen in the ensuing sleeping times but this increase seemed to be unrelated to the increases in threshold.These late changes in threshold after a second treatment seem to be due to a summation of changes induced by the two treatments. In this respect ethanol and barbital are probably related. They are, however, not identical with respect to their effects on the hexobarbital threshold after interruption of chronic treatment. This is shown by the longer latency of the immediate changes after ethanol treatments.     

Brain catecholamines modifications. The effects on memory facilitation induced by oxotremorine in mice

The immediate posttrial injection of oxotremorine (0.250 Mol/kg, IP) can facilitate the retention of a passive-avoidance response in mice. After the administration of alfa-methyl-p-tyrosine methylester (-MPT) by intracerebroventricular injection at doses that had no effect on retention (100 g, 10 l, 60 min before trial), the immediate posttrial injection of oxotremorine did not enhance retention.The employed dose of -MPT reduced brain levels of norepinephrine by about 40% and those of dopamine by about 25%.Pretreatment with nialamide (30 mg/kg, 20 h IP), which prevents the catecholamine depletion induced by -MPT, counteracted the effects of -MPT on the actions of oxotremorine on retention.These results suggest a participation of brain catecholamines on the actions of oxotremorine on retention and a possible interaction of cholinergic neurons with catecholaminergic system in memory processes.