Alcohol and drug research最新文献

The effects of ethanol, t-butanol and pentobarbitone on the membrane order of rat synaptosomal membranes have been compared using 3 spin-label probes, 5-doxyl-stearic acid which reports from a lipid site near the membrane surface, 16-doxyl-stearic acid which reports from a deeper lipid site, and maleimide-TEMPO which covalently binds to membrane protein. The sensitivity of the membrane proteins to a fluidizing effect of ethanol was increased by lowering the concentration of protein-binding probe. Significant decreases in membrane order were observed at anaesthetic concentrations of ethanol and t-butanol with all three probes; pentobarbitone produced a similar effect but only at very high concentrations. Pentobarbitone caused a marked change in high-field peak shape of the 16-doxyl-stearic acid spectra at anaesthetic concentrations; this effect was seen slightly with t-butanol and trichlorethanol but not with ethanol. These studies indicate that the membrane sites of action of ethanol and pentobarbitone as shown by ESR probes are different.

The effects of the stereoisomers of the prototypic sigma agonist N-allylnormetazocine were evaluated in squirrel monkeys trained to respond on an electric shock titration schedule. The monkeys responded on a fixed-ratio schedule to decrease the level of shock delivered to their tails. The effects of the isomers were compared to the effects of phencyclidine and morphine administered alone and also in combination with a rate-suppressing dose of morphine. Morphine increased the level at which shock was maintained without decreasing rates of responding in the presence of shock. Both the (+)-isomer and PCP produced increases in the levels at which the monkeys maintained the shock, but only in some animals. The (-)-isomer of N-allylnormetazocine resulted in either decreases or no effect on the level at which the monkeys maintained the shock. The isomers were equipotent in decreasing response rates. When tested in combination with morphine, only the (-)-isomer antagonized the shock-level increasing effects of morphine. Thus, the isomers had similar effects on response rates but the (+)-isomer, like PCP, was more effective in increasing the level at which the monkeys maintained electric shock, while only the (-)-isomer was effective as a morphine antagonist. These results suggest analgesic-like effects for the (+)-isomer of N-allylnormetazocine and substantiate the opiate-antagonist properties of the (-)-isomer.

The chronic ingestion of alcohol has been correlated with cardiac dysfunction. This study looked at the effect of chronic ethanol ingestion on the rat ventricle. The studies were carried out on hearts from male Long-Evans hooded rats, pair-fed on ethanol (E) or normal (N) liquid diet. The E rats received 35-39% of calories as ethanol. The studies were carried out after 40 weeks on the diet. The data show the E rats had reduced papillary muscle function, and increased incidence of isoproterenol induced extra beats and failure. There was no difference in responsiveness to isoproterenol, alpha, beta, or muscarinic receptor number or agonist binding characteristics between hearts from E and N rats. The cardiac dysfunction in the E group is thought to be due to possible membrane structural changes, or to changes in the characteristics of the autonomic receptor system beyond the receptor level.

Central nervous system (CNS) depressants such as ethanol and barbiturates under acute or chronic conditions can induce changes in rat brain protein synthesis. While these data demonstrate the individual effects of drugs on protein synthesis, the response of brain protein synthesis to alcohol-drug interactions is not known. The goal of the present study was to determine the individual and combined effects of ethanol and sodium barbital on brain protein synthesis and gain an understanding of the mechanisms by which these alterations in protein synthesis are produced. Specifically, the in vivo and in vitro effects of sodium barbital (one class of barbiturates which is not metabolized by the hepatic tissue) were examined on brain protein synthesis in rats made physically dependent upon ethanol. Using cell free brain polysomal systems isolated from "Control," "Ethanol" and 24 h "Ethanol Withdrawn" rats, data show that sodium barbital, when intubated intragastrically, inhibited the time dependent incorporation of 14(C) leucine into protein by all three groups of ribosomes. Under these conditions, the "Ethanol Withdrawn" group displayed the largest inhibition of the 14(C) leucine incorporation into protein when compared to the "Control" and "Ethanol" groups. In addition, sodium barbital when added at various concentrations in vitro to the incubation medium inhibited the incorporation of 14(C) leucine into protein by "Control" and "Ethanol" polysomes. The inhibitory effects were also obtained following preincubation of ribosomes in the presence of barbital but not cycloheximide. Data suggest that brain protein synthesis, specifically brain polysomes, through interaction with ethanol or barbital are involved in the functional development of tolerance. These interactions may occur through proteins or polypeptide chains or alterations in messenger RNA components associated with the ribosomal units.

The duration of loss of the righting response (sleep time) is often used to assess central nervous system sensitivity to ethanol. It has been assumed that there is a threshold concentration of ethanol at which an animal will regain the righting response, and that this level should not change with dose or route of administration of ethanol. Five hypnotic doses of ethanol were given to Long-sleep and Short-sleep mice by intraperitoneal injection. At the time of awakening, blood and brain ethanol levels were measured. It was found that within a line, the animals awoke at the same blood and brain ethanol concentration irrespective of the ethanol dose given. The threshold blood ethanol level was 265 mg% for Long-Sleep males and 484 mg% for Short-Sleep males. These results indicate that there is a threshold value for ethanol, and that this threshold is characteristic for a given mouse line.

The N/Nih heterogeneous stock rats were tested for alcohol drinking behavior. Rats that met criteria for high (greater than 5.0 g ethanol/kg body weight/day) and low (less than 0.5 g/kg/day) alcohol consumption were chosen, and the regional brain contents of monoamine neurotransmitters were determined in these animals. The primary finding was a lower content of serotonin and 5-hydroxyindoleacetic acid in the thalamus and hypothalamus of the high alcohol preferring N/Nih rats as compared with the low preferrers. The high preferrers were also found to have a lower content of dopamine and norepinephrine in the thalamus. The findings support the hypothesis that an inverse relationship exists between the density and/or metabolic functioning of regional brain serotonin systems and alcohol preference.

Despite a paucity of data on its animal pharmacology and toxicology, MDMA [Ecstasy, XTC, ADAM; (+/-)-3,4-methylenedioxymethamphetamine] was introduced as an "underground" (FDA-unapproved) adjunct to psychotherapy in the late 1970's and early 1980's, in addition to its use as a recreational drug. Analysis of the limited experimental literature indicates that LD50's for MDMA in five species by several routes of administration tend to predict a significant human toxicity. MDMA was either equally toxic or slightly to moderately less toxic than its close congener, MDA, (+/-)-3,4-methylenedioxyamphetamine. It is suggested that extrapolation of the pharmacologic/toxicologic data available for MDA to MDMA should be assumed to be valid until disproven. Recently published canine data describe physiologic disturbances caused by acute overdosage of MDA, and also indicate the utility of chlorpromazine as an antidote preventing fatalities associated with severe hyperthermia, lactacidemia, hypertension and tachycardia. The toxicology of MDMA warrants further direct study in view of its continuing illegal distribution.

Recently, it was reported that proglumide, a cholecystokinin (CCK) antagonist, potentiates the analgetic effects of morphine and endogenous opioid peptides and reverses morphine tolerance by antagonizing the CCK system in the central nervous system of the rat. In order to provide additional insight into the mode of action of this agent, we assessed the effect of proglumide in the isolated guinea pig ileum and the mouse, rat and rabbit vas deferens. Furthermore, we studied the in vitro binding affinity of this substance to mouse brain synaptosomes. Our results show that proglumide inhibits, dose dependently, the electrically stimulated twitches in the mouse vas deferens and guinea pig ileum, but not in the rat or rabbit vas deferens. The inhibitory action of proglumide on the mouse vas deferens, but not on the guinea pig ileum, is antagonized by naloxone and by the selective delta-antagonist, ICI 174,864, in a competitive fashion. Other CCK antagonists were found to be devoid of such activity on the mouse vas deferens. In vitro binding studies showed that proglumide displaces D-ala-D-[leucine]5-enkephalin (DADLE), a delta agonist, but not ethylketocyclazocine (EKC), a preferentially selective kappa agonist. The effect of proglumide appeared to be elicited presynaptically since it did not alter the norepinephrine-induced contractions of the mouse vas deferens. Our results suggest that proglumide might exert its opiate-like effects by activation of delta-opioid receptors.

1-N,N-bis-(Dichloroethyl)carbamate-delta 9-THC (THC carbamate), a nitrogen mustard analog of delta 9-THC, was recently synthesized as a potential anti-tumor agent. The decrease in spontaneous activity, induction of hypothermia, and the antinociceptive properties of THC carbamate and delta 9-THC were compared. THC carbamate and delta 9-THC were administered by a number of peripheral routes as well as intraventricularly (ivt). THC carbamate lacked cannabinoid activity following peripheral administration, with the exception of iv administration which produced very weak cannabimimetic effects. In contrast, THC carbamate was equipotent to delta 9-THC in reducing rectal temperature by 3 degrees C, and 5 times less active in decreasing spontaneous activity following ivt administration. The apparent lack of central effects following peripheral administration might limit the effectiveness of THC carbamate as an anti-emetic agent, but its use as a site-directed alkylator (a receptor probe) holds promise.

The gastric mucosal damage induced by pylorus ligation for 6 h, hypothermic restraint stress, aspirin, indomethacin and reserpine was studied in morphine dependent rats. Morphine tolerance and dependence were produced by administering the gradually increasing concentrations of morphine sulphate in drinking water for 21-24 days. The tolerance and dependence produced by morphine were confirmed by a decreased analgesic response to morphine in the hot plate test and by producing a naloxone precipitated withdrawal syndrome respectively. The intensity of gastric mucosal damage induced by pylorus ligation, aspirin and indomethacin was significantly higher in morphine dependent rats than that observed in the naive animals. Studies on the gastric secretion did not reveal any significant change in the volume of gastric secretion, titrable acidity and gastric output of 6 h pylorus ligated rats. The average lesion scores in the reserpine treated and hypothermic restraint stressed rats were not significantly different from those obtained in the naive animals. Further studies are required to establish the exact mechanisms underlying these observations.