Alcohol and drug research最新文献

Development of tolerance to ethanol was examined using heart rate as a measure. Ethanol-treated rats were infused IG with 8-11 g/kg/day (in 3 divided doses), control rats received similar infusions of either equicaloric dextrin-maltose or water (equivolumetric) for a period of 17 days. On days 1, 5, 9, 13 and 17 of treatment heart rate was recorded before and at 10, 20 and 30 minutes after injection of a challenge dose of 2 g/kg ethanol, dextrin-maltose or water. The tachycardia produced by ethanol increased with days of chronic treatment to a maximum on the 9th day of treatment. Significant tolerance to the tachycardia was evident only on the 17th day of treatment. Neither control showed significant changes in heart rate.

Pregnant mice were exposed to phenobarbital (PhB) on gestation days 9 to 18 (3 gm/kg milled food). Their offspring, who were exposed to the drug transplacentally (B offspring), were tested at an age of 50 days for apomorphine- (0.5, 1.0 and 2.0 mg/kg) induced hypothermia. At doses of 1.0 and 2.0 mg/kg, B offspring had less hypothermic response to apomorphine than controls (p less than 0.01); the effect was similar in both sexes. In order to acquire further understanding of the alterations in apomorphine hypothermia, mainly in relation to dopamine (DA) receptors, adult intact mice were exposed to haloperidol for 4 weeks (25 mg/kg milled food) in order to increase their DA receptor number, and their hypothermic response to apomorphine was tested 4 days post withdrawal. The treated animals had an increased DA receptor number, as was attested by a 23% increase in 3H-spiroperidol binding (P less than 0.01) and a 77% increase in apomorphine-induced climbing. However, their apomorphine-induced hypothermia did not differ from control. Therefore, there is no evidence as yet that alterations in apomorphine-induced hypothermia after prenatal exposure to PhB indicates changes in DA receptors, and the implications of this phenomenon still remain an open question.

Low dose alcohol significantly altered auditory evoked potentials in normal human subjects. Effects of alcohol were studied on the P50 evoked potential wave following click stimulation, which was presented in a conditioning-testing paradigm. The conditioning-testing paradigm uses paired stimuli to demonstrate inhibitory sensory gating, measured as suppression of the amplitude of the second or "test" response following the first or "conditioning" response. Alcohol at blood levels under 0.1 g per dl caused significant decrement in the size of the P50 wave in the initial conditioning response and also decreased the suppression normally seen in the conditioning-testing paradigm. These data suggest that low doses of alcohol affect both the excitatory mechanisms responsible for the formation of the P50 wave in the conditioning response and the inhibitory mechanisms responsible for its suppression in the test response. Nine of the 17 subjects studied using this paradigm were recorded both at Denver, Colorado (5,280 feet above sea level) and on Mt. Evans (14,264 feet above sea level). Despite the commonly held belief that alcohol causes more intoxication at high altitudes there was no significant difference in the effects of alcohol on evoked potentials in these subjects at these two attitudes.

The place-conditioning capacities of morphine, ketocyclazocine, ethylketocyclazocine, bremazocine, U 50488, d,1-N-allylnormetazocine (NAN), d-NAN, 1-NAN, and the effects of the opioid antagonists naloxone, WIN 44,441-3, and MR 2266BS were assessed in adult male rats using a three-chambered place-conditioning apparatus. Morphine, ketocyclazocine, ethylketocyclazocine, d,1-NAN, and 1-NAN at doses ranging from 0.25 to 4 mg/kg induced place-preferences for the compartment that was paired with drug administration during the conditioning process. One, 2, or 4 mg/kg of d-NAN had little effect. Naloxone, at doses of 1, 2, 4, and 10 mg/kg, conditioned strong place-aversions in rats; that is, on test day, rats spent significantly more time in the compartment that was not paired with drug-treatment. Bremazocine (0.05 to 4 mg/kg) and U 50488 (0.4 to 4 mg/kg) also conditioned significant, dose-related place-aversions. The results of the putative kappa opioid antagonists were mixed; MR 2266BS caused a dose-related place-aversion while the WIN 44,441-3 produced place-preference. Two mg/kg, but not 0.02 or 0.2 mg/kg, of naloxone administered prior to conditioning with 4 mg/kg of morphine, ethylketocyclazocine, and d,1-NAN, or 2 mg/kg of ketocyclazocine, resulted in place-aversions similar in magnitude to those found after naloxone-conditioning alone. Thus, the mu agonist morphine, the kappa agonists ketocyclazocine and ethylketocyclazocine, the sigma-agonist d,1-NAN, and the levo isomer of NAN all induce place-preferences in the rat according to the place-conditioning paradigm. In contrast, the kappa agonists bremazocine and U 50488, and the kappa antagonist MR 2266BS, induced place-avoiding responses. Since the development of place-preference after morphine, ketocyclazocine, ethylketocyclazocine, and d,1-NAN was antagonized by a kappa-receptor-antagonist dose of naloxone (2 mg/kg) and not by mu-receptor-antagonist doses, these data provide evidence that these particular mu, kappa, and sigma opioids may share a common underlying pharmacologic action.

The effect of foot-shock and ethanol (2 g/kg per os) and the combination of the two on dopamine (DA) metabolism in the medial prefrontal cortex (MPFC) was studied in rats. Electric foot-shock stress (20 min stimulation) decreased DA concentration by 30% and increased dihydroxyphenylacetic acid (DOPAC) concentration by 65%. Ethanol (2 g/kg orally) decreased DA concentration by 20%, but, unlike foot-shock, failed to modify DOPAC levels. Neither treatments modified homovanillic acid (HVA) levels. The combination of ethanol (30 min before shock) and foot-shock produced about a 50% depletion of DA content and 30% increase in HVA, but no change in DOPAC levels. It is suggested that both ethanol and foot-shock activate DA release in the MPFC, but ethanol decreases DA retrieval by nerve terminals and, therefore, prevents intraneuronal deamination of the amine.

Ethanol, like other general anesthetics, probably acts through an interaction with excitable membranes. When ethanol is present in membranes, the lipid structure of membranes is disordered. This effect can lead to alterations in functional entities that require a particular lipid environment. Sodium channels, requiring such an environment, have been studied for their sensitivity to ethanol. In synaptosomes, ethanol in vitro reversibly inhibits sodium influx stimulated by batrachotoxin or veratridine in concentrations equivalent to those found in animals during ethanol intoxication. Only the maximum stimulation of the toxins is altered by ethanol. The potencies of aliphatic alcohols are directly related to their lipid solubilities. Acute and chronic ethanol administration reduces the effectiveness of ethanol in vitro. This tolerance dissipates after a single dose of ethanol as it is eliminated from the body. However, after 4 days of ethanol treatment, the tolerance lasts for over 20 days. These data suggest that ethanol might disrupt one of the basic processes of neural function by acting directly on the environment of the sodium channel. The channel appears to be able to adapt to the presence of ethanol through the induction of tolerance.