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Biomedical subjects

C L Melchior

Publications and source records attributed to C L Melchior.

At least 19 recordsLinked to original sources
PubMed1994

Effect of AIT-082, a purine analog, on working memory in normal and aged mice.

Because working memory is the primary type of memory which is disrupted by Alzheimer's disease and stroke and during aging, any therapeutic drug for these conditions should improve and/or restore working memory. The win-shift memory paradigm has been shown to be an excellent model of working memory. In the present study, we examined the effects of a novel purine derivative, 4-[[3-(1,6-dihydro-6-oxo-9-purin-9-yl)-1- oxopropyl]amino]benzoic acid (AIT-082) and physostigmine (PHY) on working memory. Both AIT-082 and PHY improved memory in young mice and restored memory in mice with mild age-induced memory deficits; however only AID-082 was also effective in subjects with moderate deficits. Neither drug improved memory in mice with severe memory deficits. AIT-082 exhibited effectiveness over a broad dose range (0.5-60 mg/kg), and the effects lasted for seven days after a single high-dose drug administration. AIT-082 was devoid of any effects on performance variables and has not shown any toxic side effects, thus making it an interesting potential treatment for working memory deficits associated with aging, strokes, and Alzheimer's disease.

Aging↗
PubMed1994

Dehydroepiandrosterone is an anxiolytic in mice on the plus maze.

Dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) are neurosteroids that have been shown to interact with the GABA system. The present study examined the effects of these compounds in mice on motor activity and behavior in the elevated plus maze. Doses of 0.5 mg/kg and above of DHEA reduced motor activity. This effect was blocked by diazepam, RO15-1788, pentylenetetrazole (PTZ), and ethanol. Both DHEA and DHEAS showed anxiolytic activity in the plus maze test, with DHEA being effective over a very wide range of doses (5 micrograms/kg to 1.0 mg/kg). Both RO15-1788 and PTZ blocked the anxiolytic effect of DHEA, there was no interaction with diazepam, and ethanol enhanced the anxiolytic effect of DHEA. At 1.0 mg/kg, DHEAS blocked the anxiolytic effect of ethanol. These results support the hypothesis that neurosteroids could be involved in the termination of a stress response.

Animals↗
PubMed1994

Pregnenolone and pregnenolone sulfate, alone and with ethanol, in mice on the plus-maze.

The neurosteroids pregnenolone and pregnenolone sulfate were tested for anxiogenic/anxiolytic effects in mice on the elevated plus-maze. Pregnenolone in a dose of 0.01 micrograms/kg increased motor activity and caused an anxiogenic response, i.e., a decreased number of entries onto the open arms of the plus-maze. Pregnenolone sulfate had no effect on motor activity in the doses tested but showed a biphasic response on the plus-maze: at 10.0 and 1.0 micrograms/kg pregnenolone sulfate caused an anxiogenic response but at 0.1 microgram/kg it produced an anxiolytic response. When administered with 1.5 g/kg ethanol, neither neurosteroid altered the depression in motor activity caused by ethanol. However, all doses of pregnenolone tested blocked the anxiolytic effect of ethanol on the plus-maze while one dose of pregnenolone sulfate, 1.0 microgram/kg, attenuated the response to ethanol. These results support the suggestion that these neurosteroids could play a role in the initial response to stress and indicate that further work needs to be done to determine the mechanism for the interaction with ethanol.

Animals↗
PubMed1994

The interaction of ethanol with the cognitive enhancers tacrine, physostigmine, and AIT-082.

Because tacrine, a cognitive enhancing agent, was being considered for approval for use in Alzheimer's disease, its possible interaction with ethanol, a commonly used substance to which elderly individuals are generally more sensitive than younger individuals, was explored. For purposes of comparison, two other drugs, which have also been shown to improve memory in mice, at doses which had activity in a working memory paradigm, were evaluated for an interaction with ethanol. Ethanol-induced sedation in mice was increased by tacrine and decreased by physostigmine, whereas AIT-082 did not alter sedation. However, tacrine had no effect on body temperature or on ethanol-induced hypothermia. Neither tacrine nor physostigmine had any effect on the rate of ethanol elimination from the blood. As tacrine comes into clinical use in the treatment of Alzheimer's disease, adverse interactions with ethanol should be explored further.

Aminobenzoates↗
PubMed1993

Decreased tolerance to ethanol-induced hypothermia in long-term castrate male rats.

A potential role for central stores of vasopressin in the development of tolerance was studied in the long-term castrate rat. Vasopressin stores in the septal region are known to be dramatically depressed following long-term castration. Sprague-Dawley male rat littermates were castrated at 26 days of age or given a sham surgery. Experiments began when animals reached 130 days of age. Tolerance to the hypothermic effects of ethanol occurred in intact but not castrate animals over the course of six daily IP injections of 3.0 g/kg ethanol. Both groups exhibited tolerance to the length of time needed to return to baseline temperature over the 6 days of ethanol injections. Tolerance to this effect of ethanol was still evident in intact animals but not castrates following another injection of ethanol 1 week later. No tolerance developed to the rebound hyperthermia that occurred in both groups. Blood ethanol levels did not differ significantly between castrate and intact littermates administered a single dose of ethanol. Overall, these results support the hypothesis that endogenous vasopressin is involved in the development of some aspects of tolerance to ethanol.

Animals↗
PubMed1992

Interaction of pregnanolone and pregnenolone sulfate with ethanol and pentobarbital.

3-alpha-Hydroxy-5-beta-pregnan-20-one [pregnanolone (PA)] and 3-beta-hydroxy-5-pregnen-20-one 3-sulfate [pregnenolone sulfate (PS)] are steroids that have been shown in biochemical studies to be active at the GABA-benzodiazepine-chloride receptor complex, Pa as a "barbiturate-like" agonist and PS as a "picrotoxin-like" antagonist. Since other compounds that are active at this site interact with the effects of pentobarbital and ethanol, the behavioral effects of these steroids alone and in combination with pentobarbital and ethanol were tested. Pa blocks the convulsions caused by pentylenetetrazole (PTZ) and increases motor activity when given alone in low doses. In combination with either pentobarbital or ethanol, it enhances the depression in motor activity, hypothermia, and hypnosis. In contrast, PS has no effect on PTZ convulsions and depresses motor activity by itself. With pentobarbital, PS enhances the depression in motor activity but has no effect on hypothermia or hypnosis. With ethanol, PS enhances the hypothermia but does not affect motor activity or hypnosis. Therefore, Pa and PS show different but not opposite effects in interacting with compounds active at the GABA-benzodiazepine-chloride receptor complex.

Animals↗
PubMed1992

Dehydroepiandrosterone enhances the hypnotic and hypothermic effects of ethanol and pentobarbital.

Recent reports have indicated that the neurosteroid dehydroepiandrosterone (DHEA) and its sulfate (DHEAS) interact with the GABAA receptor complex. Because many of the behavioral effects of ethanol and pentobarbital are due to activity at this complex, DHEA and DHEAS were tested for their ability to interact with the hypnotic and hypothermic effects of ethanol and pentobarbital. DHEA, but not DHEAS, causes a dose-dependent increase in the sleep time induced by either ethanol or pentobarbital. At 20 mg/kg, DHEA and DHEAS themselves cause a fall in body temperature. DHEA enhances the hypothermic effect of both ethanol and pentobarbital. DHEAS enhances the hypothermic effect of ethanol, but with pentobarbital it only delays the return of body temperature to baseline levels. Neither DHEA nor DHEAS affects the metabolism of ethanol.

Animals↗
PubMed1991

Alterations in splanchnic blood flow after low and high doses of ethanol.

The purpose of this investigation was to determine the effect of various acute doses of ethanol (1.0, 3.0, 4.0 g/kg) on the distribution of cardiac output (%CO) and blood flow to the splanchnic vascular bed in conscious male Wistar rats. Regional blood flow and cardiac output (CO) were measured by the reference microsphere technique. Mean arterial pressure and CO were significantly reduced 60 min after 3.0 g/kg and 4.0 g/kg of ethanol, while no changes occurred over time in total peripheral vascular resistance or heart rate. Acute ethanol administration produced an early non-sustained increase in portal vein blood flow, that was most pronounced after a low dose of ethanol, and was attenuated after the 3.0 g/kg and 4.0 g/kg doses of ethanol. The early increase in portal vein blood flow produced a corresponding increase in total liver blood flow. Additionally, we found increases in hepatic arterial blood flow after the higher doses. The combined increase in portal vein and hepatic arterial supply to the liver may serve to increase oxygen delivery, more than the singular increase in portal vein blood flow. This early increase in total liver blood flow after high doses of ethanol may be important for protecting hepatocyte function in the presence of high blood ethanol levels.

Animals↗
PubMed1990

Conditioned tolerance provides protection against ethanol lethality.

To produce conditioned drug tolerance, mice were given twice daily injections of 3.5 g/kg of ethanol for four days and were tested on the fifth day in the same environment or in a novel environment. A range of doses of ethanol were utilized on the test day to assess lethality. The LD50 for ethanol was higher in mice tested in the environment previously associated with the administration of ethanol than in those tested in a novel environment. Therefore, conditioned tolerance can provide protection against ethanol lethality.

Animals↗
PubMed1990

Alterations in splanchnic blood flow following chronic ethanol exposure.

The purpose of these experiments was to determine whether or not tolerance develops to the effect of 3.0 g/kg ethanol on total and regional splanchnic blood flow in male Wistar rats. The animals were given the Lieber-DeCarli liquid diet containing ethanol for 10 days; ethanol-fed animals were withdrawn 24 hr prior to experiments. Regional blood flow and cardiac output (CO) were measured by the reference microsphere technique after an intraperitoneal injection of 3.0 g/kg of ethanol. Acute ethanol administration produced early nonsustained increases in portal vein blood flow in animals fed ethanol for 10 days and withdrawn for 24 hr and in control animals. However, after chronic exposure to ethanol, the pattern of increase in blood flow in response to ethanol in the splanchnic organs was different between the ethanol-fed and control groups. Increases in portal vein flow in control groups were due to concomitant increases in small intestinal, colonic, and cecal blood flow while the increase in the ethanol-fed group was due to a rise in small intestinal and stomach blood flow. The increase in stomach blood flow that occurred in the animals treated chronically with ethanol may be viewed as a conditioned response to ethanol, since this was not found in the control group. These results, demonstrate that the pattern of increase in blood flow in the splanchnic organs produced by an acute dose of ethanol depends on the animal's previous exposure to ethanol.

Alcohol Withdrawal Delirium↗
PubMed1988

Environment-dependent tolerance to ethanol produced by intracerebroventricular injections in mice.

In comparison to other routes of drug administration, an intracerebroventricular (ICV) injection requires the use of a very small amount of ethanol in mice to produce a brief but substantial hypothermic response. By avoiding the longer duration of drug action, use of ICV injections may facilitate the demonstration of the contribution of certain aspects of learning in the expression of tolerance. Therefore, tolerance to ethanol was developed in mice in a Pavlovian conditioning paradigm with eight ICV injections of ethanol delivered at 2-h intervals so that the animals received four injections per day for 2 days. The effect of ethanol in a different environment was tested on the following day. Environment-dependent tolerance to the hypothermic effect of ethanol and a robust conditioned compensatory response were demonstrated when the mice were trained and tested with ICV injections of 2.0 mg ethanol. The environment-dependent tolerance was also evident when the mice were trained with ICV injections and tested with intraperitoneal injections of ethanol. These results demonstrate that ICV injections are a beneficial means of clarifying the role of learning phenomena in the development of tolerance.

Animals↗
PubMed1986

The effect of 5,7-dihydroxytryptamine treatment on the response to ethanol in mice.

In order to assess the role of the serotonergic system in the development of tolerance to ethanol in the mouse, serotonin neurons in the CNS were lesioned with an intracerebroventricular injection of the neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT). Mice injected with 5,7-DHT responded to an acute dose of ethanol with a longer sleep time and greater fall in body temperature than CSF-treated mice. The increased response to acute administration of ethanol was accompanied by higher circulating levels of ethanol in mice pretreated with 5,7-DHT. When mice were fed an ethanol-containing liquid diet for five days, a higher mortality rate was observed in the 5,7-DHT group compared to the CSF pretreated group of mice. When the groups of mice were tested for tolerance 24 hours after withdrawal, the 5,7-DHT group was less tolerant than the CSF group. Therefore, damage to the serotonin neurons results in altered ethanol disposition, altered initial sensitivity to ethanol, and an inhibition in the development of tolerance in the mouse.

5,7-Dihydroxytryptamine↗
PubMed1985

Features of environment-dependent tolerance to ethanol.

Mice given multiple injections of ethanol in a standardized environment develop environment-dependent tolerance to the hypnotic and hypothermic effects of ethanol. These animals also demonstrate environment-dependent cross-tolerance to the hypnotic and hypothermic effects of pentobarbital. Examination of the levels of ethanol in the brain and blood at various times after injection of a test dose of ethanol, as well as the examination of the rate of disappearance of ethanol from the blood, indicated that environment-dependent tolerance could be explained by dispositional factors. On the other hand, mice rendered tolerant to ethanol by a liquid diet technique demonstrate tolerance that is not environment-dependent, and there is no alteration in ethanol levels in different environments for animals fed the liquid diet. When the animals in either paradigm are tested by injecting ethanol directly into the brain, tolerance is observed that is not dependent on the environment. Tolerance produced by these two different paradigms is apparently due to different adaptive strategies used by the animal. Environment-dependent tolerance is partially related to the ability of the animal to change the disposition of ethanol, while environment-independent tolerance may be entirely due to other factors, such as changes in neuronal sensitivity to ethanol.

Analysis of Variance↗
PubMed1984

Intraventricular arginine vasopressin maintains ethanol tolerance.

Tolerance to the hypnotic effect of ethanol in mice is prolonged by once daily intraventricular injections of arginine vasopressin. This action is similar to that reported previously when vasopressin was administered subcutaneously. The results indicate that maintenance of ethanol tolerance by vasopressin is a centrally mediated action of the peptide, and is not due to possible aversive properties of peripherally administered vasopressin.

Analysis of Variance↗
PubMed1984

A benzodiazepine antagonist action of CL 218,872.

The effect of the Type I benzodiazepine (BDZ) receptor agonist, CL 218,872, on convulsions generated by low doses of methyl beta-carboline-3-carboxylic acid ( MBCC ), bicuculline, picrotoxin and pentylenetetrazole (PTZ) in mice was examined. Low doses of CL 218,872 enhanced the convulsions produced by all agents except PTZ. An anticonvulsant action of CL 218,872 was observed at higher doses. Since CL 218,872 exhibits proconvulsive effects at low doses, and a proconvulsant action is a characteristic of compounds classified as BDZ antagonists, it appears that CL 218,872 has some antagonist action.

Animals↗
PubMed1984

A conditioning model of alcohol tolerance.

Tolerance to several effects of ethanol can be learned in a classical conditioning paradigm. In the conditioning model of tolerance, a response compensatory in nature to the effect of ethanol develops in association with the cues that signal the presence of ethanol. Tolerance produced by this procedure (environment-dependent tolerance) differs in several respects from tolerance produced in a paradigm in which learning would not be expected to play a significant role (environment-independent tolerance). Depletion of norepinephrine in the brain blocks the development of both types of tolerance, whereas depletion of serotonin enhances the rate of development of environment-dependent tolerance, but inhibits the development of environment-independent tolerance. Cued alterations in the volume of distribution for ethanol are an important factor in the tolerance displayed in the classical conditioning paradigm. It has been suggested that the conditioned compensatory response comprises the physiological response underlying "craving" for ethanol. This implies that an extinction procedure would be an effective treatment for the prevention of relapse.

Alcohol Drinking↗