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Biomedical subjects

V G Erwin

Publications and source records attributed to V G Erwin.

At least 55 records · Page 3Linked to original sources
PubMed1992

Chronic ethanol consumption produces genotype-dependent tolerance to ethanol in LS/Ibg and SS/Ibg mice.

It is well known that chronic ethanol administration produces tolerance to the sedative-hypnotic and hypothermic effects as well as low-dose locomotor inhibitory effects of ethanol. We report herein characterization of a convenient method of producing genotype-dependent functional tolerance to ethanol-induced locomotor inhibition. Mice, LS/Ibg (LS) and SS/Ibg (SS), which differ markedly in acute effects of ethanol on locomotor activity, hypothermia, and hypnotic sensitivity, were required to consume solutions of ethanol in water as the sole source of liquid. Mice were provided lab chow ad lib. and the following regimen of ethanol in water, v/v: 10% for 4 days, 15% for 4 days, 20% for 7 days, followed by 15% for periods longer than 2 weeks. Control animals received water only or were pair-fed sucrose (isocaloric with ethanol) solutions plus lab chow; both control and ethanol-consuming (15 g ethanol/kg/24 h) mice maintained similar body weights for up to 4 weeks. Blood ethanol concentrations from 10-200 mg% were obtained during a 12 L:12 D cycle. At 6 h following withdrawal, LS and SS mice showed differential dose-dependent tolerance to locomotor inhibitory effects of ethanol. However, low-dose locomotor activation was unaltered in either line of mice, and results indicate that an apparent sensitization in SS mice is secondary to development of tolerance to locomotor inhibition. Maximum tolerance to locomotor inhibition was observed after 2 weeks of chronic ethanol consumption, with responses returning to control values within 1-2 weeks after withdrawal. Rates of acquisition of tolerance were similar in LS and SS mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Selective breeding of rats differing in sensitivity to the effects of acute ethanol administration.

Selective breeding of rats for sensitivity to the anesthetic effects of ethanol is being carried out with rats derived from the genetically heterogeneous N/Nih stock. Thirteen generations of within family selection have been achieved with replicate high (HAS), low (LAS) and control alcohol sensitive (CAS) lines. Significant separation between lines on sleep time and blood ethanol concentration (BEC) at awakening following ethanol administration has been achieved. In general, the results obtained so far replicate the findings with short (SS) and long (LS) sleep mice. One exception is that the high alcohol sensitivity rats (HAS) also appear more sensitive to pentobarbital relative to LAS rats. This finding is opposite to that which occurs with SS and LS mice where the low ethanol sensitive SS mice appear more sensitive to pentobarbital than the LS mice.

Alcoholic Intoxication↗
PubMed1991

Cocaine actions, brain levels and receptors in selected lines of mice.

The effects of cocaine (15 mg/kg IP) versus IP saline on open-field behaviors were evaluated using a crossover design in long-sleep (LS) and short-sleep (SS) mice. Under treatment order 1, mice received saline injection on day 1 followed 24 h later by cocaine (saline-cocaine, S-C). Under treatment order 2, animals received cocaine on day 1 and saline on day 2 (cocaine-saline, C-S). Immediately following injection, animals were placed into an automated open-field apparatus with behavioral samples taken at 5-min intervals for 30 min. The behaviors measured were distance traveled, stereotypy and time spent in proximity to the margins of the test apparatus (thigmotaxis). Cocaine increased locomotor activity in both lines of mice, with S-C producing more pronounced initial activation than C-S in LS mice. Compared to S-C, C-S also increased thigmotaxis, an effect more pronounced in SS mice. In a separate experiment, brain cocaine levels were measured in brains of adapted and nonadapted LS and SS mice 5 min following injection of 15 mg/kg cocaine. Regardless of order, SS mice had significantly higher brain cocaine levels than did LS mice. Mazindol and cocaine binding studies in the forebrain indicated higher Bmax values for both ligands in LS compared to SS mice. The results of this study indicate that genetically based differences in cocaine receptors as well as treatment order contribute to behavioral actions of cocaine.

Animals↗
PubMed1991

Regional characterization of brain neurotensin receptor subtypes in LS and SS mice.

Neurotensin (NT) receptor subtypes were investigated in nine brain regions from long sleep (LS) and short sleep (SS) mice that were selectively bred for differences in sensitivity to ethanol. Differences in NT receptor densities may mediate, in part, genetically selected differences in ethanol sensitivity between the two lines of mice. The use of [3H] NT at concentrations from 0.02 to 20 nM yielded biphasic binding isotherms as revealed by Scatchard analysis. Membranes from LS ventral midbrain yielded dissociation constants (KD values) of 0.34 and 3.85 nM for the high (NTH) and low (NTL) affinity components, respectively. SS membranes displayed similar KD values, however the maximum number of binding sites (Bmax) for both receptor subtypes were significantly greater in SS than in LS membranes (46.7 vs. 71.5 fmol/mg protein for NTH and 170.2 vs. 208.2 fmol/mg protein for NTL). Using levocabastine, and H1 antagonist with selectivity for NTL, characterization of NTH and NTL binding in nine brain regions was performed. In general, membranes from each brain region of SS mice had higher densities than LS for both receptor subtypes. Significant differences for the total density of receptors and NTL were found in entorhinal cortex, nucleus accumbens, hippocampus, and ventral midbrain. The only region to differ in NTH was the ventral midbrain. Competition experiments using various NT fragments to compete for NTH binding showed the C-terminal amino acids to be essential for binding. The order of potency was NT1-13 = NT8-13 greater than Neuromedin N greater than NT1-8 = NT1-11.

Alcohol Drinking↗
PubMed1990

Isolate housing alters ethanol sensitivity in long-sleep and short-sleep mice.

Beginning at 45 days of age, male long-sleep (LS) and short-sleep (SS) mice were placed into individual cages for 21-22 days. Control animals were group-housed for the same amount of time. At 65-66 days of age, animals were given anesthetic doses of ethanol, IP. Measures taken were sleep time, body temperature at 30 and 60 minutes postinjection and blood ethanol content (BEC) at regain of righting response. Compared to the same measures in group-housed animals, sleep times and hypothermia were attenuated in isolate-housed LS and SS mice. Isolate housing resulted in a 15% increase, compared to levels observed in group-housed animals, in BEC at regain of righting in LS; there was no significant difference in BEC in SS mice. The results indicated an isolation-related decrease in sensitivity to the anesthetic effects of ethanol in LS; the effect of isolation in SS may be an increased clearance rate of ethanol.

Animals↗
PubMed1990

Low doses of ethanol reduce neurotensin levels in discrete brain regions from LS/Ibg and SS/Ibg mice.

Studies were designed to examine the previously proposed hypothesis that some of the pharmacological actions of ethanol are mediated by neurotensinergic processes. Neurotensin-immunoreactivity (NT-ir) was extracted from various brain regions and shown by high performance liquid chromatography to possess the same retention time as authentic bovine NT1-13. The highest levels of NT-ir were observed in the hypothalamus with intermediate levels in the midbrain and striatum and lowest levels in the frontal cortex. Levels of NT-ir were higher in hypothalamus and midbrain from long-sleep (LS) than from short-sleep (SS) mice. Ethanol, in vivo, produced a dose-dependent decrease in NT-ir in several brain regions; low doses, 1.5 to 3.0 g/kg, but not high doses, 4.1 g/kg, of ethanol significantly decreased NT-ir in hypothalamus, midbrain, and striatum of LS and SS mice. Levels of NT-ir in the frontal cortex were not altered by ethanol administration. Ethanol-induced decreases in NT-ir were of rapid onset with a maximum decrease in 5 min after intraperitoneal (i.p.) injection, and they were of long duration with levels remaining depressed for 4 hr. These findings show that subhypnotic, intoxicating doses of ethanol enhance NT release, in vivo, and support the hypothesis that some of ethanol's actions are mediated by neurotensinergic systems.

Animals↗
PubMed1990

Further characterization of LSxSS recombinant inbred strains of mice: activating and hypothermic effects of ethanol.

Lines of mice selected for differential initial sensitivity to the anesthetic effects of ethanol also differ in their locomotor responses to lower doses of ethanol. Sixteen recombinant inbred strains of mice derived from long-sleep (LS) and short-sleep (SS) selected lines as well as inbred LS and SS mice were used in a genetic correlational study to investigate possible associations between high-dose and low-dose indices of initial sensitivity to ethanol. Measurements of high-dose (4.1 g/kg) effects of ethanol were hypothermia, sleep time, and blood ethanol content at regaining of righting response, and the index of low-dose (1.875 g/kg) sensitivity was distance traveled during a 5-min period immediately following intraperitoneal injection with ethanol. The results indicated wide genetic variation in hypothermia and ethanol-induced locomotor activation in a manner consistent with polygenic influence. Furthermore, correlations between low-dose locomotor activity and hypnotic dose effects tended to be low and nonsignificant, indicating independence of inherited mechanisms underlying high- and low-dose ethanol sensitivity.

Alcoholism↗
PubMed1989

Neurotensin and ethanol interactions on hypothermia and locomotor activity in LS and SS mice.

Ethanol, i.p., produced a greater dose-dependent hypothermia in long sleep (LS) than in short sleep (SS) mice with significant decreases in rectal temperature observed only at doses greater than 3 g/kg, i.p. Likewise, at doses of 1 to 2 g/kg ethanol, i.p., these lines of mice differ markedly in locomotor activity. Neurotensin (NT), intracerebroventricular (I.C.V.), induced a similar hypothermia in both SS and LS mice at doses greater than 0.02 microgram. Doses of ethanol (1.0 g/kg) or NT (0.005 microgram, i.c.v.) that failed to cause hypothermia when administered separately produced a pronounced hypothermia when administered together. Potentiation of NT and ethanol-induced hypothermia was greater in SS than in LS mice. Sensitivity to NT-induced hypothermia was greater following i.c.v. administration than by infusion into the nucleus accumbens (NA) or the ventral tegmental area (VTA). Neurotensin, i.c.v. or intra-NA, markedly inhibited ethanol-induced increase in locomotor activity in both SS and LS mice; however, NT, intra-VTA, did not alter the effects of ethanol on locomotor activity. The results suggest that NT and ethanol act in a synergistic manner on specific neuronal processes mediating thermoregulation and spontaneous motor activity.

Animals↗
PubMed1989

LS X SS recombinant inbred strains of mice: initial characterization.

In order to assess the genetic correlates of differences in ethanol-induced anesthesia, a set of 27 recombinant inbred (RI) strains was derived from an initial cross of the "long-sleep" (LS) and "short-sleep" (SS) selected lines of mice. In generations F24 and F25, samples of 534 and 580 mice from the LSXSS RI strains were tested for fall time, sleep time, and blood ethanol at awakening subsequent to intraperitoneal injection of a 4.1-g/kg body weight dose of ethanol. Approximately 2 weeks later, mice from F24 were also tested for body temperature lowering and blood-ethanol elimination rate (beta 60). Differences among the average ethanol-induced sleep-time scores of the RI strains are large (ranging from 36 to 171 min) and account for over 50% of the observed variance. Effects due to generation, sex, litters within strains, and the interaction between strain and generation are also significant, but account for relatively small proportions of the total variance. Quantitative genetic analyses of these data suggest that differences in sleep-time scores are polygenic; however, allelic differences at the albino (c) locus may have a pleiotropic effect. Genetic correlations between sleep time and blood ethanol at awakening (-0.79) and between body temperature 60 min after injection and beta 60 (+0.48) are significant. Because differences among the LSXSS RI strains are large and highly reliable, they should be valuable animal models for testing more searching hypotheses about the etiology of individual differences in ethanol-induced anesthesia.

Animals↗
PubMed1988

Central muscarinic cholinergic influences on ethanol sensitivity in long-sleep and short-sleep mice.

Sensitivity to the hypnotic effects of ethanol was increased selectively by central administration of muscarinic agonists. Carbachol or oxotremorine, but not nicotine, i.c.v., enhanced hypnotic sensitivity to ethanol markedly, as measured by blood ethanol concentration at loss or righting response, in short-sleep (SS) but not long-sleep (LS) mice. Likewise, the acetylcholinesterase inhibitor, neostigmine, i.c.v., differentially enhanced hypnotic sensitivity to ethanol in these mouse lines. LS and SS mice were equally sensitive to the hypothermic effects of carbachol, neostigmine or oxotremorine i.c.v. The muscarinic antagonists, atropine or pirenzepine, i.c.v., were without effect on ethanol sensitivity, but these compounds antagonized muscarinic agonist-enhanced ethanol sensitivity in SS mice effectively. Pirenzepine, and M1 selective antagonist, produced a parallel shift in the oxotremorine dose-response curve, indicating that the enhanced hypnotic sensitivity to ethanol may be due to interaction of oxotremorine with M1 muscarinic receptors. This possibility was supported by the finding that atropine and pirenzepine which are known to have comparable affinities for M1 but not M2 receptors, had comparable potencies in antagonizing the action of oxotremorine or neostigmine. The results suggest that LS and SS mice differ genetically in neuronal processes activated by specific muscarinic agonists and are consistent with the hypotheses that ethanol acts in part via membrane receptor coupling to intracellular processes known to mobilize intracellular Ca++.

Animals↗
PubMed1987

Neurotensin selectively alters ethanol-induced anesthesia in LS/Ibg and SS/Ibg lines of mice.

Neurotensin (NT) differentially altered ethanol-induced anesthesia as measured by duration of loss of righting response or by blood ethanol levels producing loss of righting response in mice (LS and SS) which were selectively bred for differences in response to ethanol. At doses of 5-500 ng i.c.v., NT increased ethanol sensitivity in SS mice, but not in LS mice, as measured by blood ethanol concentrations at loss of righting response. At higher doses, 0.5-10 micrograms i.c.v., NT enhanced the sensitivity of both SS and LS mice to ethanol-induced anesthesia. The hypothermic effect of ethanol determined at loss of righting response was not altered in either LS or SS mice at low doses of NT, but at higher doses NT enhanced ethanol-induced hypothermia in both lines of mice. The altered anesthetic sensitivity was specific for ethanol in that NT did not alter pentobarbital-induced sleep time in either LS or SS mice and halothane anesthesia was altered slightly only in LS mice. NT analogues, N-acetyl-NT8-13, and [D-Trp11]-NT but not NT1-8 enhanced the anesthetic action of ethanol in SS mice. Bombesin, cholecystokinin sulfate, substance P, [D-Trp8, D-Cys14]-somatostatin and corticotropin releasing hormone (CRF) were not effective in enhancing ethanol-induced anesthesia in LS or SS mice. CRF appeared to decrease ethanol sensitivity in LS but not in SS mice. Beta-Endorphin (beta-END) markedly increased the ethanol sensitivity of SS and to a lesser extent of LS mice at relatively high doses, e.g. 0.5-1.0 micrograms i.c.v. The results of the present study indicate that differences in brain sensitivity of LS and SS mice to ethanol may be mediated by genetic differences in NT systems. Likewise, NT, and probably beta-endorphin, may interact with other neurochemical processes that are involved in the mechanism of ethanol-induced anesthesia and that differ genetically in LS and SS mice.

Animals↗
PubMed1987

Calcium differentially alters behavioral and electrophysiological responses to ethanol in selectively bred mouse lines.

Sensitivity to the hypnotic action of ethanol has been found to increase in SS/Ibg (SS) but not in LS/Ibg (LS) mice after intracerebroventricular (icv) administration of calcium. In the present investigation, a correlation was found between calcium-induced changes in behavioral sensitivity and in the sensitivity of cerebellar Purkinje neurons to the depressant effects of locally applied ethanol. Cerebellar Purkinje neuron sensitivity was measured as the dose of ethanol pressure ejected from a multibarreled micropipette required to produce a 50% depression of spontaneous firing rate of single neurons. Administration of 0.2-0.4 mumol calcium chloride into the lateral ventricle of the brain increased the sensitivity of SS but not LS mice to the hypnotic behavioral effect of systemically administered ethanol. Similarly, Purkinje neuron sensitivity to locally applied ethanol was also enhanced in SS but not in LS mice 15 min following administration of calcium (0.25 mumol) icv. Furthermore, locally applied ethanol was more effective in depressing spontaneous Purkinje neuron discharge in SS mice when a 1 mM calcium solution was concomitantly pressure ejected with ethanol from the micropipette. Magnesium chloride did not mimic the effects of calcium on either behavioral or electrophysiological effects of ethanol, suggesting that the action of calcium is not a nonspecific effect of divalent cations. These data suggest that calcium-dependent processes may be involved in behavioral and electrophysiological effects associated with ethanol intoxication. Further research will be required to determine if the genetically selected difference in ethanol sensitivity expressed in LS and SS mice is regulated by calcium mechanisms.

Action Potentials↗