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A C Collins

Publications and source records attributed to A C Collins.

At least 55 records · Page 3Linked to original sources
PubMed1996

Inbred mouse strains vary in oral self-selection of nicotine.

Inbred mouse strains differ in sensitivity to a first dose of nicotine and in the development of tolerance to nicotine. The experiments reported here used six inbred mouse strains (A, BUB, C3H, C57BL/6, DBA/2, ST/b) that differ in sensitivity to an acute challenge dose of nicotine to determine whether differences in oral self-selection of nicotine exist. Animals were presented with solutions containing nicotine or vehicle (water or 0.2% saccharin) and their daily intake of the two fluids was measured for 4 days starting with a 10 micrograms/ml nicotine solution. This was followed by sequential 4-day testing with 20, 35, 50, 65, 80, 100, 125, 160 and 200 micrograms/ml nicotine solutions. The strains differed dramatically in their self-selection of nicotine and in maximal daily dose (mg/kg); the rank order of the strains was C57BL/6 > DBA > BUB > A > or = C3H > or = ST/b for both the tap water and 0.2% saccharin choice experiments. Correlations between nicotine consumption and sensitivity to nicotine, as measured by a battery of behavioral and physiological responses, were also calculated. Strain differences in nicotine intake were highly correlated with sensitivity to nicotine-induced seizures. As sensitivity to nicotine-induced seizures increases, oral self-selection of nicotine decreases. This finding may suggest that this toxic action of nicotine serves to limit intake.

Animals↗
PubMed1996

Changes in sensitivity to nicotine and brain nicotinic receptors following chronic nicotine and corticosterone treatments in mice.

Chronic nicotine treatment often results in tolerance to nicotine as well as increases in brain [3H]-nicotine binding and [125l]-alpha-bungarotoxin (alpha-BTX) binding. Chronic corticosterone (CCS) treatment also produces tolerance to nicotine, but it does not change [3H]-nicotine binding; decreases in alpha-BTX binding are observed, which suggests that tolerance to nicotine may be related to decreases in the number of this nicotinic receptor subtype. In the studies reported here, C57BL/6 mice were implanted subcutaneously with cholesterol or 60% CCS/40% cholesterol-containing pellets and were infused continuously with saline (control) or nicotine for a total of 9 days. Effects of acute nicotine challenge on Y-maze crossing and rearing activities, heart rate, and body temperature were measured. Both chronic nicotine and CCS treatment resulted in tolerance to nicotine for all of the measures, and some evidence for additivity was seen in the animals that were cotreated with CCS and nicotine. Chronic nicotine infusion increased brain nicotine binding and CCS treatment reduced alpha-BTX binding. Decreases in alpha-BTX binding were not detected in the cotreated animals. The latter finding argues that changes in alpha-BTX binding are not reliable predictors of or a cause of tolerance to nicotine.

Animals↗
PubMed1996

ST/b and DBA/2 mice differ in brain alpha-bungarotoxin binding and alpha 7 nicotinic receptor subunit mRNA levels: a quantitative autoradiographic analysis.

Inbred mouse strains vary in sensitivity to a number of behavioral and physiological effects produced by nicotine. Differences in sensitivity to nicotine are correlated with variance in the number of brain nicotinic receptors as measured in regionally dissected brain tissue. The studies reported here used quantitative autoradiography and in-situ hybridization methods to measure regional levels of alpha-bungarotoxin (alpha BTX) binding and alpha 7 mRNA levels. Two inbred mouse strains, ST/b and DBA/2, were compared because these strains differ maximally in sensitivity to nicotine-induced seizures and in alpha BTX binding measured in regional brain homogenates. The binding of alpha BTX was significantly greater in the St/b strain in 42 of 127 brain regions that were analyzed, and a trend towards increased binding was seen in many additional brain regions. The most consistent strain differences were found in hippocampal, thalamic and pontine nuclei. Strain differences in alpha 7 mRNA levels were also detected, but these were not as widespread as were the alpha BTX binding differences. The alpha 7 mRNA levels were significantly correlated with alpha BTX binding in both mouse strains which suggests that the strain differences in binding are related, in part, to the levels of alpha 7 mRNA.

Animals↗
PubMed1996

Chronic corticosterone treatment elicits dose-dependent changes in mouse brain alpha-bungarotoxin binding.

Previous studies have shown that adrenalectomy results in a small increase in hippocampal alpha-bungarotoxin binding, whereas seven days of chronic treatment with high doses of corticosterone results in decreases in alpha-bungarotoxin binding in several brain regions. The studies reported here examined the effects of different doses of corticosterone on brain alpha-bungarotoxin binding. C3H mice were adrenalectomized and treated with corticosterone-containing pellets (0.5-60%) for four days. Alpha-Bungarotoxin binding was measured in eight brain regions. Chronic treatment with corticosterone resulted in plasma corticosterone levels ranging from the low levels observed in an unstressed mouse during the daytime to levels significantly above those observed in mice during the night or as a result of stress. Adrenalectomy resulted in small increases in binding in hippocampus which was reversed by low dose corticosterone treatment. Chronic high-dose corticosterone treatment resulted in significant decreases in binding in four of the eight brain regions examined. Similar, but not identical, results were obtained in two other mouse strains (C57BL and DBA/2). These results argue that corticosterone levels play an important role in modulating the level of the brain nicotinic receptors that bind alpha-bungarotoxin with high affinity.

Animals↗
PubMed1996

Genetic correlation of inhibitory gating of hippocampal auditory evoked response and alpha-bungarotoxin-binding nicotinic cholinergic receptors in inbred mouse strains.

One function of the hippocampus is to ascertain the novelty of incoming sensations and encode significant new information into memory. The regulation of response to repeated stimuli may prevent overloading of this function by redundant sensory input. Recent pharmacological studies implicate the role of alpha-bungarotoxin-sensitive nicotinic cholinergic receptors in the inhibition of hippocampal response to repeated auditory stimuli. The number of hippocampal alpha-bungarotoxin-sensitive receptors has a major genetic determinant, as demonstrated by a significant variance between different inbred mouse strains. The purpose of the present study was to determine whether there was a related genetic correlation for the gating of auditory response. Nine inbred mouse strains, representing a continuum of hippocampal alpha-bungarotoxin binding, were tested for the electrophysiological response to repeated auditory stimulation, followed by whole hippocampus membrane alpha-bungarotoxin binding studies. Several parameters of the auditory evoked response showed significant genetic variance over the nine strains, and a significant correlation was found between hippocampal alpha-bungarotoxin binding and both the amplitude of the initial evoked response and its inhibition to repeated auditory stimuli. There was no correlation of the auditory evoked response with high-affinity nicotine binding. These data further support the hypothesis that alpha-bungarotoxin-sensitive nicotinic receptors are involved in the regulation of hippocampal response to repeated auditory stimuli and suggest that this function is genetically controlled.

Acoustic Stimulation↗
PubMed1996

Quantitative trait locus analyses of sleep-times induced by sedative-hypnotics in LSXSS recombinant inbred strains of mice.

The long-sleep (LS) and short-sleep (SS) selected lines of mice show highly significant differences in sleep-time for many sedative-hypnotic drugs, and the quantitative genetic nature of these differences has been well-established. Using an interval-mapping approach, quantitative trait locus (QTL) analyses of LSXSS recombinant inbred (RI) strains have been applied to sleep-time responses for various classes of sedative-hypnotic drugs: alcohols (ethanol, n-propanol, and n-butanol), the atypical anesthetic chloral hydrate, barbiturates (pentobarbital and secobarbital), and benzodiazepines (chlordiazepoxide and flurazepam). Several provisional QTLs were mapped to similar locations within and between drug classes, suggesting that some common loci are involved in sleep-times elicited by these drugs. Consistent with correlations of strain mean sleep-times between drugs tested in the LSXSS recombinant inbred strains, the number of provisional QTLs mapping to the locations of highest significance for ethanol decreases when the lipid solubility of a particular drug becomes less similar to that of ethanol. Provisional QTLs mapped for the benzodiazepines, however, revealed considerable overlap with those mapped for ethanol, although these drugs represented the most lipid-soluble category of sedative-hypnotics tested. Provisional QTLs for pentobarbital and secobarbital differed from most of those mapped for the alcohols, which supports the hypothesis that alcohols and barbiturates exert their effects mainly through different biological mechanisms in the LS and SS lines. Blood ethanol concentrations at regaining the righting reflex also mapped to several provisional QTLs corresponding to ethanol-induced sleep-times that support the contention that sleep-time is a reasonable index of the observed differences in central nervous system sensitivities to ethanol between LS and SS mice.

1-Butanol↗
PubMed1996

Long-term ethanol and nicotine treatment elicit tolerance to ethanol.

Several previous studies have shown that 1 to 2 weeks of treatment with ethanol elicits tolerance to several effects produced by ethanol and cross-tolerance to nicotine-induced hypothermia. Similarly, short-term, high-dose nicotine treatment produces tolerance to nicotine and cross-tolerance to ethanol-induced hypothermia. In the studies reported here, C57BL/6 mice were force-fed ethanol, nicotine, or an ethanol/nicotine combination in the drinking water for 6 months. All of the chronic drug-treated mice developed tolerance to ethanol as measured by open-field activity, body temperature, and sleep-time tests. Ethanol tolerance is due, in part, to enhanced metabolism and reduced CNS sensitivity in the two ethanol-treated groups but only to reduced CNS sensitivity in the nicotine-treated group. Similar levels of tolerance to nicotine developed in those two groups that were nicotine-treated, but no tolerance to nicotine was seen in those animals treated with ethanol alone. The tolerance to nicotine may be related to an upregulation of brain (cortex, hippocampus, and hypothalamus) [3H]-nicotine binding, but ethanol tolerance is not readily explained by changes in the number of the brain high affinity nicotine binding sites.

Animals↗
PubMed1996

Nicotinic agonists differ in activation and desensitization of 86Rb+ efflux from mouse thalamic synaptosomes.

The effects of the nicotinic agonists acetylcholine, (+)-anatox in-a, carbachol, cytisine, dimethylphenylpiperazinum, (+)-epibatidine, (-)-epibatidine, methylcarbachol, D-nicotine, L-nicotine, and tetramethylammonium on 86Rb+ efflux from mouse thalamic synaptosomes were investigated. All 11 agonists evoked a concentration-dependent stimulation of 86Rb+ efflux as well as a time- and concentration-dependent reduction of response (desensitization). The agonists varied widely in potency, efficacy and rate of desensitization. (+)-Epibatidine was the most potent agonist (EC50 = 10 nM), whereas tetramethylammonium was the least potent (EC50 = 65 microM). The agonists containing a quaternary ammonium group were generally more efficacious than the other agonists, except for both of the enantiomers of epibatidine, which stimulated 86Rb+ efflux at least as well as acetylcholine. Cytisine was the least efficacious compound tested with a maximal response approximately 10% that of (-)-epibatidine. Exposure of the thalamic synaptosomes to agonist concentrations that generally stimulated little or no efflux reduced in a concentration-dependent manner a subsequent response to 10 microM nicotine. The IC50 values for this functional blockade (desensitization) were highly correlated with the Ki values for the inhibition of [3H]nicotine binding. Furthermore, exposure of the thalamic synaptosomes to 300 nM L-nicotine reduced the responses evoked by a subsequent exposure to a stimulating concentration of all 11 agonists. The observation of desensitization by both stimulating and substimulating concentrations of each agonist is consistent with the predictions of the two-state model of Katz and Thesleff.

Acetylcholine↗
PubMed1996

Chronic nicotine and mecamylamine treatment increase brain nicotinic receptor binding without changing alpha 4 or beta 2 mRNA levels.

It has recently been shown using regionally dissected tissue that both chronic mecamylamine treatment and chronic nicotine treatment increase the number of [3H]-nicotine binding sites in mouse brain, and that additive increases in the number of binding sites is observed after cotreatment with the two drugs. The studies reported here extend these findings by using quantitative autoradiographic methods to analyze the brains of chronically treated mice at a finer anatomical level of resolution. DBA/2 mice were chronically infused (i.v.) with saline, 4.0 mg/ kg/hr nicotine, 4.0 mg/kg/hr mecamylamine or both drugs for 7 days. The brains of these mice were subsequently analyzed to determine the effects of chronic drug treatment on [3H]-nicotine binding and on the levels of mRNA encoding the nicotinic receptor subunits, alpha 4 and beta 2. [3H]-Nicotine binding was increased in 37 of 46 brain regions after chronic nicotine treatment (average increase = 66.5%), in 41 of 46 regions after chronic mecamylamine treatment (average increase = 56.5%), and in 45 of 46 brain regions after chronic treatment with both drugs (average increase = 107.1%). The changes in [3H]-nicotine binding produced by the two drugs across brain regions were highly (r = 0.98) and significantly correlated. These results are consistent with the proposal that the same receptors are affected by agonist or antagonist treatment. Chronic treatment had no significant effect on the levels of alpha 4 or beta 2 mRNA as measured by in situ hybridization. Therefore, the increases in [3H]-nicotine binding do not arise from changes in the steady-state levels of either alpha 4 or beta 2 mRNA which are believed to encode the subunits of this nicotinic receptor subtype.

Animals↗
PubMed1996

RJR-2403: a nicotinic agonist with CNS selectivity II. In vivo characterization.

We have evaluated the physiological and behavioral effects of the CNS-selective nicotinic agonist (E)-N-methyl-4-(3-pyridinyl) -3-butene-1-amine (RJR-2403) using a number of different methods, including 1) reversal of pharmacologically induced amnesia in a step-through passive avoidance paradigm, 2) radial arm maze performance in rats with chemically induced brain lesions, 3) changes in HR and blood pressure in rats and 4) changes in body temperature, Y-maze activity, acoustic startle response and respiration in mice. Our results indicate that RJR-2403 is equal to or better than nicotine on measures of CNS function and cognitive enhancement. Specifically, RJR-2403 significantly improved passive avoidance retention after scopolamine-induced amnesia and enhanced both working and reference memory in rats with ibotenic acid lesions of the forebrain cholinergic projection system in an 8-arm radial maze paradigm. By comparison, RJR-2403 was 15 to 30-fold less potent than nicotine in decreasing body temperature, respiration, Y-maze rears and crosses and acoustic startle response. RJR-2403 also demonstrated greatly reduced cardiovascular effects. RJR-2403 was approximately 10-fold less potent than nicotine in increasing HR and 20-fold less potent in increasing blood pressure. These results are consistent with in vitro data indicating this compound's high selectivity for CNS nicotinic ACh receptor subtypes relative to peripheral ganglionic and muscle-type nicotinic ACh receptors. Therefore, RJR-2403 may be a valuable tool for understanding the central and peripheral pharmacology of nicotinic cholinergic systems as well as a potential lead compound for the development of nicotinic therapeutics to treat neurological diseases where cholinergic neurotransmission has been compromised.

Animals↗
PubMed1995

A simple genetic basis for a complex psychological trait in laboratory mice.

Psychological traits are commonly inferred from covariation in sets of behavioral measures that otherwise appear to have little in common. Emotionality in mice is such a trait, defined here by covariation in activity and defecation in a novel environment and emergence into the open arms of an elevated plus maze. Behavioral and quantitative trait analyses were conducted on four measures obtained from 879 mice from an F2 intercross. Three loci, on murine chromosomes 1, 12, and 15, were mapped that influence emotionality. This trait, inferred from studies of strain, sex, and individual differences in rodents, may be related to human susceptibility to anxiety or neuroticism.

Animals↗
PubMed1995

Corticosterone reversibly alters brain alpha-bungarotoxin binding and nicotine sensitivity.

Previous studies have shown that chronic corticosterone (CCS) treatment via subcutaneous pellets elicits reduced sensitivity to many actions of nicotine in mice as well as decreased brain alpha-bungarotoxin (alpha-BTX) binding. We report here the time courses of altered sensitivity to nicotine, as measured by acoustic startle, Y-maze crossing and rearing activities, heart rate, and body temperature, and alpha-BTX binding during and after CCS treatment. CCS treatment resulted in rapid decreases in sensitivity to nicotine for four of the five responses that were measured, as well as rapid changes in alpha-BTX binding. Sensitivity to nicotine returned to control levels within 3 days following pellet removal, but alpha-BTX binding returned to control levels in most brain regions 9-11 days after pellet removal. Because the restoration of control sensitivity to nicotine occurred long before alpha-BTX binding returned to control levels, it seems likely that factors other than changes in alpha-BTX binding cause chronic CCS-induced changes in sensitivity to nicotine.

Adrenalectomy↗
PubMed1995

Sodium channel blockers partially inhibit nicotine-stimulated 86Rb+ efflux from mouse brain synaptosomes.

The possible contribution of non-nicotinic cation channels to nicotine-stimulated 86Rb+ efflux was investigated. Dendrotoxin, charybdotoxin and apamin did not affect nicotine-stimulated 86Rb+ efflux. Although 4-aminopyridine and tetraethyl-ammonium completely inhibited nicotine-stimulated 86Rb+ efflux, the concentrations required to achieve this inhibition differed markedly from those required to inhibit K(+)-stimulated 86Rb+ efflux. Cs+ reduced basal 86Rb+ efflux, but did not affect nicotine-stimulated efflux. Tetrodotoxin completely inhibited veratridine-stimulated 86Rb+ efflux (IC50 = 3.4 nM) and partially inhibited (about 42%) nicotine-stimulated efflux (IC50 = 1.3 nM). Saxitoxin also completely inhibited veratridine-stimulated efflux (IC50 = 19.5 nM) and partially inhibited (about 47%) nicotine-stimulated efflux (IC50 = 5.4 nM). Tetrodotoxin had no significant effect on the EC50 for nicotine, but decreased the efflux rate and reduced modestly the rate of desensitization measured with prolonged exposure to nicotine. Tetrodotoxin (50 nM) also inhibited maximal nicotine-stimulated 86Rb+ efflux to approximately the same extent in each of ten brain regions examined. Nicotine-stimulated 86Rb+ efflux measured in the presence or absence of 100 nM tetrodotoxin is correlated with the density of [3H]nicotine, but not [3H]saxitoxin, binding sites in 12 regions, suggesting that the density of nicotinic receptors, not the number of Na+ channels, is the rate-limiting step for nicotine-stimulated 86Rb+ efflux. Therefore, activation of Na+ channels secondary to the stimulation of nicotinic receptors seems to contribute to the nicotine-stimulated 86Rb+ efflux observed in mouse brain synaptosomes. In contrast, no evidence for K+ channel modulation of nicotine-stimulated 86Rb+ efflux from thalamic synaptosomes was obtained.

Animals↗
PubMed1995

Plasma concentrations of carotenoids and antioxidant vitamins in Scottish males: influences of smoking.

OBJECTIVE: To quantify the major carotenoids in plasma of Scottish males and establish which were affected by habitual smoking. DESIGN: Concentrations of carotenoids, vitamin C and vitamin E (alpha and gamma-tocopherol) were determined in plasma samples from 50 fasted male smokers and 50 age-matched males who had never smoked (aged 50-59 years). RESULTS: Significantly less alpha-carotene, beta-carotene and beta-cryptoxanthin and vitamin C in plasma of smokers than in never-smokers whereas concentrations of lycopene, lutein/zeaxanthin, phytofluene and vitamin E were similar between the groups. CONCLUSION: Whether lower carotenoid and vitamin C concentrations in smokers than never-smokers reflect different dietary patterns or increased metabolic turnover is unclear but smokers may benefit from increased carotenoid and vitamin C intakes.

Ascorbic Acid↗
PubMed1994

An analysis of response to nicotine infusion using an automated radiotelemetry system.

Previous studies from our laboratory have demonstrated that chronic nicotine infusion evokes tolerance to nicotine injected IP several hours after withdrawal from chronic infusion. This method may introduce problems related to withdrawal reactions and to stress associated with handling of the animals. The studies reported here measured tolerance to nicotine in mice using an automated radiotelemetry system. DBA/2 mice were infused intravenously with saline for 4 days followed by infusion of a 4 mg/kg per h dose of nicotine for 7 days. After the nicotine treatment, the mice were infused with saline for 7 days. The nicotine was infused continuously or in four 1 mg/kg pulses, two 2 mg/kg pulses or one 4 mg/kg pulse each hour. Home cage activity and body temperature were measured throughout the treatment periods using a radiotelemetry system. Nicotine infusion produced an abrupt decrease in body temperature and activity, but this effect was totally reversed within 12 h in the continuously infused and four infusions/h treatment groups. Mice that received one or two infusions/h also showed a rapid response to nicotine that was reversed as treatment proceeded, but nicotine continued to produce a measurable effect for several days. After nicotine withdrawal, temperature and activity returned to predrug infusion values in all of the groups except those infused once per hour. This group showed depressed activity for a minimum of 3 days after nicotine treatment stopped. Thus, the kinetics of nicotine administration affected the intensity of response during continued treatment as well as activity after cessation of chronic treatment.

Animals↗
PubMed1994

Prenatal nicotine alters nicotinic receptor development in the mouse brain.

Maternal smoking during pregnancy may affect development of the child, but little is known about potential mechanisms of these effects. Since chronic nicotine treatment alters brain nicotinic receptors in adults and also evokes tolerance which is regulated by genetic factors, pregnant mice of two inbred strains underwent chronic nicotine infusion to determine whether the developmental pattern of mouse brain nicotinic receptors would be altered. C3H/2ibg and C57BL/6ibg mice were infused SC with saline or 2.0 mg/kg/h nicotine during the last half of pregnancy. The developmental profiles of [3H]nicotine and alpha-[125I]bungarotoxin binding in seven brain regions obtained from the offspring were measured. Prenatal nicotine treatment increased levels of [3H]nicotine binding at birth in the C3H hypothalamus, hippocampus, and possibly the cortex, and in the C57BL cortex. At later ages (20-30 days), [3H]nicotine binding was elevated in the C3H hindbrain, hippocampus, striatum, midbrain, and possibly the cortex. The C57BL hindbrain, hippocampus, midbrain, and cortex also showed increased binding at 20-30 days. Little, if any, effect of prenatal nicotine treatment was observed on the development of the alpha-[125I]bungarotoxin binding site. Since upregulated [3H]nicotine binding returns to control levels in adult animals within seven days following termination of chronic nicotine infusion, it is unlikely that simple upregulation is responsible for the changes observed in 20-30-day-old mouse brains.

Age Factors↗
PubMed1994

Effects of chronic nicotine infusion on kinetics of high-affinity nicotine binding.

It is well established that chronic nicotine treatment produces a dose-dependent increase in high-affinity L-[3H]nicotine binding. This increase may be due to chronic desensitization of the receptor. Sophisticated kinetic analyses of high-affinity nicotine binding to rat brain have demonstrated that the association rate is biphasic; the fast phase may represent binding to a high-affinity predesensitized state and the slow phase may represent binding to a lower affinity ground state that then isomerizes to form the high-affinity binding site. This isomerization presumably leads to receptor desensitization. The studies reported here assessed whether binding to mouse brain nicotinic receptors shows these same properties and whether chronic intravenous infusion of nicotine results in changes in these kinetic properties. The results obtained indicate that mouse brain nicotine binding also shows biphasic association kinetics and uniphasic dissociation kinetics, which supports the assertion that the receptor exists in two interconvertible states. However, unlike other results obtained with rat brain, the rate of the slow association process did not change with ligand concentration. Chronic infusion resulted in a dose-dependent increase in L-[3H]nicotine binding, but the ratio of fast/slow phases of binding was not changed by these treatments. These results suggest that chronic infusion does not alter measurably the kinetics of nicotinic receptor binding when measured in vitro.

Animals↗