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A C Collins

Publications and source records attributed to A C Collins.

At least 73 records · Page 4Linked to original sources
PubMed1994

Desensitization of nicotine-stimulated [3H]dopamine release from mouse striatal synaptosomes.

Potential desensitization of brain nicotinic receptors was studied using a [3H]dopamine release assay. Nicotine-stimulated [3H]dopamine release from mouse striatal synaptosomes was concentration-dependent with an EC50 of 0.33 +/- 0.13 microM and a Hill coefficient of 1.44 +/- 0.18. Desensitization by activating concentrations of nicotine had a similar EC50 and a half-time of 35 s. Concentrations of nicotine that evoked little release also induced a concentration-dependent desensitization (EC50 = 6.9 +/- 3.6 nM, t1/2 = 1.6-2.0 min, nH = 1.02 +/- 0.01). Both types of desensitization produced a maximum 75% decrease in [3H]dopamine release. Recovery from desensitization after exposure to low or activating concentrations of nicotine was time-dependent with half-times of 6.1 min and 12.4 min, respectively. Constants determined for binding of [3H]nicotine to striatal membrane at 22 degrees C included a KD of 3.7 +/- 0.5 nM, Bmax of 67.5 +/- 2.2 fmol/mg, and Hill coefficient of 1.07 +/- 0.06. Association of nicotine with membrane binding sites was biphasic with half-times of 9 s and 1.8 min. The fast rate process contributed 37% of the total reaction. Dissociation was a uniphasic process with a half-time of 1.6 min. Comparison of constants determined by the release and binding assays indicated that the [3H]-nicotine binding site could be the presynaptic receptor involved in [3H]dopamine release in mouse striatal synaptosomes.

Animals↗
PubMed1994

Desensitization of nicotine-stimulated 86Rb+ efflux from mouse brain synaptosomes.

The desensitization of nicotine-stimulated 86Rb+ efflux from synaptosomes prepared from C57BL/6 mouse brain was investigated. Nicotine stimulated a saturable, concentration-dependent efflux of 86Rb+ from synaptosomes (EC50 = 0.60 microM), but the response decreased with time of exposure to nicotine. The rate of decrease of the response (desensitization) increased as the nicotine concentration was increased (EC50 = 0.35 microM; maximal rate of desensitization = 1.1 min-1). Desensitization of nicotine-stimulated 86Rb+ efflux was also observed when synaptosomes were exposed to low (1-200 nM) concentrations of nicotine that caused little or no stimulation of efflux (EC50 = 13 nM). The rate of desensitization observed with low nicotine concentrations (0.30 min-1) was less than that measured at stimulating concentrations. Desensitization was not fully reversible for synaptosomes exposed to nicotine concentrations between 10 nM and 10 microM: Only 60-40% of the control response was regained after a 10-min washout period. The kinetics of functional desensitization were compared with the kinetics of [3H]nicotine binding. [3H]Nicotine binding to midbrain particulate fractions displayed both a fast and a slow phase. The EC50 values for these two phases were 2.6 and 14 nM, respectively. Data obtained from functional desensitization and ligand binding experiments were analyzed using a two-state model. The kinetic constants obtained from the analyses of these two processes were very similar. Overall, the results suggest that nicotinic receptor function measured with ion flux desensitizes when exposed to either stimulating or nonstimulating concentrations of nicotine. In addition, the kinetic properties calculated for the functional desensitization are comparable to those for [3H]nicotine binding.

Animals↗
PubMed1994

Sensitivity to nicotine and brain nicotinic receptors are altered by chronic nicotine and mecamylamine infusion.

DBA/2 mice were chronically infused with saline (control), 4 mg/kg/hr of nicotine, 4 mg/kg/hr of mecamylamine or nicotine+mecamylamine for 7 days. The binding of L-[3H]nicotine was significantly increased in seven of eight brain regions dissected from mice 5 hr after cessation of drug treatment. Similarly, [3H]nicotine binding was increased in six of eight regions by chronic mecamylamine treatment. Treatment with both drugs led to increases in [3H]nicotine binding that were at least the sum of the those observed with either drug alone. These increases were partially reversed 48 hr after cessation of treatment. No significant effects of nicotine or mecamylamine treatment on alpha-[125I]bungarotoxin binding were observed 5 hr after treatment was stopped when assayed using a single ligand concentration. However, saturation analyses of the cerebral cortex detected small increases from control after treatment with nicotine or both drugs. No effects of chronic treatment on alpha-[125I]bungarotoxin binding were evident 48 hr after treatment was stopped. Mice treated with nicotine, mecamylamine or both drugs tested 5 hr after withdrawal were less sensitive to acute injection with nicotine than were saline-infused mice. However, the effects of mecamylamine may have been influenced by continued presence of this drug at the time of testing. Mice tested 48 hr after cessation of treatment were more sensitive to nicotine than those tested after 5 hr, but some tolerance to the effects of nicotine persisted in the nicotine-treated mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Chronic corticosterone administration enhances behavioral sensitization to amphetamine in mice.

The role of corticosterone (CCS) in regulating sensitization to amphetamine's locomotor activating effects was measured in female DBA/2 mice that had been sham-operated or adrenalectomized and implanted with CCS-containing or cholesterol pellets. Three days following surgery, the mice were injected with saline and circular open field locomotor activity was measured for a 5-min time period starting 15 min after injection. Over the next 4 days, amphetamine (1.0-10.0 mg/kg) was injected and locomotor response measured. Control animals (sham-operated, cholesterol pellet) showed increased locomotor activity following their first injection of 5.0 mg/kg and 10.0 mg/kg amphetamine, while ADX animals showed increased activity only after treatment with the 10 mg/kg dose. Chronic CCS treatment did not significantly alter initial responsiveness to amphetamine in either sham-operated or ADX animals, but it did alter the dose-dependent sensitization to amphetamine. Both sham-operated and ADX animals implanted with cholesterol pellets showed increased locomotor response to amphetamine (sensitization) following injection with 2.5, 5.0 and 10.0 mg/kg doses of amphetamine. However, the enhancement of locomotor activity was greater in the sham-operated control animals. CCS-treated sham-operated animals exhibited sensitization to the locomotor-activating effects of amphetamine at the lowest dose used (1.0 mg/kg) and increased stereotype following treatment with the higher doses. ADX/CCS animals developed sensitization to the locomotor-activating effects of amphetamine following chronic injection with the 2.5 mg/kg dose, and showed sensitization to amphetamine-induced stereotypy at higher doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenalectomy↗
PubMed1993

Storage temperature and differing methods of sample preparation in the measurement of urinary albumin.

Microalbuminuria is a predictor of persistent proteinuria, renal failure and cardiovascular disease and therefore accurate determination of urinary albumin concentration is important. We examined the stability of albumin in urine under different conditions of storage, temperature and sample preparation. There was no significant difference in urinary albumin concentration between fresh urine and urine stored at either 4 degrees C or 20 degrees C for up to 7 days. Similarly in urine samples from diabetic patients there was no significant difference in albumin concentration at levels ranging from 1.3 to 1999.3 mg/l between fresh urine at 4 degrees C and urine stored frozen for 1 week, 1 month or 6 months. Neither storage temperature (-20 degrees C or -40 degrees C) nor centrifugation of sample prior to assay made a significant difference to the albumin concentration. Multiple freezing and thawing of urine samples during 6 weeks of storage at -20 degrees C made no difference to albumin concentrations. Storage of urine samples in either polypropylene, polystyrene or borosilicate glass tubes did not result in a significant change in urinary albumin concentration after either 1 week or 1 month at -20 degrees C although, after 1 month of storage, urinary albumin concentrations tended to be lower by an average of approximately 7%. In tubes to which gelatine had been added this was reduced to 4%. We conclude that fresh urine can be kept at 4 degrees C or 20 degrees C for up to 7 days. Frozen urine samples can be stored for up to 6 months before assay without any loss of albumin concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Albuminuria↗
PubMed1993

A genetic comparison of behavioral actions of ethanol and nicotine in the mirrored chamber.

Human alcoholics are almost invariably heavy users of tobacco, perhaps because both ethanol and nicotine may have anxiolytic activity. However, studies in humans have not uniformly detected anxiolytic effects because significant individual differences in anxiolytic actions of these agents seem to exist. One factor that seems to contribute to these individual differences is tolerance to ethanol. Individuals who are more sensitive to depressant actions of alcohol seem to show anxiolytic actions more readily. Consequently, we examined the relative sensitivities of the ethanol-sensitive (to the anesthetic actions of ethanol) long-sleep (LS) and ethanol-resistant short-sleep (SS) mouse lines to diazepam, ethanol, nicotine, and ethanol-nicotine combinations in the mirrored chamber test. This test measures approach-conflict behavior. Ethanol and nicotine evoked changes in mirrored chamber activities that resembled those elicited by diazepam. These effects were seen at doses that did not markedly affect locomotor activity, thereby suggesting that these changes in behavior represent anxiolytic actions. The LS-SS mice did not differ in sensitivity to diazepam, but the SS were more uniformly responsive to the other drugs. Only the SS showed clear evidence for interactions between ethanol and nicotine. If the changes in mirrored chamber behavior elicited by ethanol, nicotine, and combinations of the two drugs occur because of anxiety reduction, it seems that the SS mouse line is more responsive to anxiolytic actions of these drugs.

Animals↗
PubMed1993

Why some people smoke and others do not: new perspectives.

Because initial reinforcement consequences set the stage for subsequent nicotine use, elucidation of the contribution of environmental and inherited factors is crucial to an understanding of nicotine dependence as well as of individual differences in susceptibility to cigarette smoking. A review of some recent animal research and laboratory studies of smokers and never-smokers suggests that vulnerability to nicotine dependence is related to high initial sensitivity to nicotine and that the development of acute pharmacodynamic tolerance in these individuals--particularly to effects of nicotine that are toxic or aversive--may be an adaptation for protecting homeostasis.

Animals↗
PubMed1993

An autoradiographic analysis of alterations in nicotinic cholinergic receptors following 1 week of corticosterone supplementation.

Previous studies from our laboratory have established an interaction between central nervous system nicotinic cholinergic systems and glucocorticoid hormones. When mice are treated for 1 week with exogenous corticosterone (CORT) they become insensitive to the behavioral and physiological actions of nicotine and also have a reduction in brain alpha-bungarotoxin (BTX) receptor binding. In the present study, mice were treated with high stress levels of CORT and nicotinic receptor binding was measured using quantitative autoradiographic methods. L-[3H]-nicotine and alpha-[125I]-bungarotoxin were used to label both high- and low-affinity nicotinic sites. Chronic CORT administration reduced BTX binding in 77 of 115 (67.0%) brain regions examined. In general, forebrain regions were more sensitive to this regulation than were more posterior brain regions. Hippocampal and hypothalamic regions were particularly susceptible, with binding in treated animals being reduced by up to 80% in some nuclei. L-[3H]-nicotine sites were not as sensitive to CORT regulation as binding was significantly reduced in only 7 of the 83 (8.4%) regions measured. Regions affected were restricted to the thalamus and septum. The mechanism by which CORT reduces brain nicotinic cholinergic receptor binding is unknown and may or may not be dependent on CNS glucocorticoid receptors.

Amygdala↗
PubMed1993

Animal models of alcoholism: genetic strategies and neurochemical mechanisms.

Evidence from human studies indicates that response to alcohol consumption and the probability of developing alcoholism have a heritable basis. The involvement of several genes encourages the application of classical genetics to elucidate the genetic basis of alcohol abuse. Quantitative genetics can provide evidence for modes of inheritance and estimates of gene number. Therefore, inbred strains and selective breeding programmes have been used to demonstrate a genetic basis for the physiological and behavioural effects of ethanol in rodents. Neurochemical studies have shown that ethanol has effects on membrane fluidity, and on membrane receptors, ion channels and enzymes (Fig. 1). Comparison of these in animal lines selected for a particular response (or lack of response) to ethanol has disclosed differences in membrane composition (notably in polysialogangliosides), and in the functioning of NaK-ATPase, Na+ channels and gamma-aminobutyric acid (GABAA) receptors. Not all of these effects were observed at relevant ethanol concentrations, but differences in the properties of GABAA receptors between lines are the most compelling. Thus classical genetic strategies, while labour intensive with respect to the generation and maintenance of animal lines, have proven useful in dissecting the molecular, cellular and behavioural effects of alcohol and their genetic variability.

Alcoholism↗
PubMed1993

Downregulation of nicotinic receptor function after chronic nicotine infusion.

Chronic nicotine treatment generally results in tolerance to several actions of nicotine and a paradoxical increase in brain nicotinic receptor numbers. Receptor upregulation, it has been argued, arises as a consequence of functional desensitization. In the studies reported here, mice were chronically infused with saline (control) or one of five doses of nicotine (0.25-4.0 mg/kg/hr) for 10 days. This treatment resulted in a dose-dependent tolerance to nicotine-induced decreases in body temperature as well as decreases in locomotor and rearing activities in a Y-maze. The anticipated increase in [3H]nicotine binding was also observed. To assess functional status of the nicotinic receptors, nicotine-stimulated release of [3H]dopamine from striatal synaptosomes and 86Rb+ efflux from cortical and midbrain synaptosomes were also measured. Chronic nicotine infusion resulted in an infusion dose-dependent decrease in [3H]dopamine release from striatum and 86Rb+ efflux from midbrain; cortical 86Rb+ efflux was not affected by chronic nicotine treatment. Dose-response analyses of the release and efflux assays demonstrated that chronic nicotine infusion evoked decreases in the maximal effects of nicotine on the functional assays; potency was not altered by chronic drug treatment. These results are consistent with the hypothesis that behavioral tolerance to nicotine is a consequence of down-regulation of brain nicotinic receptor function.

Animals↗
PubMed1993

A comparison of the effects of chronic nicotine infusion on tolerance to nicotine and cross-tolerance to ethanol in long- and short-sleep mice.

Several recent studies suggest that common genes regulate sensitivity to an acute dose of ethanol and nicotine. The studies reported here attempted to determine whether common genes regulate the development of cross-tolerance between these drugs. Long-sleep (LS) and short-sleep (SS) mice, which were selectively bred for differential sensitivity to ethanol as measured by duration of ethanol-induced anesthesia (sleep time), were used in this study. The mice were infused i.v. with saline (control) or one of several doses of nicotine (0.5-4.0 mg kg-1 hr-1) for 10 days. The LS mice were more sensitive to the acute actions of nicotine than were the SS and they developed more tolerance to nicotine. LS mice were tolerant to nicotine as measured by all four of the behavioral and physiological tests used but this tolerance was readily seen only after treatment with the highest infusion dose. The SS mice developed some tolerance to nicotine but this effect was less than that seen in the LS, was restricted to two of the tests (Y-maze crosses and body temperature) and was seen only after treatment with the 4.0-mg kg-1 hr-1 dose of nicotine. The LS mice developed cross-tolerance to ethanol as measured by the Y-maze crosses and the heart rate and body temperature tests. Cross-tolerance to ethanol was not seen in the LS mice for the Y-maze rears and sleep-time tests. Almost no evidence for cross-tolerance to ethanol was seen in nicotine-infused SS mice.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

A comparison of the development of tolerance to ethanol and cross-tolerance to nicotine after chronic ethanol treatment in long- and short-sleep mice.

Previous studies have shown that inbred mouse strains differ in the development of tolerance to both nicotine and ethanol, indicating that genetic factors regulate tolerance development. Those mouse strains that are most sensitive to an acute challenge dose of either drug develop the most tolerance to that drug. The ethanol-sensitive long-sleep (LS) mice are more sensitive to several behavioral and physiological effects of nicotine than are the ethanol-resistant short-sleep (SS) mice. The experiments reported here assessed whether the LS and SS mice develop tolerance to ethanol after chronic treatment with ethanol-containing liquid diets and whether cross-tolerance to nicotine also developed. Tolerance and cross-tolerance were measured by assessing the effects of acute challenge doses of drug on Y-maze crossing and rearing activities, heart rate and body temperature. The LS mice developed tolerance to ethanol's effects on three of the four measures and were cross-tolerant to nicotine on all of the measures. In contrast, the SS mice developed tolerance to ethanol for only two of the measures, but failed to develop cross-tolerance to any action of nicotine. These findings support the hypothesis that ethanol and nicotine share sites of action and that common genes regulate responses to these two drugs. Evidence suggests that tolerance to nicotine may be related to an up-regulation of brain nicotinic receptors, at least in some inbred mouse strains, but chronic ethanol treatment did not reproducibly change either [3H]nicotine or alpha-[125I]bungarotoxin binding. Therefore, other mechanisms must underlie the tolerance and cross-tolerance that was seen.

Animals↗
PubMed1993

Nicotinic receptor function determined by stimulation of rubidium efflux from mouse brain synaptosomes.

The ability of nicotinic agonists to activate ion channels resulting in Na+ and K+ fluxes has been used to develop a functional assay by using mouse brain synaptosomes. Synaptosomes prepared using Percoll gradients were enriched in binding sites for [3H]nicotine and were capable of accumulating the K+ analog, 86Rb+. The efflux of 86Rb+ from the synaptosomes was subsequently monitored using continuous superfusion at 21 degrees C. Ion flux was stimulated in a concentration-dependent manner by several nicotinic agonists, including L-nicotine, acetylcholine, N-methylcarbamylcholine and dimethylphenylpiperazinium. The process was stereoselective: L-nicotine was 30-fold more potent than D-nicotine. Cytisine stimulated ion flux at low concentrations, but this drug was less efficacious than most other agonists tested. Anabasine was also less efficacious than the other agonists. The EC50 values for agonist-stimulated efflux correlated closely to the IC50 values for inhibition of [3H]nicotine binding, but concentrations required to inhibit binding were lower than those required to stimulate ion flux. Nicotine-induced 86Rb+ efflux was blocked by several nicotinic antagonists including mecamylamine, D-tubocurarine, hexamethonium and decamethonium. Mecamylamine was approximately 50 times as potent as hexamethonium. Neither alpha-bungarotoxin nor atropine were effective antagonists and neuronal-bungarotoxin was a relatively ineffective inhibitor. The amount of nicotine-induced efflux varied among brain regions with midbrain (thalamus and mesencephalon) having the largest response and cerebellum the smallest. The magnitude of the ion flux correlated closely with the amount of [3H] nicotine binding in each brain region. The results indicate that a nicotinic-receptor-mediated ion flux can be measured in brain tissue and that the ion flux may serve as a useful functional assay for nicotinic receptors in the central nervous system. Furthermore, it is postulated that the nicotinic-agonist stimulated ion flux may be mediated by receptors measured by high affinity [3H]nicotine binding.

Acetylcholine↗
PubMed1992

Tolerance to nicotine following chronic treatment by injections: a potential role for corticosterone.

C57BL/6 male mice were injected intraperitoneally with nicotine (2.0 mg/kg) or saline three times each day (0800 h, 1300 h and 1800 h) for a period of 12 days and then tested for nicotine tolerance using a series of behavioral and physiological tests. For each of these tests, animals that received chronic nicotine treatment were significantly less sensitive to nicotine challenge than were animals that received chronic saline treatment, as indicated by shifts to the right of dose-response curves. Animals were retested for nicotine sensitivity 2 weeks following cessation of chronic nicotine injections. Tolerance to acute nicotine challenge persisted in nicotine-treated animals. Chronic nicotine treatment by injections did not alter the binding of L-[3H]-nicotine or alpha-[125I]-bungarotoxin in any of eight brain regions. Plasma corticosterone (CCS) levels were determined in animals prior to the initiation of the injection series (day 0), and on days 4, 8 and 12 of chronic treatment, immediately before the first injection of the day. CCS levels in nicotine-treated animals were elevated as compared to saline-injected controls by day 12 of treatment. Nicotine-treated animals also had elevated CCS levels 2 weeks after the last chronic injection. Nicotine-treated animals were, however, tolerant to nicotine-induced CCS release. Since previous studies from our laboratory have demonstrated that plasma CCS levels are inversely correlated with sensitivity to nicotine, it is possible that the tolerance to nicotine measured following chronic treatment by injections is due, at least in part, to the elevation in plasma CCS levels.

Animals↗
PubMed1992

Adrenalectomy reverses chronic injection-induced tolerance to nicotine.

A recent study from our laboratory has demonstrated that C57BL/6 male mice that are chronically injected with nicotine develop a profound tolerance to nicotine that is not associated with changes in brain nicotinic receptors. We have proposed that alterations in the secretion of corticosterone (CCS) may regulate tolerance development in chronically injected animals. In the present study we have directly tested this hypothesis. Female DBA/2 mice were injected three times each day for 12 days with saline or 2 mg/kg nicotine. Blood samples were collected at various time points during the course of treatment and plasma CCS levels were determined. The animals were divided into two groups following the last injection on day 12. The first group of animals was tested for nicotine-induced release of corticosterone on day 13 of the experiment and then sacrificed. The brains of these animals were subsequently used to measure nicotinic receptor binding. The second group of animals was adrenalectomized (ADX) or sham-operated on day 13 of the experiment and tested for nicotine sensitivity on day 14 of the experiment. Plasma CCS levels were significantly elevated in animals that were chronically injected with nicotine (versus saline controls) by the fourth day of the experiment. Chronic nicotine-injected animals were tolerant to nicotine-induced CCS release. Animals that were chronically injected with nicotine and sham-operated were tolerant to acute nicotine challenge; however, tolerance to nicotine was not detected in ADX animals. These data support the hypothesis that the capacity to release CCS may underscore the expression of tolerance to nicotine in chronically injected animals.

Adrenal Glands↗
PubMed1992

Species differences in diisopropylfluorophosphate-induced decreases in the number of brain nicotinic receptors.

DBA and C3H mice were injected chronically with 2.0 mg/kg diisopropylfluorophosphate (DFP) every other day for 2 or 4 weeks. Although acetylcholinesterase (AChE) activity and muscarinic receptor numbers ([3H] quinuclidinyl benzilate (QNB) binding) were decreased in DFP-treated DBA and C3H mice, the number of nicotinic receptors (L-[3H]nicotine and alpha-[125I]bungarotoxin (BTX) binding) was unchanged by chronic DFP treatment. Sprague-Dawley rats injected chronically with lower doses of DFP than were used in mice exhibited a greater reduction in AChE activity, as well as accompanying decreases in [3H]QNB and [3H]nicotine binding. Neither species exhibited changes in alpha-[125I]BTX following chronic DFP injection. The effects of chronic DFP treatment on sensitivity to DFP and to nicotine were also assessed in the two mouse strains using a battery of behavioral and physiological tests that included rotarod performance, Y-maze crossing and rearing activity, heart rate, and body temperature. No tolerance to DFP was observed in either mouse strain after 2 weeks of treatment. Following 4 weeks of treatment, DFP-treated DBA mice exhibited modest tolerance to the effect of DFP on body temperature. C3H mice did not survive the 4-week treatment. Some evidence for reduced sensitivity to nicotine's effects was detected in the DFP-treated DBA mice, but cross-tolerance to nicotine was not observed in the DFP-injected C3H mice. Because chronic DFP treatment did not evoke a change in the number of brain nicotinic receptors, the reduced sensitivity to some of nicotine's effects seen in DBA mice must be due to some factor other than receptor downregulation.

Animals↗