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A C Collins

Publications and source records attributed to A C Collins.

At least 127 records · Page 7Linked to original sources
PubMed1988

The effect of chronic nicotine treatment on nicotine-induced seizures.

Tolerance to nicotine occurs in mice after its chronic administration. This tolerance is accompanied by an up-regulation of nicotinic receptors as assessed by the binding of (3H)-nicotine and alpha-(125I)-bungarotoxin (BTX). Past studies (Marks et al. 1983, 1986) have shown that the increase in BTX binding sites is most evident in the hippocampus. Mice that have a greater concentration of BTX binding sites in the hippocampus are more sensitive to the convulsant effects of nicotine (Miner et al. 1984, 1985, 1986). In the study reported here, mice from the DBA/2Ibg strain, which are relatively resistant to nicotine-induced seizures and have a relatively low concentration of hippocampal BTX binding sites (Miner et al. 1984), were infused with nicotine for 10 days. At various time points after cessation of nicotine administration, sensitivity to the convulsant effects of nicotine was assessed. Mice were then sacrificed and BTX binding was determined in three regions: cortex, midbrain, and hippocampus. As expected, chronic treatment with nicotine resulted in a significant up-regulation of BTX binding sites in the hippocampus. Chronic nicotine treatment also produced significant tolerance to nicotine-induced seizures. Hippocampal BTX binding sites returned to control levels within 2 days after stopping nicotine infusion, whereas tolerance was not lost until 5 days. These results suggest that factors other than the number of hippocampal BTX binding sites affect nicotine-induced seizure sensitivity, at least following chronic nicotine treatment.

Animals↗
PubMed1988

Nicotine tolerance: an analysis of the time course of its development and loss in the rat.

The time course of the development and loss of tolerance to nicotine was measured in female rats that were injected subcutaneously (SC), twice daily with 1.6 mg/kg nicotine. Tolerance to nicotine-induced decreases in locomotor activity and body temperature were observed. Tolerance to the effects of nicotine on both of these measures developed rapidly, with maximal changes occurring within 2-4 days after initiation of treatment. The binding of L-[3H]-nicotine was measured in six brain regions. Chronic nicotine treatment resulted in increases in binding in most brain regions. The increase in binding correlated significantly with the development of tolerance. Rats that had been injected chronically with nicotine did not lose their tolerance throughout a 7-day post-treatment test period. Control levels of binding were regained in all of the brain regions except cortex by 7 days after nicotine treatment was stopped. These findings indicate that changes in receptor binding may relate to the development of tolerance but the retention of tolerance is clearly not related to the number of brain nicotinic receptors, unless nicotine-induced decreases in body temperature and locomotor activity are controlled by cortical [3H]-nicotine binding sites.

Animals↗
PubMed1988

Adrenocortical hormone regulation of nicotine sensitivity in mice.

The possibility that nicotine-induced corticosterone (CCS) release regulates nicotine sensitivity was investigated in female mice of the C3H strain. Adrenalectomy (ADX) resulted in an increase in nicotine sensitivity as measured in a number of physiological and behavioral tests. In ADX animals, chronic CCS (100 micrograms/ml) administered in the drinking solution normalized nicotine sensitivity. Dexamethasone (DEX), a potent synthetic glucocorticoid which interacts with a distinct population of CNS steroid receptors, did not reverse the effects of ADX. Unoperated animals administered CCS (200 micrograms/ml) were protected from the effects of nicotine for several test battery parameters. ADX had no effect on the number of brain nicotinic cholinergic receptors and also did not alter nicotine metabolism. These data support the hypothesis that CCS secretion modulates nicotine sensitivity in the mouse; however, the mechanisms by which this regulation occurs are unknown.

Adrenal Cortex↗
PubMed1988

Genetic differences in plasma corticosterone levels in response to nicotine injection.

Changes in plasma corticosterone (CCS) levels following intraperitoneal injections of nicotine were measured in four inbred mouse strains: DBA/2Ibg, C57BL/6Ibg, C3H/2Ibg, and A/J. In all four strains, nicotine produced a dose-dependent (0.5-2.0 mg/kg nicotine) increase in plasma CCS levels which peaked 10-30 min after injection. Saline increased plasma CCS levels in C57BL, A, and C3H, but not in DBA mice. After correcting for plasma CCS levels produced by saline injection, the nicotine-induced rise in plasma CCS was significantly lower for the C57BL strain than for the other three strains tested. These mouse strains also varied in their responses to saline injection with the rank order: C57BL greater than A = C3H greater than DBA. However, the two most divergent strains (C57BL and DBA) did not differ in the effects of a cold water stress. The response to nicotine was completely inhibited by mecamylamine in two strains tested (C3H and C57BL) whereas the response to saline injection was unaffected, suggesting that only the response to nicotine was mediated by nicotinic receptors. It is clear that elevations in plasma CCS induced either by saline injection or by nicotine are influenced by genetic factors.

Animals↗
PubMed1988

Tolerance to and cross tolerance between ethanol and nicotine.

Female DBA mice were subjected to one of four treatments: ethanol-containing or control diets, nicotine (0.2, 1.0, 5.0 mg/kg/hr) infusion or saline infusion. After removal from the liquid diets or cessation of infusion, the animals were challenged with an acute dose of ethanol or nicotine. Chronic ethanol-fed mice were tolerant to the effects of ethanol on body temperature and open field activity and were cross tolerant to the effects of nicotine on body temperature and heart rate. Nicotine infused animals were tolerant to the effects of nicotine on body temperature and rotarod performance and were cross tolerant to the effects of ethanol on body temperature. Ethanol-induced sleep time was decreased in chronic ethanol- but not chronic nicotine-treated mice. Chronic drug treatment did not alter the elimination rate of either drug. Chronic ethanol treatment did not alter the number or affinity of brain nicotinic receptors whereas chronic nicotine treatment elicited an increase in the number of [3H]-nicotine binding sites. Tolerance and cross tolerance between ethanol and nicotine is discussed in terms of potential effects on desensitization of brain nicotinic receptors.

Alcoholism↗
PubMed1988

Effect of nicotine pretreatment on nicotine-induced seizures.

Inactivation of the nicotinic receptor via the process of desensitization has been well characterized for the nicotinic receptor in vitro, but potential behavioral manifestations of desensitization have received little study. To test whether behavioral desensitization occurs, C3H and DBA mice were pretreated with subseizure-producing doses of nicotine and nicotine-induced seizure sensitivity was determined at various time intervals after pretreatment. Fifteen minutes after nicotine pretreatment, DBA mice were significantly less sensitive to nicotine-induced seizures than were saline pretreated mice after both IP and IV administration. Seizure sensitivity returned to baseline levels at 60 minutes after pretreatment for the IP route of administration and at 30 minutes for the IV route of administration. Sensitivity to nicotine-induced seizures was altered for C3H mice under only one experimental condition; 7.5 minutes after IP injection with 2.0 mg/kg nicotine. Thus, DBA mice display a marked behavioral desensitization as a result of nicotine pretreatment whereas C3H mice do not. These results, in conjunction with our previous studies, indicate that nicotine-induced seizure sensitivity may be influenced by a minimum of two factors: the concentration of nicotinic receptors in the brain and possibly the ability of these receptors to inactivate in the presence of nicotine.

Animals↗
PubMed1988

An analysis of cocaine effects on locomotor activities and heart rate in four inbred mouse strains.

The effects of cocaine on Y-maze activity and heart rate have been examined in four inbred strains of mouse (BALB, C57BL, C3H and DBA). In addition, brain [3H]-cocaine concentrations were measured at the time of maximal response to cocaine. Cocaine produced a dose-related increase in Y-maze cross activity in C3H, DBA and C57BL, with C3H mice being considerably more sensitive than DBA or C57BL. Cocaine was without effect on Y-maze cross activity in BALB mice. Cocaine produced a biphasic effect on rearing activity in C3H mice, a dose related depression in BALB mice, and was without effect on C57BL and DBA mice. At the highest dose studied (15 mg/kg), cocaine produced a small decrease in heart rate in C3H mice. Strain differences in behavior were maximal 15 minutes after a dose of 5 mg/kg, IP. At this dose and time interval, brain [3H]-cocaine concentrations were not significantly different among the four strains of mice. The results suggest a genetically-determined difference in CNS sensitivity to cocaine.

Animals↗
PubMed1988

Genetic influences on acute responses to nicotine and nicotine tolerance in the mouse.

Nineteen inbred mouse strains were tested for their relative sensitivity to nicotine's effects on respiratory rate, acoustic startle response, heart rate, Y-maze activity (crosses and rears) and body temperature. Separate animals were tested for their sensitivity to nicotine-induced seizures following IP injection or IV infusion. Dose-response curves were constructed for each measure. Large strain differences were obtained for all of these measures. Nicotine's effects on heart rate, Y-maze activity and body temperature segregated together into the various mouse strains whereas seizure sensitivity segregated independently which suggests that these responses are under separate genetic control. Evidence was obtained which suggests that nicotine-induced seizures are regulated, in part, by the number of hippocampal nicotinic receptors measured with alpha-bungarotoxin (BTX). Strain differences in the development of tolerance to nicotine were also observed. Four mouse strains were tested and one of these strains (C3H) did not exhibit tolerance to nicotine. The binding of (3H)nicotine and (125I)BTX increased in the brains of all four mouse strains. These changes may relate to tolerance in some mouse strains, but since C3H mice did not exhibit tolerance even though brain nicotinic receptors changed following chronic treatment, other explanations for the role of receptor changes in tolerance to nicotine must be sought.

Animals↗
PubMed1988

Sulfhydryl modification of two nicotinic binding sites in mouse brain.

Two distinct binding sites with properties corresponding to those expected for nicotinic cholinergic receptors can be identified in brain by the specific binding of nicotine (or acetylcholine) and alpha-bungarotoxin. The effects of modification of these binding sites by treatment with the disulfide-reducing agent dithiothreitol were examined in tissue prepared from DBA mouse brains. Treatment with dithiothreitol reduced the binding measured with either ligand, and reoxidization of the disulfides fully restored binding. The effects of dithiothreitol treatment appeared to be due to a reduction in the maximal binding of nicotine and to a decrease in the binding affinity for alpha-bungarotoxin. Agonist affinity for the alpha-bungarotoxin binding site was reduced by treatment with low concentrations of dithiothreitol. The nicotine binding sites remaining after disulfide treatment displayed rates of ligand association and dissociation similar to those of unmodified tissue, but treatment of previously unmodified tissue with dithiothreitol accelerated the rate of nicotine dissociation. After reduction, both binding sites could be selectively alkylated with bromoacetylcholine. The results suggest that both putative nicotinic receptors in brain respond similarly to disulfide reduction and that their responses resemble those known for the nicotinic receptor of electric tissue.

Alkylation↗
PubMed1987

Genetic influences on tolerance development with chronic oxotremorine infusion.

Mice of four inbred strains (BALB, C57BL, DBA and C3H) were administered either saline or oxotremorine, a muscarinic agonist, at a dose of 0.5 mg/kg/hr by constant infusion through cannulas implanted in the right jugular veins. Chronic treatment resulted in the development of tolerance to the effects of oxotremorine both on rotarod performance and on body temperature. For drug-treated BALB mice, the dose-response curves for both measures were parallel to those for saline-treated mice, while for DBA and C3H mice the slopes of the dose-response curves were significantly less for treated mice than they were for controls. The equi-effective doses for the drug-treated animals were at least 8-fold greater than those for saline-treated mice. Drug treatment resulted in a significant decrease in the total number of muscarinic receptors in cortex as measured by the binding of [3H]quinuclidinyl benzilate (QNB) without effect on the KD for this ligand. Similarly, drug treatment did not affect the affinity of carbamylcholine as an inhibitor of QNB binding, but did significantly decrease the levels of both the high- and low-affinity agonist binding sites in cortex. The number of M1 muscarinic receptors measured by high affinity [3H]pirenzepine (PZ) binding was also significantly decreased in cortex without effect on the KD. The experiments were extended to five other brain regions. Full saturation curves were not constructed, however. Oxotremorine treatment significantly reduced QNB binding in every brain region. While the binding to agonist affinity states measured by carbamylcholine inhibition of QNB binding and M1 receptor levels measured by high affinity PZ binding tended to decrease with oxotremorine treatment not all changes were statistically significant. The changes in muscarinic receptor subtype levels induced by oxotremorine infusion did not differ among the strains. The results demonstrate that chronic treatment with a muscarinic agonist results in substantial tolerance to the effects of the drug in all four mouse strains. Although some differences in tolerance development exist, these differences are not readily explained by differences in the number or affinity states of brain muscarinic receptors.

Animals↗
PubMed1987

Influence of kinetics of nicotine administration on tolerance development and receptor levels.

Nicotine was administered intravenously to DBA mice through cannulae implanted in the jugular veins. Five groups of animals were treated: a control group which received saline and four nicotine treatment groups. All of the nicotine treatment groups received a dose of 4.0 mg/kg/hr. The first group received continuous infusion, the second group received 1 mg/kg pulses four times an hour, the third group received 2 mg/kg pulses twice an hour, and the fourth group received 4 mg/kg pulses once an hour. After a 10-day treatment period, the animals were tested for tolerance to an acute intraperitoneal administration of nicotine. Tolerance was measured using a test battery composed of the following tests: respiratory rate, acoustic startle response, Y-maze crosses and rears, heart rate, and body temperature. Mice from each of the four nicotine treatment groups were tolerant to the acute effect of nicotine, but the extent of tolerance varied among the groups as follows: continuous infusion less than 1 mg/kg pulses four times/hr less than 2 mg/kg pulses twice/hr less than 4 mg/kg pulse once/hr. Chronic nicotine infusion resulted in significant increases in the binding of L-[3H]nicotine in all six brain regions assayed and in significant increases in the binding of alpha-[125I]bungarotoxin binding in cerebral cortex and hippocampus. All increases in binding resulted from increases in Bmax for these ligands. In contrast to the effects observed for tolerance development, the increases in [3H]nicotine binding were not significantly affected by the kinetics of nicotine infusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Cross-tolerance between muscarinic agonists: role of muscarinic receptors.

In order to explore the relationship between response to muscarinic agonists and brain muscarinic receptors, two mouse strains that differ in acute sensitivity (DBA and C3H) were injected chronically with DFP or infused with oxotremorine. Chronic DFP-treated DBA mice were not tolerant to DFP's effects on any measure, but they were cross-tolerant to the effects of oxotremorine on heart rate and body temperature. DFP-treated C3H mice were not tolerant to DFP or cross-tolerant to oxotremorine on any measure. Oxotremorine infusion resulted in tolerance to oxotremorine in both mouse strains, and chronically infused DBA mice were cross-tolerant to DFP on five of the six measures. Oxotremorine-infused C3H mice were cross-tolerant to DFP on two of the measures. These results suggest that genetic factors influence the development of tolerance or cross-tolerance. These genetic factors do not seem to be related to changes in brain QNB binding. Both mouse strains showed comparable changes in QNB binding following chronic DFP and oxotremorine with DFP eliciting reductions in QNB binding in striatum and hippocampus and oxotremorine eliciting reductions in nearly every brain region. However, tolerance and cross-tolerance did not seem to correlate with changes in binding which suggests that the relationship between receptor changes and responses to muscarinic agonists must be examined further.

Animals↗
PubMed1987

Sex differences in the recovery of brain acetylcholinesterase activity following a single exposure to DFP.

Male and female C57BL, DBA, and C3H mice were injected intraperitoneally with a single 6.33 mg/kg dose of diisopropylphosphofluoridate (DFP). The time course of recovery of acetylcholinesterase (AChE) activity as well as effects on choline acetyltransferase (ChAT) activity and brain muscarinic and nicotinic receptors were measured. DFP treatment did not affect ChAT activity or the muscarinic and nicotinic receptors. Near control levels of AChE activity were regained in female mice within the first 20 days. However, levels of whole brain AChE activity remained depressed for as long as 40 days following a single dose of DFP in male mice. An analysis of the recovery of AChE activity in several brain regions indicated that control activity was regained in striatum, hindbrain, and hippocampus, but not in cortex, midbrain, and hypothalamus. These data are discussed in terms of potential neurotoxicity induced by a single dose of DFP.

Acetylcholinesterase↗
PubMed1987

Postnatal development of cholinergic enzymes and receptors in mouse brain.

The developmental profiles for the cholinergic enzymes acetylcholinesterase and choline acetyltransferase, and the muscarinic and nicotinic receptors were determined in whole mouse brain. The enzyme activities (per milligram of protein) increased steadily from birth, reaching adult levels at 20 days of age. These increases were primarily due to increases in Vmax. Muscarinic receptor numbers, measured by [3H]quinuclidinyl benzilate binding, also increased from birth to 25 days of age. Brain nicotinic receptors were measured with the ligands L-[3H]nicotine and alpha-[125I]-bungarotoxin. Neonatal mouse brain had approximately twice the number of alpha-bungarotoxin binding sites found in adult mouse brain. Binding site numbers rose slightly until 10 days of age, after which they decreased to adult values, which were reached at 25 days of age. The nicotine binding site was found in neonatal brain at concentrations comparable to those at the alpha-bungarotoxin site followed by a steady decline in nicotine binding until adult values were reached. Thus, brain nicotinic and muscarinic systems develop in totally different fashions; the quantity of muscarinic receptors increases with age, while the quantity of nicotinic receptors decreases. It is conceivable that nicotinic receptors play an important role in directing the development of the cholinergic system.

Acetylcholinesterase↗
PubMed1986

Time course of ethanol's effects on brain prostaglandins in LS and SS mice.

Prostaglandin synthesis inhibitors antagonize behavioral responses to alcohols. Recent work has shown that ethanol increases brain prostaglandin (PG) levels. The study reported here examined the time course for ethanol-stimulated brain PGE and PGF production in Long Sleep and Short Sleep mice, animals bred selectively for high vs. low acute response to ethanol. Increases in brain PGE levels correlated highly with the absorption phase but only partially with the elimination phase of ethanol. PGF levels correlated significantly with blood ethanol levels across the entire three hour period. These results, plus sex and genotype interactions, provide further evidence to support the hypothesis that ethanol produces its intoxicating effects to a significant degree through a prostaglandin mediated mechanism.

Animals↗
PubMed1986

Dissociation of decreased numbers of muscarinic receptors from tolerance to DFP.

Several studies have demonstrated that chronic treatment with organophosphates, such as DFP, elicits a decreased number of brain muscarinic receptors (measured by the binding of QNB) which has been presented as an explanation for tolerance to the organophosphates. The purpose of the studies presented here was to assess whether graded changes in QNB binding could be attained following different methods of chronic DFP treatment, and whether tolerance to DFP paralleled these changes. Male DBA mice were injected with DFP every 4 days or 2 days for 30 days or daily for 14 days. The animals were subsequently challenged with DFP or the muscarinic agonist, oxotremorine, and respiratory rate, heart rate, body temperature, Y-maze activity and rearing were recorded. Chronic DFP-treated animals were supersensitive to the effects of DFP on respiratory rate, heart rate, and body temperature whereas a modest tolerance to the effects of oxotremorine on respiratory rate, heart rate, and body temperature was seen. Neither tolerance nor supersensitivity were observed for the effects of DFP and oxotremorine on the Y-maze measures. Chronic DFP treatment elicited reduced binding of QNB in striatum, cortex, and hippocampus with the group that had been treated every other day exhibiting the greatest changes. The changes in drug response did not parallel changes in QNB binding which raises questions as to the cause of the reduction in binding.

Animals↗
PubMed1986

A strain comparison of physiological and locomotor responses of mice to diisopropylfluorosphosphate.

The effects of acute treatment with the organophosphate, diisopropylfluorophosphae (DFP), were studied in three inbred mouse strains. C57BL, DBA and C3H. A battery of physiological and locomotor tests including respiratory rate, heart rate, body temperature, Y-maze activity and rotarod performance was used. Dose-response and time course studies were carried out. Approximately 15 min after injection the animals were markedly affected by the drug with maximal effects occurring approximately 2 hours after injection. Strain comparisons were made at the 2 hr time point. In all strains, males and females were affected about equally except for respiratory rate and rotarod performance in which females were slightly more affected. Strain comparisons revealed that for most of the tests the C57BL mice were most affected by the DFP and the C3H mice were least affected. For the heart rate test the DBA mice were the most sensitive. Previous studies from our laboratory have demonstrated a similar rank ordering of the strains in their responses to oxotremorine and nicotine. The strain differences in response to these agents is not easily explained by differences in number or affinity of brain muscarinic or nicotinic receptors. The genetic influence on cholinergic drug response may involve receptor coupling mechanisms.

Animals↗