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M J Marks

Publications and source records attributed to M J Marks.

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

Nicotine binding and nicotinic receptor subunit RNA after chronic nicotine treatment.

DBA mice were chronically treated with nicotine by continuous intravenous infusion of 4.0 mg/kg/hr for 10 d. Drug-treated mice were tolerant to the acute effects of nicotine on locomotor activity and body temperature. The effect of chronic treatment on the amount of L-3H-nicotine binding and RNA encoding for alpha 4, the most widely expressed nicotinic alpha-subunit, was measured in three brain regions. Chronic treatment increased L-3H-nicotine binding in cortex and midbrain but had no effect in cerebellum. In contrast, chronic treatment had no effect on the levels of mRNA encoding for alpha 4 in any of the three brain regions. Subsequently brains were sectioned and L-3H-nicotine binding was measured using quantitative autoradiographic methods. In addition, the relative amounts of mRNA for the major nicotinic receptor subunits (alpha 4 and beta 2), as well as for three additional minor subunits (alpha 2, alpha 3, and alpha 5), were determined by in situ hybridization histochemistry followed by quantitation of image intensity. Chronic nicotine treatment resulted in increases in the amount of L-3H-nicotine binding in many but not all brain areas measured. In contrast, chronic treatment had little effect on the intensity of the hybridization signal for the nicotinic subunit mRNA. The results suggest that chronic treatment with nicotine under conditions resulting in maximal steady-state increases in L-3H-nicotine binding has little effect on RNA levels encoding any of four nicotinic alpha-subunits and the beta 2-subunit.

Animals↗
PubMed1991

Regulation of brain nicotinic receptors by chronic agonist infusion.

Several studies have demonstrated that chronic treatment with nicotine elicits an increase in the number of brain nicotinic receptors. To determine whether this effect is elicited by other nicotinic agonists found in tobacco, the effects of chronic infusion with nicotine on brain nicotinic receptors were compared with those after anabasine and lobeline. C57BL/6 mice were infused with saline or equimolar doses (18.5 mumol/kg/h) of nicotine, anabasine, or lobeline for 8 days. Nicotinic receptors, quantified by the binding of [3H]nicotine and [125I]iodo-alpha-bungarotoxin (alpha-[125I]BTX), and muscarinic receptors, quantified by the binding of [3H]quinuclidinyl benzilate ([3H]QNB), were then assayed in eight brain regions. An increase in [3H]nicotine binding was observed in all regions except cerebellum following chronic infusion with nicotine and anabasine, whereas lobeline did not alter the number or affinity of these binding sites. This increase was due to changes in Bmax and not in the affinity of the receptor for the ligand (KD). A slight increase in alpha-[125I]BTX binding was observed in cortex following chronic anabasine infusion. [3H]QNB binding sites were largely unaltered following chronic infusion with any of the nicotinic analogs. The levels of the agonists in the brain were also determined after chronic treatment, and the amounts of lobeline and anabasine were found to be higher than that of nicotine. Thus, the failure of lobeline to elicit changes in nicotine binding is not due to reduced brain concentrations.

Anabasine↗
PubMed1991

Genetic selections for nicotine and cocaine sensitivity in mice.

We are using selective breeding to develop lines of mice which differ maximally in their responses to nicotine, and independent lines of mice which differ maximally in their responses to cocaine. The foundation population was the genetically heterogeneous HS mice. On day 1, baseline (saline injected) activity of each mouse was measured in an automated Y-maze over 3 minutes. On day 2, animals were tested for sensitivity to nicotine (0.75 mg/kg) in the same apparatus. A residual score, calculated from the regression of nicotine scores on saline scores for the whole population, was calculated for each animal. The most severely affected mice (lowest residual scores) were mated to form duplicate Nicotine-Depressed lines; the most stimulated mice (highest residual scores) were mated to form duplicate Nicotine-Activated lines. A random sampling of individuals was chosen without regard to residual scores for production of duplicate Control lines. Duplicate lines of mice activated and depressed by cocaine are being produced in an analogous fashion using 50 mg/kg cocaine as the test dose. Successful selective breeding for a drug-related trait provides clear evidence of a heritable component for that trait. These selected lines of mice will ultimately be used to study hypotheses involving genetic control of response to these drugs.

Animals↗
PubMed1991

Progress towards the development of animal models of smoking-related behaviors.

Human twin studies have indicated that genetic factors influence whether people do, or do not, smoke and may also influence amount of tobacco used. Studies in the authors' laboratory have demonstrated that inbred mouse strains differ in sensitivity to many actions of a first challenge dose of nicotine. These strain differences are due, in part, to differences in the number of brain nicotinic receptors. Mouse strains also differ in the development of tolerance to nicotine and subtle differences in chronic nicotine-induced increases in the number of brain nicotinic receptors have been detected. Preliminary data suggest that mouse strains differ in oral self-selection of nicotine containing solutions which may suggest genetic influences on rewarding effects on nicotine. These results suggest that humans may also differ, for genetic reasons, in sensitivity to nicotine, in the development of tolerance to nicotine and in rewarding effects of nicotine. Presumably, those individuals who are resistant to nicotine's toxic actions and sensitive to its rewarding effects are more likely to become smokers if tobacco experimentation is initiated.

Animals↗
PubMed1991

An autoradiographic analysis of cholinergic receptors in mouse brain after chronic nicotine treatment.

Quantitative autoradiographic procedures were used to examine the effects of chronic nicotine infusion on the number of central nervous system nicotinic cholinergic receptors. Female DBA mice were implanted with jugular cannulas and infused with saline or various doses of nicotine (0.25, 0.5, 1.0 or 2.0 mg/kg/hr) for 10 days. The animals were then sacrificed and the brains were removed and frozen in isopentane. Cryostat sections were collected and prepared for autoradiographic procedures as previously described. Nicotinic cholinergic receptors were labeled with L-[3H]nicotine or alpha-[125I]bungarotoxin; [3H]quinuclidinyl benzilate was used to measure muscarinic cholinergic receptor binding. Chronic nicotine infusion increased the number of sites labeled by [3H]nicotine in most brain areas. However, the extent of the increase in binding as well as the dose-response curves for the increase were widely different among brain regions. After the highest treatment dose, binding was increased in 67 of 86 regions measured. Septal and thalamic regions were most resistant to change. Nicotinic binding measured by alpha-[125I]bungarotoxin also increased after chronic treatment, but in a less robust fashion. At the highest treatment dose, only 26 of 80 regions were significantly changes. Muscarinic binding was not altered after chronic nicotine treatment. These data suggest that brain regions are not equivalent in the mechanisms that regulate alterations in nicotinic cholinergic receptor binding after chronic nicotine treatment.

Animals↗
PubMed1991

Genotype influences the development of tolerance to nicotine in the mouse.

Previous studies have demonstrated that chronic infusion of DBA/2 inbred mice with nicotine results in a dose- and time-dependent tolerance to many of the effects elicited by a challenge dose of nicotine. This tolerance was paralleled by increases in the number of brain nicotinic receptors measured with L-[3H]nicotine and alpha-[125I]bungarotoxin binding, suggesting that receptor up-regulation may underlie tolerance to nicotine. The studies reported here assessed the development of tolerance to nicotine in five inbred mouse strains that differ markedly in sensitivity to acute doses of nicotine. Mice were infused with nicotine doses ranging between 0 and 6 mg/kg/hr for 10 days and were tested for sensitivity to nicotine using several tests 2 hr after infusion was stopped. Some mouse strains, such as the C57BL/6, developed tolerance to nicotine, as measured by shifts to the right of dose-response curves, at the lowest infusion doses, whereas other strains, such as the C3H/2 and BUB, did not develop measurable tolerance until the highest infusion doses were used. A correlation between sensitivity to acute nicotine treatment and the threshold for tolerance development was observed, suggesting that tolerance develops only after a physiological effect is elicited. All of the mouse strains exhibited a dose-dependent increase in nicotine binding in all brain regions; no marked strain differences were seen in up-regulation of this binding site. Chronic nicotine infusion also evoked increases in alpha-bungarotoxin binding, but higher doses were required to elicit this effect. Changes in this binding site were observed after treatment with nicotine doses that elicited tolerance in those mouse strains that are more resistant to an acute dose of nicotine. These results indicate that the relationship between tolerance development and brain nicotinic receptor up-regulation may not be simple.

Animals↗
PubMed1990

Modulation of nicotine receptors by chronic exposure to nicotinic agonists and antagonists.

Although numerous studies have demonstrated that chronic nicotine treatment often results in tolerance to this drug, the mechanisms that underlie this tolerance are not well defined. Recent evidence suggests that chronic nicotine treatment results in an up-regulation of brain nicotinic receptors, but the majority of these receptors may be desensitized or inactivated, thereby explaining tolerance. There is evidence that while all mouse strains show increased receptor numbers following chronic nicotine treatment, some mouse strains develop maximal changes in [3H] nicotine binding before any tolerance is detected. Other strains show a high correlation between increase in receptor number and tolerance. Studies with several other nicotinic agonists indicate that up-regulation of nicotine receptors can occur without changes in drug sensitivity. Similarly, chronic antagonists treatment can also elicit changes in receptors without affecting sensitivity to nicotine. Some of these discrepancies may be due to genetically influenced interactions between the adrenal steroid, corticosterone (CCS), and the nicotinic receptors. The addition of CCS in vitro inhibits binding to nicotinic receptors, and chronic CCS treatment results in decreases in the number of brain nicotinic receptors measured by [125I] bungarotoxin binding. Either of these biochemical measures may explain why altering CCS concentrations in vivo results in altered sensitivity to nicotine. It may be that both changes in the number of receptors and altered steroid interactions with the nicotinic receptors explain tolerance to nicotine.

Animals↗
PubMed1990

Purification of L-[3H]nicotine eliminates low affinity binding.

Some studies of L-[3H]nicotine binding to rodent and human brain tissue have detected two binding sites as evidenced by nonlinear Scatchard plots. Evidence presented here indicates that the low affinity binding site is not stereospecific, is not inhibited by low concentrations of cholinergic agonists and is probably due to breakdown products of nicotine since purification of the L-[3H]nicotine eliminates the low affinity site.

Alkaloids↗
PubMed1990

Postnatal development of two nicotinic cholinergic receptors in seven mouse brain regions.

The developmental profiles for binding of alpha-[125I]bungarotoxin and L-[3H]nicotine to putative nicotinic cholinergic receptors were determined in seven mouse brain regions. The overall pattern of development of alpha-bungarotoxin binding was similar in all of the regions. Neonatal binding values tended to be greater than those observed in adult brain regions. Maximal binding occurred within 10 days of birth and adult binding values were reached by 20 days of age. The patterns of development of nicotine binding in each of the seven brain regions differed according to region. Gross similarities in developmental profiles for nicotine binding were found among the more caudal and among the more rostral regions. In hindbrain and cerebellum, maximal nicotine binding was found at birth (5 days of age in cerebellum); binding declined approximately 4-fold by 20 days and remained relatively constant thereafter. In midbrain and hypothalamus, a less extensive decrease in nicotine binding occurred from birth to adulthood (midbrain, 25%; hypothalamus, 50%). Nicotine binding in hippocampus and cortex remained unchanged between birth and adulthood. The developmental pattern for nicotine binding in striatum differed from that found in the other brain regions. At 5 days of age, binding was about 65% of adult binding, which was reached at 30 days of age. In most of the brain regions the developmental profile for alpha-bungarotoxin binding was different from that of nicotine. This difference was especially notable in striatum, where adult nicotine binding was higher than neonatal nicotine binding, whereas adult alpha-bungarotoxin binding was lower than neonatal alpha-bungarotoxin binding.

Aging↗
PubMed1990

A comparison of sensitivity to oxotremorine and muscarinic receptors in LS and SS mice.

Several studies have suggested that ethanol interacts with muscarinic cholinergic systems in the brain. In order to assess whether muscarinic systems regulate sensitivity to ethanol, the effects of oxotremorine pretreatment on sensitivity to ethanol were determined in the long-sleep (LS) and short-sleep (SS) mice, which were selectively bred for differential sensitivity to ethanol. In addition, the relative sensitivity of these two lines to intraperitoneally (ip) injected oxotremorine and total muscarinic receptors, as measured by quinuclidinyl benzilate (QNB) binding, M1 receptor subtypes, as measured by pirenzepine (PZ) binding, and ratios of high and low agonist affinity were measured in seven brain regions. SS mice were more sensitive to oxotremorine-induced increases in sensitivity to ethanol but the LS mice were more sensitive to the effects elicited by ip oxotremorine injection. Because the effects of oxotremorine were blocked by scopolamine but not by methylscopolamine, it is likely that the effects of oxotremorine that were measured are centrally mediated. QNB binding did not differ between the LS and SS mice except for cortex where the SS mice exhibited slightly larger numbers. The mouse lines did not differ in the number of M1 receptors or in ratio of high to low affinity agonist sites. Therefore, it does not seem likely that differences in receptor numbers are important in regulating the differential sensitivities of the LS and SS mice to oxotremorine or ethanol. Differences in receptor coupling processes may be critically involved.

Animals↗
PubMed1990

Selective changes in sensitivity to cholinergic agonists and receptor changes elicited by continuous physostigmine infusion.

A reduction in nicotinic receptors has been observed in brains of patients with Alzheimer's disease, and physostigmine, an indirect acting cholinergic agonist, has been suggested as a treatment of this disease. However, the effects of physostigmine treatment have not been thoroughly characterized. The central and peripheral effects of physostigmine were evaluated in C57BL/6 mice using a battery of behavioral and physiological tests that included respiratory rate, Y maze crossing and rearing activities, heart rate and body temperature. With the exception of the heart rate test, which was blocked by a peripheral muscarinic antagonist, all responses to physostigmine measured in the test battery seem to be mediated centrally. Sensitivity to physostigmine and to nicotine and oxotremorine were examined as were nicotinic and muscarinic receptors after continuous infusion of physostigmine. Mice (C57BL/6) continuously infused with physostigmine (0.1 mg/kg/h) for 10 days developed marked tolerance to physostigmine and exhibited a slight decrease in sensitivity to nicotine; sensitivity to oxotremorine was largely unaltered. Chronic physostigmine treatment resulted in a 62% inhibition of AChE activity and elicited a significant increase in the amount of L-[3H] nicotine binding in midbrain, hippocampus, striatum and colliculi; alpha-[125I]bungarotoxin and [3H]quinuclidinyl benzilatl binding were not changed. Although physostigmine treatment might partially reverse the reduction of brain nicotinic receptors seen with Alzheimer's disease, it is questionable whether it would be effective for a prolonged period since the up-regulated nicotinic receptors may not have normal function.

Acetylcholinesterase↗
PubMed1989

Genetic influences on nicotine responses.

Male mice from 19 inbred strains were tested for the effects of nicotine on six responses: respiratory rate, acoustic startle response, Y-maze crosses, Y-maze rears, heart rate and body temperature. Dose-response curves were constructed for each strain on each test in a multitest battery. Results indicated that the responses were strongly influenced by the genotype of the animal. Comparison of the results from the six tests measured in this study and the results previously reported for nicotine-induced seizures in these same strains indicated that the responses could be grouped into two major classes: a set characterized by Y-maze crosses, Y-maze rears and body temperature and a set characterized by seizure sensitivity and seizure latency. Responses observed for respiratory rate and startle response shared characteristics with both of these sets, while nicotine effect on heart rate was fairly unique. The results have identified strains of mice which are differentially sensitive to the effects of nicotine.

Acoustic Stimulation↗
PubMed1989

Variation of nicotinic binding sites among inbred strains.

The specific binding of L-nicotine and alpha-bungarotoxin, two ligands which label different populations of putative nicotinic receptors, was determined in eight brain regions of 19 inbred mouse strains. The dissociation constants for L-nicotine (average = 2.26 nM) and alpha-bungarotoxin (average = 0.31 nM) did not vary significantly among the brain regions or strains. In contrast, significant variability among the maximal binding sites was observed between regions and among the strains within a region. Significant differences in L-nicotine binding were observed among the strains in midbrain, hindbrain, hippocampus, hypothalamus and colliculi, while little variability was noted in cortex or cerebellum. In general, those strains that had high L-nicotine binding in one region had high nicotine binding in the other regions. The strains clustered into two large groups: one group expressing relatively low binding and a second group expressing relatively high binding. Significant differences in alpha-bungarotoxin binding were observed in seven of the eight regions measured and, in general, those strains with high binding in one region tended to have high binding in the other regions. The strains clustered into three groups: those with low binding (DBA/1 and DBA/2), those with high binding (ST/b alone) and those with intermediate binding (the remaining 16 strains). The amount of binding of the two ligands did not correlate with each other. Comparison of nicotinic ligand binding with physiological response to nicotine suggests a relationship of L-nicotine binding with several responses observed after injection of low doses of nicotine and a relationship between alpha-bungarotoxin binding and nicotine-induced seizures.

Animals↗
PubMed1989

An autoradiographic analysis of cholinergic receptors in mouse brain.

Autoradiographic techniques were used to localize cholinergic receptors in the central nervous system of female DBA mice. Nicotinic receptors were identified using [3H]-L-nicotine and alpha-[125I]-bungarotoxin (BTX); [3H]-quinuclidinyl benzilate (QNB) was used to examine muscarinic receptor binding. There was little overlap between the regional distribution of binding sites for these ligands. Nicotine binding was highest in thalamic nuclei, the superior colliculus and the interpeduncular nucleus. For BTX binding, high density receptor populations were identified in the hippocampus, caudate putamen, colliculi (superior and inferior) and various nuclei in the hypothalamus and hindbrain. Muscarinic receptors were distributed more uniformly than nicotinic receptors; the colliculi, hippocampus and cerebral cortex had the highest level of QNB binding. Species differences between rats and mice in terms of cholinergic receptor binding are discussed.

Animals↗
PubMed1989

Differential effect of chronic nicotine treatment on nicotinic receptor numbers in various brain regions of mice.

Studies of smoking behavior in human twin pairs indicate that genetic factors may influence whether people do, or do not, smoke. Because the ability to develop tolerance to behavioral and physiological effects of nicotine may regulate nicotine intake, studies of potential genetic influences on tolerance development were carried out using inbred mouse strains that differ in initial (first dose) sensitivity to nicotine. Nicotine-sensitive strains such as the C57BL and DBA strains develop tolerance to nicotine following chronic intravenous infusion of lower doses of nicotine than are required to elicit tolerance to nicotine in the nicotine-resistant strains such as C3H and BUB. Chronic nicotine infusion results in a dose-related increase in binding of [3H]-nicotine to brain membranes in all strains. Differences in this effect were seen among brain regions as well as between the strains. A quantitative autoradiographic analysis of the effects of chronic nicotine infusion on DBA/2 mice, which develop marked tolerance to nicotine, clearly indicates that nicotine binding is affected to various degrees in various brain nuclei. These results are discussed in terms of genetic influences on tolerance development.

Animals↗
PubMed1988

Chronic ethanol or nicotine treatment results in partial cross-tolerance between these agents.

Female DBA/2Ibg mice were treated chronically (21 days) with ethanol- or dextrin-containing liquid diets or infused chronically with nicotine (8 mg/kg/h) or saline for 10 days. The responses of these animals to challenge doses of ethanol (2.5 g/kg) or nicotine (1 or 2 mg/kg) were measured using a test battery consisting of respiration rate, acoustic startle response, Y-maze crosses and rears, heart rate and body temperature. Chronic ethanol-treated animals were tolerant to the effects elicited by a challenge dose of ethanol on four of the six measures and were cross-tolerant to nicotine's effects on the acoustic startle test. Chronic nicotine-treated animals were tolerant to nicotine's effects on five of the six measures and cross-tolerant to ethanol's effects on heart rate and body temperature. Thus, partial cross-tolerance between ethanol and nicotine exists. Chronic nicotine treatment resulted in significant increases in L-[3H]-nicotine binding in six of seven brain regions and in alpha-[125I]-bungarotoxin binding in three of seven brain regions. Chronic ethanol treatment failed to alter the binding of either ligand. Therefore, the cross-tolerance that develops between ethanol and nicotine is not totally dependent on alterations in the number of brain nicotinic receptors.

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↗