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A C Collins

Publications and source records attributed to A C Collins.

At least 181 records · Page 10Linked to original sources
PubMed1982

An overview of the genetics of psychopathology.

The suggestion that psychopathologies are in part mediated by aberrant catecholamine metabolism has resulted in one of the more rapidly growing areas of pharmacogenetics. Collectively, the studies conducted to date indicate that psychopathological conditions have multiple causes which cannot be related to single genetic or biochemical deficits. However, through multidisciplinary research integrating behavioral, genetic, and biochemical approaches, a great deal of insight may be gained concerning the causes of psychopathological disorders and the use of drug therapy to modify the course of these illnesses.

Animals↗
PubMed1982

Acute ethanol effects on blood pH, PCO2, and PO2 in LS and SS mice.

The effects of ethanol on blood pH, PCO2, and PO2 were measured in LS and SS mice in an attempt to ascertain whether these lines of mice, which differ in CNS sensitivity to the behavioral effects of ethanol, also differ in sensitivity to physiological effects of this drug. Long-sleep (LS) female mice were injected intraperitoneally with 1.8, 2.5, 3.3, or 3.8 g/kg ethanol; short-sleep (SS) female mice were administered 2.5, 3.3, 4.1, or 4.7 g/kg. Blood pH, PCO2, and PO2 were assessed at 15, 30, 60, 120, or 180 min after injection of the 2.5 and 4.1 g/kg doses or at 60 min after injection of the 1.8, 2.5, 3.3, 3.8, 4.1, and 4.7 g/kg doses. Opposite effects on blood pH and PCO2 over time were obtained in LS and SS mice at the 2.5 g/kg dose. Acidosis characterized the LS line, whereas alkalosis characterized the SS. The results obtained with SS mice at 4.1 g/kg dose were similar to those obtained with LS mice at the 2.5 g/kg dose. The dose-response curve for the SS mice generated at 60 min post-injection lies to the right of that for the LS mice. The effects of high ethanol doses on SS mice resemble the effects of low doses on LS animals. Thus, the two lines of mice differ in response to the effects of ethanol on these parameters related to respiration. The difference in sensitivity to the respiratory depressant effects of ethanol may contribute to the differences in behavioral sensitivity between the two lines.

Acid-Base Equilibrium↗
PubMed1982

Effects of pentobarbital in mice selected for differential sensitivity to ethanol.

Two lines of mice have been genetically selected for differential sensitivity to ethanol. These lines have been designated long sleep (LS) and short sleep (SS) on the basis of their hypnotic response to the ethanol selection dose. Earlier studies of these mice suggested that this difference was limited to alcohols and did not extend to other classes of hypnotics. The present study examined hypnotic and hypothermic responses produced by pentobarbital in recent generations of these mice. Dose-dependent differences in sleep time and in hypothermia were found, with SS mice affected to a greater degree than LS mice. Pharmacokinetic studies showed that the half-life of pentobarbital disappearence from SS blood was twice that reported for SS mice of the 18th generation. The half-life in the LS line had not changed. The volumes of distribution and waking brain concentrations were identical in LS and SS mice. An altered rate of elimination (not differential CNS sensitivity) appeared to be the major factor responsible for the differences observed between these lines.

Alcohol Drinking↗
PubMed1982

Seizure susceptibility of the pregnant mouse.

The effect of pregnancy on chemically-induced seizures in mice was studied. Latencies to myoclonic and clonic seizures induced by inhalation of flurothyl were significantly reduced at days 12 through 18 of gestation. Parturition resulted in a return of seizure susceptibility to control levels. The possibility that this effect might be mediated by decreased neurotransmitter levels subsequent to the decreased vitamin B6 levels which are known to occur during pregnancy was suggested. A pregnancy-associated liver cytosolic aldehyde dehydrogenase (pi-AlDH) utilized pyridoxal as a substrate, and the peak of pi-AlDH activity was shown to coincide with the peak of seizure susceptibility. The activity of aldehyde oxidase, the major enzyme normally responsible for the metabolism of pyridoxal, was reduced in pregnant animals. The pyridoxal 5'-phosphate synthesizing enzymes, pyridoxal kinase and pyridoxamine phosphate oxidase, were marginally increased in activity during pregnancy. It was suggested that the increased activity of pi-AlDH was indirectly responsible for the increased seizure susceptibility due to increased metabolism of pyridoxal.

Aldehyde Dehydrogenase↗
PubMed1982

The influence of age, sex and genotype on the subcellular distribution of hepatic aldehyde dehydrogenase activity in the mouse.

1. The influence of age on hepatic aldehyde dehydrogenase (AlDH) was studied in both sexes of two selectively bred lines of mice (Mus musculus). 2. Whole liver AlDH activity increased from the 60-day-old level linearly up to 200 days of age. The enzyme activity of the females remained at the 200-day-old level, but in males. AlDH continued to increase up to 400 days of age. Males had higher AlDH activity than females. 3. The AlDH activities of 3 subcellular fractions: cytosol, mitochondria and microsomes also increased with age, but were more dependent on sex and genotype than was the whole liver activity. 4. It was concluded that AlDH activity increases with age in mouse liver but it was influenced greatly by sex, genotype and subcellular fraction studied.

Age Factors↗
PubMed1982

Circadian and genetic effects on ethanol elimination in LS and SS mice.

Behavioral studies using mice have suggested circadian influences on response to ethanol. Studies examining possible circadian influences on ethanol elimination are ambiguous as to whether changes in elimination contribute to circadian variations in response. Therefore, the linear declines in blood alcohol concentrations (BACs) were assessed in long-sleep (LS) and short-sleep (SS) male mice at 0300, 0900, 1500, or 2100 hr following an intraperitoneal injection of either 2.5 or 4.1 g/kg ethanol. Overall mean BAC for LS mice was significantly higher than for SS mice at both ethanol doses. With the 4.1 g/kg dose, LS mean BAC was higher at 2100 hr than at 0900 hr. Both lines of mice exhibited faster elimination rates at 0300 and 0900 hr than at 1500 and 2100 hr. SS mice generally showed a more rapid decline in BAC than did LS mice at this dose. With the 2.5 g/kg dose, the rate of decline was faster at 0900 hr than at 2100 hr for both lines of mice. SS mice showed a significantly greater overall rate of decline than did LS mice. The line differences in blood alcohol concentration and elimination rate may have resulted from a change in the doses used to select these mice and may contribute to circadian influences on ethanol response.

Animals↗
PubMed1982

Indomethacin significantly reduces mortality due to acute ethanol overexposure.

Previous studies in our laboratory have demonstrated that indomethacin, a potent prostaglandin synthetase inhibitor, significantly antagonizes the depressant, activating, and hypothermic responses to ethanol. In this study, male SS mice, a line selectively bred for low sensitivity to the hypnotic effects of ethanol, were pretreated with indomethacin or vehicle up to 24 hr prior to administration of an LD69 dose of ethanol. Indomethacin pretreatment significantly reduced the mortality rate independent of pretreatment time and produced an increase in the number of animals exhibiting a depressed behavioral response as measured by loss of the righting reflex. These results suggest that indomethacin antagonized the effects of ethanol to an extent such that a lethal dose was transformed into a depressant dose. These data are consistent with our hypothesis that pretreatment with prostaglandin synthetase inhibitors serves to shift the ethanol dose response curve to the right, suggesting that the arachidonic acid cascade is an important system in the mechanism of ethanol's actions.

Alcoholic Intoxication↗
PubMed1982

Norepinephrine, gamma-aminobutyric acid, and choline reuptake kinetics and the effects of ethanol in long-sleep and short-sleep mice.

The reuptake characteristics of norepinephrine, gamma-aminobutyric acid (GABA), and choline were investigated in the long-sleep (LS) and short-sleep (SS) mouse lines. Kinetic analysis revealed no significant differences between lines in affinity (Km) or maximal velocity (Vmax) for norepinephrine and GABA measured in cortex and cerebellum or for choline measured in striatum and cortex. In vitro ethanol dose-response curves (0-1.7 M) for these neurotransmitters showed highly significant inhibition of reuptake except for reuptake of choline in cortex. All responses to ethanol were identical in both lines of mice. The magnitude of GABA reuptake inhibition was greater in cortex than in cerebellum. On the other hand, choline reuptake was very sensitive to ethanol in striatum, but was unaffected in cortex. These data suggest some regional specificity in ethanol's solubility. Inhibition of reuptake by ethanol concentrations greater than 0.86 M was determined to be irreversible and not due to hypertonic lysis. Our data are in complete agreement with previously published studies which suggest that ethanol inhibits neurotransmitter reuptake. However, since the LS and SS mice were selected for differential sensitivity to ethanol, and since we found no differences between lines in kinetic parameters or acute responses to in vitro ethanol, it appears that inhibition of neurotransmitter reuptake is not involved in the depressant effects of ethanol.

Animals↗
PubMed1982

Characterization of nicotine binding in mouse brain and comparison with the binding of alpha-bungarotoxin and quinuclidinyl benzilate.

The binding of [3H]nicotine to mouse brain has been measured and subsequently compared with the binding of [125I]alpha-bungarotoxin (alpha-BTX) and L-[3H]quinuclidinyl benzilate (QNB). The binding of nicotine was saturable, reversible, and stereospecific. The average KD and Bmax were 59 nM and 88 fmoles/mg of protein, respectively. Although the rates of association and dissociation of nicotine were temperature-dependent, the incubation temperature had no effect on either KD or Bmax. When measured at 20 degrees or 37 degrees, nicotine appeared to bind to a single class of binding sites, but a second, very low-affinity, binding site was observed at 4 degrees. Nicotine binding was unaffected by the addition of NaCl, KCl, CaCl2, or MgSO4 to the incubation medium. Nicotinic cholinergic agonists were potent inhibitors of nicotine binding; however, nicotinic antagonists were poor inhibitors. The regional distribution of binding was not uniform: midbrain and striatum contained the highest number of receptors, whereas cerebellum had the fewest. Differences in site densities, regional distribution, inhibitor potencies, and thermal denaturation indicated that nicotine binding was not the same as either QNB or alpha-BTX binding, and therefore that receptors for nicotine may represent a unique population of cholinergic receptors.

Animals↗
PubMed1981

Prostaglandin synthetase inhibitors antagonize hypothermia induced by sedative hypnotics.

Previous studies in our laboratory have demonstrated that inhibition of prostaglandin biosynthesis through pretreatment with aspirin and other prostaglandin synthetase inhibitors (PGSI) significantly reduces CNS sensitivity to a hypnotic dose of ethanol. Indomethacin, a potent PGSI, was administered to male LS, SS, and HS/Ibg mice (65 +/- 10 days of age) 15 min prior to administration of a hypnotic dose of ethanol or pentobarbital. Doses of indomethacin used were identical to those previously reported as optimally antagonizing ethanol-induced sleep. Another group received a vehicle-control injection, while a third group also received a control injection, but were placed in a incubator maintained at 30 +/ 1 degrees C. Body temperatures were recorded periodically for several hours. Both indomethacin and incubation significantly reduced hypothermia induced by ethanol and pentobarbital. Incubation increased sleep time after ethanol, but did not affect pentobarbital sleep time. These results suggest that the hypnotic and hypothermic effects of ethanol, although possibly mediated through prostaglandins, apparently are not causally linked.

Body Temperature↗
PubMed1981

Viability and sensorimotor development of mice exposed to prenatal short-term ethanol.

The identification of the fetal alcohol syndrome in man has led to an abundant, but sometimes contradictory body of research examining the effects of prenatal ethanol exposure in animals. The present study examines the early sensorimotor development of heterogenous stock mice after ethanol exposure during one of two time periods in gestation, days 8--12, or days 14--18. Animals received either a liquid diet containing 20% ethanol derived calories, an isocalorically balanced yoked control diet or a lab chow control diet. Results indicated no apparent effects due to administration of alcohol during the middle of gestation, but a marked decrease in offspring viability, birthweight, and growth due to administration during the last part of gestation. The late gestation treatment group also showed a slight delay in the rate of development of the grasping and horizontal screen tasks. Overall, animals that survived showed relatively normal sensorimotor development.

Aging↗
PubMed1981

Genetic influences on cholinergic drug response.

Three mouse strains were tested for oxotremorine effects on open-field activity and body temperature. Open-field activity was depressed less severely in C3H mice than in C57BL, which were less affected than DBA. While no differences in the hypothermic effects of oxotremorine were observed 15 min after injection, the time courses of the drug effect on body temperature indicated that C3H were less affected than C57BL or DBA. No differences in the activities of acetylcholinesterase of choline acetyltransferase were found among the three strains in cortex, cerebellum, hindbrain (pons-medulla), or total midbrain. While no differences in muscarinic receptor levels were found in the four large brain areas, finer dissection of the midbrain revealed small differences in total receptor number in striatum, hippocampus, and remaining midbrain areas. C3H mice exhibited greater QNB binding than C57BL and DBA mice in striatum; DBA mice exhibited greater QNB binding in hippocampus than C57BL (C3H mice were not different from either strain); and C57BL had less QNB binding than the other two strains in midbrain. All of these differences were small (20% or less). No differences in KD were observed. The inhibition of receptor binding by either oxotremorine or nicotine was the same in all strains, but the IC50 for oxotremorine varied from region to region. While behavioral differences in the effects of oxotremorine are clear, there is no obvious biochemical explanation for these differences.

Acetylcholinesterase↗
PubMed1981

Liver cytosolic aldehyde dehydrogenase activity in the pregnant mouse.

A 3-fold increase in aldehyde dehydrogenase (A1DH) was found in the cytosolic fraction of mouse liver homogenates during pregnancy. The increase in A1DH activity began at day 10 of pregnancy, peaked at parturition, and declined in a biphasic manner with half-lives of 4.15 and 47.7 days. Enzymes from control (beta A1DH), pregnant (pi A1DH) and phenobarbital-treated (phi AlDH) were partially purified and compared. All had molecular weights of approximately 60,000 daltons. Substrate specificities were similar except that phi A1DH had a lower Km for propionaldehyde than beta or pi and both pi and phi oxidized 4-carboxybenzaldehyde poorly compared to beta. Electrophoretic and thermal denaturation studies showed some similarities between beta and pi, but phi A1DH behaved quite differently. It was concluded that pregnancy caused an increase in one of the A1DHs already present in control mice, while phenobarbital treatment resulted in induction of a unique cytosolic A1DH.

Aldehyde Dehydrogenase↗
PubMed1981

Cholinergic adaptations to chronic oxotremorine infusion.

The development of tolerance to cholinergic agonists such as oxotremorine is a well established phenomenon. The hypothesis that such tolerance may be explained by a decrease in the number of affinity of muscarinic receptors was tested by chronically treating C3H mice with oxotremorine. Chronic treatment was achieved by continuously infusing oxotremorine via an indwelling i.v. catheter. Doses ranged from 0.03 to 1.0 mg/kg/hr. Clear tolerance was observed in that symptoms such as salivation, lacrimation and muscle tremor decreased or disappeared during the infusion period. Similarly, chronically treated animals exhibited minimal hypothermia or impairment of rotarod performance when challenged with an oxotremorine dose which significantly depressed both of these measures in naive animals. The activities of the enzymes, acetylcholinesterase and choline acetyltransferase, as well as the binding of [3H]-3-quinuclidinyl benzilate in seven brain regions, were assessed. Chronic oxotremorine treatment failed to alter acetyltransferase activity in any of the brain regions. Choline acetyltransferase activity was only marginally decreased in several brain regions. A significant decrease in maximal [3H]-3-quinudidinyl binding was observed in six of the regions examined. No alteration in [3H]-3-quinuclidinyl affinity was detected. Tolerance to oxotremorine was detected at doses which failed to alter choline acetyltransferase activity or receptor number. These data support the observations of others who noted that chronic muscarinic stimulation results in a decrease in muscarinic receptors, but suggest the importance of mechanisms other than decreased receptor number in early stages of tolerance development.

Acetylcholinesterase↗
PubMed1980

Components of the GABA system in mice selectively bred for differences in open-field activity.

Mice selectively bred for differences in open-field activity were utilized to test the hypothesis that differences in open-field behaviour are mediated at least in part by components of the GABA system, including brain glutamic acid decarboxylase activity (V, Vmax, and Km), as well as glutamate and GABA concentrations. Enzyme velocity was found to be inversely correlated with open-field activity, but it accounted for less than 15% of the variance. Moreover, the rank order of the lines was not as predicted for a genetically correlated character and the magnitude of the differences in enzyme activity among the lines was not large. It was therefore concluded that the GABA system is not an important mediator of differences in open-field behaviour in these lines of mice.

Animals↗
PubMed1980

The influence of genotype and sex on behavioral sensitivity to nicotine in mice.

The influences of genotype and sex on spontaneous motor activity in a Y-maze after nicotine administration and on nicotine concentrations in liver and brain were assessed in three inbred mouse strains. The rank order of liver nicotine elimination rates in these strains was found to be C57 > C3H = DBA for females and DBA > C3H = C57 for males. Within the C57 and C3H strains, females eliminated nicotine significantly faster than males, while DBA females and males eliminated nicotine at similar rates. The rank order of motor depression at early time points after nicotine administration was found to be DBA = C57 > C3H for both males and females. Females of all three strains demonstrated less sensitivity to nicotine's depressant effects than males. There did not appear to be any consistent association between rate of liver nicotine elimination or brain nicotine level and motor depression as measured in the Y-maze. Although variability in liver nicotine elimination and in brain nicotine content may account for some of the observed behavioral effects, these data suggest that strain and sex differences in tissue sensitivity to nicotine are of primary importance.

Animals↗
PubMed1979

Prostaglandin synthetase inhibitors antagonize the depressant effects of ethanol.

Several studies indicate that ethanol may depress the central nervous system by altering neurotransmitter release. Evidence obtained from the peripheral nervous system suggests that prostaglandins act as negative feedback inhibitors of transmitter release. If a similar process occurs in the brain, then perhaps ethanol affects transmitter release via a mechanism involving prostaglandins. Prostaglandin synthetase inhibitors were administered to adult HS/Ibg male mice prior to intraperitoneal injection of a hypnotic dose of either ethanol, propanol, or t-butanol. A significant decrease in the length of alcohol sleep time was found: in the ethanol study, this was coupled with a significant increase in waking blood alcohol levels. These results indicate that inhibition of prostaglandin synthesis alters CNS sensitivity to the depressant effects of alcohol. When the same inhibitors were administered prior to other sedative hypnotics, i.e., pentobarbital and chloral hydrate, no effect was found. This suggests that prostaglandins may be specifically involved in the biochemical mechanism of alcohol depression.

Acetaminophen↗