Biomedical subjects

N R Rustay

Publications and source records attributed to N R Rustay.

5 recordsLinked to original sources

PubMed2001

Sensitivity and tolerance to ethanol-induced incoordination and hypothermia in HAFT and LAFT mice.

Acute functional tolerance (AFT) manifests as rapid adaptation during a single ethanol exposure, leading to a decrease in the behavioral response to ethanol. In order to investigate the genetic and environmental components of the development of AFT, mice were selectively bred in replicate from HS/Ibg mice. High (HAFT) and low (LAFT) acute functional tolerance selected lines were bred to differ in the rate of development and magnitude of AFT to ethanol's intoxicating effects using a static dowel-balancing task. In the present set of experiments, HAFT and LAFT mice were tested for development of AFT on a fixed-speed rotarod using a protocol similar to that for which they were selected. HAFT mice developed greater AFT to ethanol than did LAFT mice. In a separate experiment, other mice from these lines were tested for initial sensitivity and the development of chronic tolerance to ethanol-induced hypothermia, and ethanol-induced incoordination in the grid test. Previous research has detected possible common genetic control of these phenotypes. No differences between lines were found in initial sensitivity to ethanol or in the development or magnitude of chronic tolerance in either test. These experiments show that genetic factors influencing the development of acute tolerance to ethanol-induced intoxication are at least partially distinct from those influencing initial sensitivity and the development of chronic tolerance to ethanol-induced hypothermia and incoordination. Furthermore, these experiments show that AFT measured by the stationary dowel generalizes to AFT measured by the fixed-speed rotarod.

Animals↗

PubMed2000

Acute neuroactive steroid withdrawal in withdrawal seizure-prone and withdrawal seizure-resistant mice.

Allopregnanolone (3alpha-hydroxy-5alpha-pregnan-20-one) is an endogenously derived metabolite of progesterone, and a potent positive modulator of gamma-aminobutyric acid(A) (GABA(A)) receptors. A withdrawal syndrome, characterized by central nervous system (CNS) hyperexcitability, has been demonstrated following abrupt discontinuation of high progesterone levels in rats, which was due in part to altered levels of allopregnanolone. The purpose of the present study was to determine if a single administration of pregnanolone or allopregnanolone could produce an acute withdrawal response in mice selected for susceptibility (Withdrawal Seizure-Prone, WSP) or resistance (Withdrawal Seizure-Resistant, WSR) to ethanol withdrawal convulsions. WSP mice administered 75 mg/kg pregnanolone showed a significant increase in handling-induced convulsion (HIC) scores over a 25-h testing period. In contrast, HIC scores in WSR mice were negligible after acute administration of 25, 50, 75, or 100 mg/kg pregnanolone. WSP mice also showed a similar increase in HIC after withdrawal from 75 mg/kg allopregnanolone. This effect was evident at both the 10-h and 25-h overall withdrawal severity assessment. These results demonstrate that neuroactive steroids can elicit an acute withdrawal response similar to that of other positive modulators of GABA(A) receptors in WSP mice, supporting the notion that a common set of genes underlie acute and chronic withdrawal severity from multiple agents with depressant effects on the central nervous system.

Animals↗

PubMed2000

Sensitivity and tolerance to ethanol in mouse lines selected for ethanol-induced hypothermia.

Within-family selective breeding techniques have been used to create two lines of mice to be insensitive (HOT) and two lines to be sensitive (COLD) to the hypothermic effects of an acute 3.0-g/kg ethanol (EtOH) injection. Previous studies have found HOT mice to be relatively resistant to the development of tolerance to this effect, whereas COLD mice readily develop tolerance. The breeding program is currently in selected Generation 52, and the HOT and COLD mice differ by about 10 degrees C (average of both replicates) in their selected hypothermic response. Starting with selection Generation 20, separate lines of mice were inbred from the HOT-2 and COLD-2 selected lines, while selection continued for the original two replicate lines of HOT and COLD mice. To assess whether different dose treatments would produce differential tolerance development in the HOT and COLD selected lines, we administered different dose regimens across 5 days to HOT and COLD mice. The COLD mice developed tolerance while the HOT mice did not, regardless of total EtOH administered. In a separate study, we administered EtOH (3.0 g/kg) to mice for 3 days to assess a shorter tolerance paradigm. We also present here responses to the selection dose of 3.0-g/kg EtOH in the inbred HOT (IHOT-2) and COLD (ICOLD-2) mice tested after 41 generations of brother-sister mating. In addition, we report recent attempts to find doses of EtOH that would produce an equivalent initial hypothermic response in each of the six lines (HOT-1, COLD-1, HOT-2, COLD-2, ICOLD-2, and IHOT-2). When doses were selected to produce similar initial hypothermic sensitivity, tolerance was tested by giving three daily doses and examining the attenuation of the hypothermic response on the third day. All three COLD lines developed significant tolerance, while the HOT lines did not. The HOT and COLD mice provide a genetic model to study mechanisms mediating acute EtOH-induced hypothermia as well as tolerance development.

Animals↗

PubMed2000

Anxiety and sensitivity to ethanol and pentobarbital in alcohol withdrawal seizure-prone and withdrawal seizure-resistant mice.

BACKGROUND: Withdrawal Seizure-Prone (WSP) and Withdrawal Seizure-Resistant (WSR) mice were selectively bred for high and low handling-induced convulsions, respectively, after chronic ethanol treatment. Withdrawal severity is one factor that may contribute to the development of alcoholism and/or substance abuse, and anxiety is another. We sought to explore whether these factors are genetically related. METHODS: WSP and WSR mice of two replicate pairs of selected lines were tested for anxiety-related behaviors on the canopy stretched-attend-posture apparatus 20 min after intraperitoneal injection of ethanol (2 g/kg, 20% v/v), pentobarbital (20 mg/kg), or an equivalent volume of saline. Dependent measures of anxiety included number of stretched attend postures (SAP) and time spent in the exposed area of the apparatus. Number of line crossings, which measures overall activity, was also scored. RESULTS: WSP mice given saline exhibited more SAP than WSR mice given saline, which indicated greater baseline anxiety. Ethanol and pentobarbital both reduced SAP and increased time spent in the exposed area of the apparatus, which indicated that both drugs exerted an anxiolytic effect. Despite baseline differences in SAP between selected lines, both anxiolytic drugs reduced SAP to similar levels in WSP and WSR mice. CONCLUSIONS: These results support the hypothesis that WSP mice are more sensitive than WSR mice to the anxiety-reducing effects of ethanol and pentobarbital. Some genes that influence this difference are likely to be the same as those that influence ethanol withdrawal severity. Thus, higher basal anxiety and greater genetic sensitivity to anxiolytic drug effects may relate to a greater genetic predisposition to the development of severe alcohol withdrawal signs.

Alcohol Withdrawal Seizures↗

PubMed1999

Predicting relapse to cocaine-seeking behavior: a multiple regression approach.

Recovery of previously extinguished responding to stimuli paired with the administration of drugs of abuse is becoming a widely utilized animal model of relapse to drug-seeking behaviors. While this approach is useful for identifying factors such as conditioned stimuli that are associated with drug-seeking, it has not directly identified behaviors that might predict susceptibility to relapse. In this study, rats were initially screened for locomotor activity in response to a novel environment. Rats were then trained to self-administer cocaine. A stimulus light and tone were paired with each infusion of cocaine. After 14 days of self-administration (maintenance) rats underwent 7 days of extinction trials (extinction phase 1), in which responding yielded neither cocaine nor the presentation of the conditioned stimulus. After extinction phase 1, rats responded for presentations of the compound stimulus in the absence of cocaine (test day 1). Rats then underwent 3 more days of extinction (extinction phase 2). After extinction phase 2, rats were once again allowed to self-administer cocaine (test day 2) and received presentations of the compound stimulus. Hierarchical regression equations, utilizing data from locomotor screening and the average responding during maintenance and extinction phases 1 and 2, were then constructed in order to predict the magnitude of responding on test days 1 and 2. A model utilizing locomotor activity, maintenance responding and extinction phase 1 responding accounted for over 76% of the variance associated with responding on test day 1, with extinction phase 1 as best predictor. A further model indicated that locomotor activity was the best predictor of propensity to self-administer cocaine on test day 2. These regression models provide a novel approach to determining factors that may predict relapse to drug-seeking behaviors.

Animals↗