Divergent selection for pentobarbital-induced sedation times in mice.

Divergent selection for pentobarbital sedation-time response was practiced in mice for 9 generations. At the end of 9 generations of selection, the long-sedation-time line (LST) slept an average of 433 min; the short sedation time line (SST) slept an average of 29 min. The control line (C) slept an average of 71 min. These differences represent an almost 15-fold increase in sedation time for the LST compared to the SST line and a 6-fold increase compared to the C line. The SST line slept about 40% less than the C line after 9 generations of selection (measured in tenth generation progeny). Analysis of selection differentials and realized heritabilities indicated that selection response did not diminish after 9 generations of selection. Realized heritabilities for sedation time ranged from 0.43 to 0.83 for the LST line and from 0.55 to 0.81 for the SST line. Realized heritabilities did not decrease in magnitude due to selection progress, indicating that more progress can still be achieved. Comparing corrected (for environmental factors) to uncorrected heritabilities showed the importance of including a control line in selection experiments. Crossing of lines to study gene action responsible for this trait revealed that this trait was controlled by a number of genes with additive gene action without dominance, overdominance, epistasis, or maternal effects.

Decreased endurance to cold water swimming and delayed sexual maturity in the rat following neonatal lead exposure.

The effects of neonatal lead (Pb) exposure on ability to endure stress and on the onset of sexual maturity were investigated using rats. Sprague-Dawley dams (n = 17/treatment) were treated with or without lead acetate (0.3%) in drinking water from parturition until postnatal day (PND) 21, at which time the pups were weaned. A set of sex-balanced pairs of pups (24 male and 24 females/treatment) from randomly selected control and Pb-treated dams was tested for cold water (4 degrees C) swimming-endurance on PND 15, 21, 25 and 30. Lead treated-female pups showed significantly (P < 0.05) lower endurance on PND 21 and 30, while Pb-treated males exhibited lower (P < 0.05) endurance on PND 21 compared to their respective controls. The results of this study indicate that neonatal exposure to Pb decreased cold water swimming-endurance. Neonatal exposure to either Pb or swimming stress delayed (P < 0.002) the onset of sexual maturity in both sexes. However, exposure to both treatments masked the effect of swimming stress on the onset of maturity in females but not in males.

Hypothermic effect of ethanol in mice selected for differential sleep-time response to pentobarbital.

The hypothermic action of ethanol was investigated in genetically distinct lines of mice selected for sleep-time response to pentobarbital for six generations. Ethanol (3 g/kg, intraperitoneally) was administered to alcohol-naive males and females from each of the unselected control, long-, and short-sleep mouse lines. Rectal temperatures were measured immediately before, and at 15, 30, 60, 90, 120, and 240 min after ethanol injection. Eight female and eight male mice from each line were sacrificed at each time point, and trunk blood was collected for plasma ethanol analysis. The results show that short-sleep mice were less hypothermic (p < 0.05) compared to long-sleep mice at 15 and 30 min after ethanol administration. However, plasma ethanol concentrations were not significantly different between the mouse lines at any time point. Therefore, the line-dependent differential ethanol-induced hypothermia observed may be a result of differences in "brain sensitivity" rather than in the rates of ethanol metabolism among the mouse lines.

Bioavailability and pharmacokinetics of metoclopramide in cattle.

The bioavailability of metoclopramide was investigated in three steers following administration of 8 mg/kg by the oral, abomasal (cannula), and intravenous routes, using a Latin square design. The mean (+/- SD) oral and abomasal bioavailabilities were 51.3 +/- 30.7% and 76.2 +/- 15.5%, respectively. The mean value for clearance (Cl) was 20.1 +/- 5.9 ml/min and the volume of distribution (Vd) was 0.51 +/- 0.19 l/kg. Additional pharmacokinetic parameters for metoclopramide were determined following intravenous administration to seven cows. A predominate two-compartment model of distribution was found in six cows with a t 1/2 alpha harmonic mean of 24.2 min and a range of 11.2-72.4 min, a t 1/2 beta harmonic mean of 53.1 min and a range of 31.1-134.1 min, a Cl of 42.2 +/- 8.7 ml/min, and a Vd of 2.1 +/- 0.8 l/kg. To better define the relationship between metoclopramide concentration and release of prolactin, a treatment-by-subjects infusion study was conducted in which four different loading doses followed by constant infusion were used. A steady-state metoclopramide concentration (MCPss) of 8.8 +/- 2.6 ng/ml was associated with a three-fold elevation of prolactin to a mean value of 12.1 +/- 3.1 ng/ml in six yearling steers. Steady state serum prolactin concentrations (PRLss) did not rise significantly above 23.3 +/- 6.9 ng/ml, even when MCPss reached a concentration of 518.5 +/- 151.2 ng/ml. The short half-life, moderate Vd, low minimum pharmacologically effective concentration, and rapid Cl found for metoclopramide in cattle in this study, suggest that a continuous release device could potentially be useful in the application of this drug in the prevention and treatment of fescue toxicosis.

Circadian variation in tolerance to the hypothermic action of CNS drugs.

Male SAF mice (30-35 g) or male Sprague-Dawley rats (180-250 g) were used to study the circadian variation in tolerance to the hypothermic action of ethanol, apomorphine, and nicotine. Animals were treated for 2 or 3 consecutive days during the light phase (1000, 1400, or 1800 h) or the dark phase (2200, 0200, or 0600 h) and hypothermia produced measured. In one experiment, repeated injections of 20% ethanol (3 g/kg, IP) to mice resulted in varying degrees of hypothermia depending upon the time of injection. Tolerance to hypothermic action was observed only in animals treated during the light phase. On the contrary, the hypothermic response in animals treated during the dark phase increased. In another experiment, apomorphine (15 mg/kg, IP) was used and tolerance to apomorphine-induced hypothermia observed following repeated injections during the light phase with maximum tolerance noticed at 1400 h. In the third experiment, nicotine (2 mg/kg, IP) was repeatedly administered and resulted in tolerance development when given during the light phase. These results indicate that the rapid development of tolerance to CNS drugs studied is a diurnally controlled phenomenon.

Neural dopamine D2 receptors in rats fed endophyte-infected fescue seed.

To study the effect of endophyte (Acremonium coenophialum) on hypothalamic and striatal dopamine D2 receptors, male rats (n = 14/group) were pair-fed diets containing 50% Rat Chow and 50% either endophyte-infected (E+) or noninfected (E-) fescue (Festuca arundinacea Schreb.) seed for 21 days. Concentrations of ergovaline and saturated pyrrolizidines were 1.91 micrograms/g and 2.84 mg/g, respectively in E+, and undetectable in E- fescue seed. To monitor endophyte effects, rats were weighed weekly and serum derived from trunk blood (d 21) was analyzed for prolactin. Corpus striatum and hypothalamic tissue was assayed for dopamine D2 receptors using [3H]spiperone and [125I]epidepride, respectively. The endophyte depressed (P < .06) serum prolactin concentrations. Average daily gain during the study (21 d) was depressed (P < .0043) in rats fed E+ compared to controls. The endophyte increased (P < .03) striatal D2 receptor affinity (KD = 48.70 vs 54.95 pM) with no change (P > .28) in receptor density (Bmax = 25.59 vs 28.00 pmol/mg of tissue) in E+ and E- rats, respectively. Hypothalamic D2 receptor density (Bmax = 1.79 vs 1.57 pmol/mg of tissue) and affinity (KD = 17.5 vs 17.26 pM) were not (P > .66) different between E+ and E- rats, respectively. These data suggest changes in D2 receptor binding characteristics, particularly receptor affinity, may contribute to signs of fescue toxicosis.

Effects of feeding diets containing endophyte-infected fescue seed on luteinizing hormone secretion in postpartum beef cows and in cyclic heifers and cows.

Two experiments were conducted to investigate the effect of feeding endophyte (Acremonium coenophialum)-infected fescue (Festuca arundinacea Shreb.) seed on LH secretion in postpartum beef cows and in cycling heifers and cows. In Exp. 1, spring-calving primiparous Angus cows (n = 16) were pair-fed for 75 d diets that contained endophyte-free or endophyte-infected (95%) fescue seed that contained 1.3 micrograms/g of ergovaline and 5.2 mg/g of saturated pyrrolizidines. Serial blood samples for basal and GnRH-stimulated serum LH analysis were obtained on d 7, 28, 42, and 56 of the study. The endophyte had no effect on LH secretion (basal, pulse frequency, and amplitude) or milk production. Average daily gain was decreased (P < .05) in cows that consumed infected fescue seed compared with controls (-.20 vs -.01 kg, respectively). Basal serum prolactin concentrations were reduced (P < .01) in treated compared with control cows (8.9 vs 25.4 ng/mL, respectively) on d 70. In Exp. 2, cycling Angus heifers (n = 8; age = 2 yr) and cows (n = 8; age = 4 yr) stratified by age were pair-fed for 40 d diets that contained the noninfected or the highly infected fescue seed. Estrus was synchronized by prostaglandin F2 alpha (d 18 and 28). Serial blood samples for serum LH analysis were obtained on d 28 (luteal phase) and d 30 (follicular phase). The endophyte did not affect LH (P > .28) or prolactin (P > .16) secretion, whereas ADG was decreased (P < .05) in treated compared with control animals (.32 vs .70 kg/d, respectively).

Effect of metoclopramide on luteinizing hormone secretion in postpartum anestrous cows.

The effect of metoclopramide (MC), a dopamine antagonist on luteinizing hormone (LH), was examined in anestrous primaparous cows. Metoclopramide has been found to be beneficial in overcoming fescue toxicosis; increasing LH secretion stimulates return to ovulatory function after parturition. Consequently, if MC had negative effect on LH secretion, it would indicate that administration of MC to reproducing animals might be limited. Of 14 postpartum (47 to 66 days) cows, 7 were given MC (4 mg/kg of body weight, IV), and 7 served as controls. Blood was obtained via jugular cannulas at 15-minute intervals for 8 hours; MC was given at the end of the first hour, and gonadotropin-releasing hormone (GnRH, 7 mg/kg), was given IV at the end of hour 7 as a challenge stimulus for LH secretion. Prior to GnRH administration, MC did not have significant effect on LH secretion, as judged by mean serum LH concentration, LH pulse frequency, and LH pulse amplitude. Administration of MC resulted in greater (P less than 0.05) LH response to GnRH, indicating enhanced secretory ability when the pituitary gland was challenged. Serum prolactin concentration was increased (P less than 0.01) by MC administration. Therefore, MC did not have adverse effect on LH secretion in postpartum cows.

Difference in luteinizing hormone response to an opioid antagonist in beef heifers and cows.

In three experiments, we examined endogenous opioid inhibition of luteinizing hormone (LH) secretion during the bovine estrous cycle. An increase in serum LH in response to the opioid antagonist naloxone (Na; 1 mg/kg i.v.) was the criterion for opioid inhibition. Estrous cycles were synchronized via prostaglandin administration. In Experiment 1, mean serum LH was not different during the luteal phase in yearling heifers (n = 6/group) at Hour 1 after Nal (2.1 ng/ml) compared to controls (1.8 ng/ml). However, LH peak amplitude was increased (p less than 0.05) in the Nal compared to the control group. Serum LH was increased (p less than 0.01) during the follicular phase in heifers at Hour 1 post-Nal compared to controls (4.7 and 3.5 ng/ml, respectively). Again, Nal administration was followed by increased (p less than 0.05) LH pulse amplitude compared to control. In Experiment 2, no effect of Nal upon serum LH was detected in cows (n = 9) during proestrus, metestrus, midluteal and late luteal portions of the estrous cycle. In Experiment 3, the LH response to Nal was examined simultaneously in yearling heifers and cows (n = 5/group) during the luteal and follicular phases. Serum LH increased (p less than 0.001) during Hour 1 post-Nal in heifers compared to cows during the follicular (3.4 vs. 1.7 ng/ml) but not during the luteal phase. LH pulse amplitude also increased (p less than 0.05) during Hour 1 post-Nal in heifers compared to cows during the luteal (2.5 vs. 1.1 ng/nl and follicular (2.5 vs. 1.3 ng/ml) phases.(ABSTRACT TRUNCATED AT 250 WORDS)

LHRH - Induced ovulation and fertility of anestrous goats.

Seventeen female mature anestrous does were used to study the effect of luteinizing hormone-releasing hormone (LHRH) on ovulation (Experiment I) and on fertility rate and blood estrogen/progesterone concentrations (Experiment II). Laparotomy after day 8 of treatment with a single injection of LHRH (300 ug) and estradiol cypionate (0.2 mg/kg) revealed evidence of ovulation in two out of three and a developed follicle in the third. Similar treatment to six does in Experiment II, when followed by natural mating with a fertile buck, produced pregnancy in two does, pseudopregnancy in two and no effect (nonpregnancy) in the remaining two animals. The pregnant does had normal parturition after 148 to 150 days of gestation. In pregnant does, blood progesterone levels first showed a gradual increase until day 130 (10.07 ng/ml) and then declined sharply at 48 hours before parturition. Estrogen concentration, on the other hand, failed to increase until day 80, and thereafter it reached a peak (1800 pg/ml) at 24 hours prior to parturition; the level declined sharply at 24 hours after parturition. In pseudopregnant does, progesterone levels remained in close proximity with those of pregnant does until day 90, when they started to decline.