H.Dix Christensen

Cardiovascular effects of coffee and caffeine

This study evaluated the cardiovascular effects and elimination kinetics of coffee and caffeine in 54 volunteers selected according to 3 gradations of daily caffeine consumption, cigarette smoking status and the presence of caffeine intolerance. After 24 hours of caffeine abstinence, subjects received coffee and 2.2 mg/kg of caffeine (equivalent to 2 cups of coffee). Blood pressure, heart rate, systolic time intervals and plasma concentrations of caffeine were measured before and at timed intervals after coffee and caffeine. There were no differences in response to coffee and caffeine. The average systolic/diastolic blood pressure increased 9/10 mm Hg. The maximal decrease in heart rate averaged 10 beats/min, and there were small increases in the systolic time intervals. There were no cardiovascular differences among the various groups. Caffeine in the smokers and heavy caffeine users had a shorter half-life (3.2 and 4.1 hours) than that in nonsmokers and nonusers (5.1 and 5.3 hours). In the caffeine-intolerant group it had a longer half-life, while the cardiovascular effects were similar to those of the other groups. Thus, irrespective of the amount of daily caffeine consumption, smoking status or caffeine intolerance, the cardiovascular responses were similar and tolerance, if present, was gone by 24 hours.

A placebo-controlled comparison between betamethasone and dexamethasone for fetal maturation: Differences in neurobehavioral development of mice offspring

OBJECTIVE Our purpose was to determine whether antenatal betamethasone or dexamethasone is the preferred drug by use of neurobehavioral development assessment of exposed mice offspring. STUDY DESIGN Thirty adult CD-1 mice were randomly assigned to one of three groups (n = 10) to be administered a single subcutaneous dose of either a placebo (0.9% sodium chloride), betamethasone (0.10 mg), or dexamethasone (0.10 mg) on day 14 (74%) of gestation. The offspring then performed a battery of sensory, motor, motivational-anxiety, cognitive, and social tasks. Data were compared with use of analysis of variance, Kruskal-Wallis, or chi2 testing where appropriate. RESULTS The offspring from the three treatment groups were indistinguishable at birth. Dexamethasone exposure induced a brief developmental delay. Separation anxiety was increased in the dexamethasone-exposed group in the perinatal period, whereas exposure to both corticosteroids decreased anxiety in the juvenile period, continuing into adulthood among male betamethasone-exposed mice. Selective enhancement of a memory process occurred in betamethasone-exposed mice, whereas dexamethasone exposure resulted in a decrement. Socialization as to place preference while awake and asleep varied among the three treatment groups. Corticosteroid treatment did not induce significant changes in sensory, motor, motivation, and learning performances or in reproductive capability and progeny development. CONCLUSION Subtle differences in offspring performances of neurobehavioral development tasks favored antenatal betamethasone rather than dexamethasone. This finding, along with the knowledge that dexamethasone is less potent in accelerating lung maturity in the fetal mouse, suggests that betamethasone may be the preferred corticosteroid to use when human preterm delivery is imminent.

Placebo-controlled comparison between a single dose and a multidose of betamethasone in accelerating lung maturation of mice offspring

OBJECTIVE Our purpose was to determine, in a placebo-controlled manner with a mouse model, whether a multidose of betamethasone is more beneficial than a single dose in accelerating fetal lung maturation. STUDY DESIGN Ninety gravid CD-1 mice were randomly assigned to 1 of 3 groups (n = 30) to receive either a placebo (0.25 mL subcutaneously) or betamethasone (0.1 mg subcutaneously) as a single dose on gestational day 14 or as a multidose twice daily on gestational day 14 and 15. Ten pregnancies in each group were terminated at gestational day 16.5 to observe the neonatal breathing pattern (scale 0 to 5; 5 is unlabored breathing) and the lung histologic findings (scale 0 to 5; 5 is alveolar budding). The lungs of the offspring belonging to the remaining 20 pregnancies in each group were removed and weighed at postnatal day 1, 3, 5, or 120. RESULTS Fetuses exposed to a multidose of betamethasone displayed a higher breathing score at gestational day 16.5 than either to a single dose or to the placebo (mean score 4.6 vs 3.8 or 1.3; P <. 001). Alveolar development was greater after exposure to a multidose of betamethasone than after a single dose or after a placebo (mean score 4.4 vs 3.5 or 1.6; P <.001). The lung weights at gestational day 16.5 were less after a multidose of betamethasone than after a single dose of either betamethasone or a placebo (18.3 +/- 1.0 g vs 21.4 +/- 1.3 g or 23.3 +/- 1.3 g; P <.02). The lung/body weight ratio was similarly affected. This reduced weight of the lungs persisted postnatally into adulthood. CONCLUSIONS With a CD-1 mouse model, a multidose of antenatal betamethasone accelerated fetal lung maturation more than after a single dose but was accompanied with a decrease in lung weight that persisted into adulthood.

Behavioral changes in developing mice after prenatal exposure to paroxetine (Paxil)

OBJECTIVE The aim of this study was to conduct in a randomized, placebo-controlled manner behavioral testing on mice offspring exposed prenatally to the selective serotonin reuptake inhibitor paroxetine. STUDY DESIGN Forty-one CD-1 mice consumed paroxetine (Paxil, n = 21) or a placebo (n = 20) for 2 weeks before conception and throughout gestation. The daily dose of paroxetine used, 30 mg x kg(-1) x d(-1), is known to achieve concentrations in the rat serum equivalent to the upper therapeutic level in human beings and to achieve concentrations in the fetal rat brain equivalent to those in the adult mouse. Behavioral testing consisted of multiple tasks during early development, followed by motor, anxiety, reproduction, and depression tasks in the juvenile and adult periods. RESULTS Offspring in the 2 treatment groups showed no statistical differences in many early development tasks (geotaxis, homing, social play) or in locomotor and exploratory activities throughout development. Performances during a depression task (forced swim), anxiety tasks (elevated plus maze as juveniles and adults), and reproduction revealed no treatment differences. Offspring exposed prenatally to paroxetine had a 15% to 25% increase in separation vocalization (P <.04) and a significant increase in male aggression during cage changing (P <.03). CONCLUSION Prenatal exposure to a clinically relevant dose of paroxetine in mice produced no major behavioral alterations but did heighten performance on select anxiety testing in infant offspring and on aggressive behavior in adult males.

Effect of In Utero Exposure to Betamethasone on Motivation/Anxiety Testing in Mice Offspring

In utero exposure to a single dose of the long-acting corticosteroid betamethasone at GD 14 has been shown to induce specific differences in motivation/anxiety testing among offspring. Because multidosings are desired to enhance fetal lung maturation, our objective was to compare effects of multidosings of betamethasone with a placebo on postnatal tests of motivation and anxiety. Sixty gravid CD-1 mice were randomly assigned to receive one of six treatment regimens (n = 10) that consisted of a single or a double SC dosing of either betamethasone (Celestone soluspan 0.2 mg on GD 14; 0.1 mg on GD 13 to 16; 0.1 mg b.i.d. on GD 14 and 15; 0.1 mg b.i.d. on GD 13 to 16) or saline (0.25 ml on GD 13 to 16; 0.25 ml b.i.d. on GD 13 to 16). The percent of pups exhibiting separation vocalization was temporarily less at PND 5 after betamethasone exposure to four doses (p < 0.05) and to eight doses (p < 0.01). The percents of pups being successful in homing (PND 9) and in responding to startle stimulation (PND 12-15) were not different between the betamethasone-exposed and placebo-exposed groups. Exploratory performance in the radial arm maze revealed no delay in the activities of juvenile and adult offspring exposed to betamethasone. The percent of male offspring that fought as juveniles and as adults was not different between the betamethasone-exposed and the placebo-exposed groups. The previously reported altered responses using the elevated plus maze, among juvenile and adult offspring, after a single dose of betamethasone was not replicated in this multidose study. These data indicate that prenatal exposure to betamethasone did not affect the mouse offsprings long-term responses to motivation/anxiety testing.

Impact of hypericum (St.-John's-wort) given prenatally on cognition of mice offspring

This study investigated the cognitive impact of prenatal exposure to the herbal antidepressant hypericum in CD-1 mice. Hypericum (182 mg/kg/day) or a placebo was consumed in food bars for 2 weeks before mating and throughout gestation. The hypericin content in our hypericum formulation was in the middle range of standardized hypericum products. One offspring per gender from each litter (hypericum 13, placebo 12) was tested on each of the following tasks: juvenile runway with adult memory, adult Morris maze, adult passive avoidance, or adult straight water runway followed by a dry Cincinnati maze. Learning occurred in both genders in all tasks (P<.003) with no significant differences between treatments at the final trial. Female offspring exposed to hypericum, rather than to a placebo, required more time to learn the Morris maze task (P<.05). Postlearning sessions did not show any significant differences. In conclusion, prenatal exposure to a therapeutic dose of hypericum did not have a major impact on certain cognitive tasks in mice offspring.

Effect of Antenatal Exposure to Paroxetine (Paxil) on Growth and Physical Maturation of Mice Offspring

OBJECTIVE Our purpose was to determine, in a placebo-controlled manner, whether antenatal exposure to paroxetine affected long-term growth and physical maturation of mice offspring. METHODS Forty-one CD-1 mice consumed paroxetine (n = 21) or a placebo (n = 20) for 2 weeks before conception and throughout gestation. The daily dose of paroxetine (Paxil; 30 mg/kg/d) was known to achieve concentrations in the serum equivalent to the upper therapeutic level in humans and in the fetal brain equivalent to that of the adult mouse. Growth and physical maturation of the offspring were compared by paired t-test, Welchs corrected test, and Fishers exact test. RESULTS The maternal weight gain, litter sizes, number of fetal resorptions, and gestational age at delivery were not different between the paroxetine and the placebo-exposed offspring. Newborn pups exposed to paroxetine were more likely to have low birthweights (1.65 gm vs. 1.70 gm; P < 0.05) and narrower heads (7.7 mm vs. 8.1 mm; P < 0.05). Body weight, body length, and head circumference measurements increased in a manner that was indistinguishable between the two groups of offspring, regardless of gender. No differences in achievement of physical milestones (lower incisor eruption, eye opening, and development of external genitalia) were noted between the two groups. The reproductive capability and the perinatal outcomes of the second-generation offspring were unaffected by paroxetine exposure. CONCLUSION A clinically relevant dose of paroxetine, when given throughout gestation, did not affect long-term growth and physical maturation of mice offspring.

Chronic prenatal exposure to paroxetine (Paxil) and cognitive development of mice offspring.

This study investigated the impact on cognitive development in CD-1 mice from chronic prenatal exposure to the antidepressant paroxetine. CD-1 mice were given either paroxetine as 30 mg/kg/day or a placebo in food bars for 2 weeks before mating and throughout gestation. One offspring per gender from each litter was tested on each of the following tasks: tube runway, spatial maze, passive avoidance chamber, and water straight runway followed by an unforced decision maze. Learning occurred in both genders in all tasks (p<0.001) with no significant differences between treatment groups at the final learning session. Juvenile runway was the only task in which the paroxetine-exposed males demonstrated a learning rate that was slower than the placebo-exposed offspring (p=0.06). Post learning sessions did not show any significant treatment differences during the juvenile and adult periods during the water straight runway, mazes, and avoidance chamber tasks. In conclusion, chronic prenatal exposure in mice of paroxetine did not impact cognition on select tasks.

A Placebo-Controlled, Blinded Comparison Between Betamethasone and Dexamethasone to Enhance Lung Maturation in the Fetal Mouse

Objective: To compare the effects of betamethasone and dexamethasone used to enhance lung maturity of the fetal mouse. Methods: Adult CD-1 mice were administered a single does of either a placebo or different strengths of betamethasone (0.01, 0.025, or 0.10 mg) or dexamethasone (0.025 or 0.10 mg) on day 14.0 (74%) of gestation. The either gravid mice in each treatment cohort were killed on day 16.5 to assess fetal lung maturity (histologic changes and respiratory patterns) in a blinded manner. Another ten gravid mice in each treatment group were allowed to deliver spontaneously to assess perinatal outcomes. Results: Compared with the effects from placebo exposure, the 0.10-mg doese of both betamethasone and dexamethasone demonstrated enhanced histologic maturational changes and improved neonatal respiratory efforts. Betamethasone was twofold to threefold more potent than dexamethasone. The fetal crown-rump lengths and the fetal body, lung, and heart weights were indistinguishable among the three treatment groups. Compared with the fetal liver weight in the placebo group 955.0 ± 2.2mg), the liver was less heavy after exposure to 0.10 mg of betamethasone (45.6 ± 2.0 mg; P <.005), 0.025 mg of dexamethasone (47.6 ± 1.7 mg; P <.02), or 0.10 mg of dexamethasone (43.8 ± 1.5 mg; P <.001). No significant differences were observed between the 0.01-mg treatments of either corticosteroid and placebo for the duration of gestation, litter size, survival rate, birth weights, or weight gains to postnatal day 26. Conclusion: A single subcutaneous dose of 0.10 mg of betamethasone was twofold to threefold more potent than dexamethasone in accelerating fetal lung maturity without impairing fetal survival or weight gain. The unexpected finding of a reduced fetal liver weight with either corticosteroid warrants clinical correlation.

Relationship between caffeine discrimination and caffeine plasma levels

Rats, trained to discriminate 32 mg/kg caffeine from saline in a two-lever operant task, were tested for the presence of caffeine-appropriate lever responding at various intervals after the intraperitoneal injection of 32 mg/kg caffeine. Following completion of all behavioral tests, caffeine plasma levels were determined in the same animals at the same intervals after caffeine administration. After injection, both caffeine levels and caffeine-appropriate responding showed rapid increases followed by a differential decline.