Biomedical subjects

S L Andersen

Publications and source records attributed to S L Andersen.

At least 37 records · Page 2Linked to original sources

PubMed1997

Sex differences in dopamine receptor overproduction and elimination.

Density of dopamine D1 and D2 family receptors was assessed using autoradiography in male and female rats from 25 to 120 days of age, focusing on transitions through puberty into full adulthood. Males had greater overproduction (approximately 4.6-fold) and elimination of striatal D1 and D2 receptors than females, though their adult densities were very similar. Males had more extensive overproduction of D1 receptors in nucleus accumbens and sustained a greater density into adulthood (57.8 +/- 21.2%). These results have implications for understanding gender differences in the prevalence of clinical disorders associated with dopamine.

Animals↗

PubMed1997

Developmental differences in dopamine synthesis inhibition by (+/-)-7-OH-DPAT.

Dopamine synthesis modulation by the D2-family agonist (+/-)-7-OH-DPAT was explored in striatum, accumbens, and prefrontal cortex of 10-40 day old rats using the gamma-butyrolactone (GBL) autoreceptor model. GBL produced an age-dependent increase in dopamine synthesis that was inhibited by (+/-) 7-OH-DPAT (0.1-13.5 mg/kg) at all ages and antagonized by eticlopride in the nucleus accumbens and striatum. The ID50 of (+/-) 7-OH-DPAT increased with age, suggesting decreased autoreceptor sensitivity with maturation. In prefrontal cortex, (+/-) 7-OH-DPAT inhibited synthesis between 10-30 days, with no evidence of autoreceptor function at 40 days. Dopamine synthesis was also inhibited with the D3/D2 agonist quinpirole at 15 days of age in vivo and yielded similar results to those obtained with (+/-) 7-OH-DPAT. Finally, under conditions that result in low D2 receptor affinity, D3 specificity was examined in vitro at 15 days with (+/-) 7-OH-DPAT, which produced comparable (yet more potent) effects to those observed in vivo. These findings illustrate D3 autoreceptor-like activity in ascending dopamine regions and provide further support for transient prefrontal cortex autoreceptor-like function that recedes by puberty.

Age Factors↗

PubMed1996

Development of an affordable hi-resolution activity monitor system for laboratory animals.

We describe a hardware and software system for recording and analyzing the spatial and temporal pattern of locomotor activity of laboratory animals. The system offers maximal spatial resolution 500-fold greater than existing light beam monitors. An infrared motion analysis systems (MacReflex, Qualysis) simultaneously tracks the location of up to 20 subjects (identified by reflective markers) to within 0.04 mm at a rate of up to 50 Hz. Macintosh software provides measures of distance traveled, amount of area traversed, number of position changes (microevents), average time between movements, number of left and right turns, number of forward movements and reversals, as well as temporal and spatial scaling exponents. This system was validated by comparing these parameters to direct observer scoring of video tapes and other commercially available activity monitors. Our findings show that applying reflective markers to the subjects does not significantly alter activity levels. The effect of pharmacological manipulation with d-amphetamine is provided to show the value of the different activity parameters. The main advantages of this system are very high spatial resolution, capacity to monitoring up to 20 animals simultaneously at reasonable cost, and lack of sensitivity of the system to ambient lighting. The main limitation is the need to apply reflective markers.

Animals↗

PubMed1996

Effects of (-)-sulpiride on dopamine release in striatum of developing rats: degree of depolarization influences responsiveness.

The purpose of this study was to determine the effects of localized delivery of the D2 antagonist (-)-sulpiride (via microdialysis) on spontaneous and evoked dopamine release in the neostriatum of urethane-anesthetized rats 5, 10, 15, 21, and 70 days of age. Sulpiride increased spontaneous dopamine release approximately threefold relative to baseline measures, and this effect decreased with maturation. The relationship between sulpiride- and potassium-evoked release was complex; sulpiride increased evoked dopamine outflow at 5, 10, and 15 days of age. At 21 and 70 days of age, however, the effects of sulpiride were inversely related to the degree of stimulation with potassium. Furthermore, the D2 agonist quinpirole (100 microM) reversed the effects of sulpiride (10 microM), suggesting receptor mediation. These experiments demonstrate that the maturational decline in the efficacy and potency of D2 antagonism appears to be related to the degree of stimulation at the nerve terminal.

Aging↗

PubMed1996

Leadership and change management.

The purpose of this article is to understand that the reason so many programs fall short in addressing and improving competitiveness is that their single focus is on information technology, to instill in our minds that there are many other elements of change that need to be considered (behavior being one), and to present an overview of the motor, the motive, and the mirror that drive behavior and its characteristics.

Behavior↗

PubMed1995

Evidence for dopamine receptor pruning between adolescence and adulthood in striatum but not nucleus accumbens.

Postnatal development of dopamine D1 and D2 receptor families in striatum and nucleus accumbens of rats was studied at 25, 35, 40, 60, 80, 100 and 120 days using autoradiography. These ages were selected to test the hypothesis that dopamine receptors were overproduced prior to puberty (day 40), and pruned back to adult levels thereafter. This hypothesis was confirmed in striatum but not nucleus accumbens. D1 receptor Bmax ([3H]SCH-23390) peaked at 40 days, with levels 67 +/- 21% greater than at 25 days. However, Bmax levels were at least 35% lower at 60-120 days than at 40 days. Similarly, D2 receptor numbers ([3H]YM-09151-2) increased 144 +/- 26% between 25 and 40 days, but were reduced by 34-38% between 60-120 days. In contrast, D1 and D2 receptor Bmax increase approximately 150% between 25 and 40 days in nucleus accumbens, levels fell slightly at 60 or 80 days, but were no different at 100 and 120 days then they were at 40 days. These findings suggest that these two major dopamine target regions follow different developmental strategies, and this has implications for etiological theories of schizophrenia that focus on anomalous receptor pruning.

Aging↗

PubMed1995

Development of an animal model of fluoxetine akathisia.

1. Akathisia describes the pattern of intense inner restlessness often associated with neuroleptic and antidepressant treatment. 2. The authors postulated that drug-induced akathisia would be characterized by more position changes and less time spent immobile, in the absence of significant increase in ambulation. In contrast, a psychomotor stimulant would produce both activation and ambulation. 3. Procedures and instruments were developed to test this hypothesis. Adult rats were habituated for 72 hours to the testing environment, and their precise pattern of movements was tracked and recorded (10 reading per second; resolution 0.04 mm) by an infrared motion analysis system. Activity was recorded for a 90 min period after a single injection of sub-stereotypic doses of d-amphetamine (0, 0.3, 1.0 mg/kg) or racemic fluoxetine (0, 3.0, 10.0, 20.0, or 30.0 mg/kg, s.c.). 4. Amphetamine produced both activation and ambulation. Activation was indicated by a decrease in time spent immobile, and an increase in the temporal scaling exponent, which reflects the degree the animal is "acting' in its environment, and the number of position changes. Enhanced locomotion was inferred from marked increases in both the total distance traversed and the ratio of forward movements-to-reversals and a decrease in the spatial scaling exponent, indicative of a less complex and more linear movement pattern. 5. Fluoxetine caused animals to spend more time active, but exerted little effect on locomotion. Activation was indicated by a decrease in time spent immobile and an increase in the temporal scaling exponent and number of position changes. Fluoxetine failed to significantly effect either the ratio of forward movements-to-reversals or the spatial scaling exponent. 6. These findings provide an operational definition and methodology that can be used to differentiate between psychostimulant effects and akathisic effects. This approach may have utility for screening drugs for akathisic potential, for exploring underlying mechanisms, and for developing novel treatments.

Akathisia, Drug-Induced↗

PubMed1995

Activity of azithromycin as a blood schizonticide against rodent and human plasmodia in vivo.

We compared the efficacy of azithromycin to the clinical antimalarial doxycycline in Plasmodium berghei-infected mice and in P. falciparum-infected Aotus monkeys. When mice were administered drug orally twice a day for three days, the minimum total dose of azithromycin that cured all mice was 768 mg/kg. Doxycycline at a dose of 1,536 mg/kg cured no mice. The efficacy of fast-acting blood schizonticides (quinine, halofantrine, artemisinin) against P. berghei was augmented by azithromycin. In monkey experiments in which there were two animals per experimental group, azithromycin (100 mg/kg/day for seven days) eliminated parasitemia; azithromycin (30 mg/kg/day) initially cleared 99.8-100% of the parasites with recrudescence in the one completely cleared case. Doxycycline (30 mg/kg/day) cleared 100% of the parasites with recrudescence in both cleared cases. Since azithromycin can be clinically administered at a somewhat higher daily dosage than doxycycline, the data suggest that it may be possible to replace drugs of the tetracycline class with azithromycin in combination with fast-acting blood schizonticides for the treatment of P. falciparum infection.

Administration, Oral↗

PubMed1995

Assessing and developing team effectiveness.

Introduction of new decision-oriented information technology, a powerful means of improving competitive performance, can be viewed as one of six elements of culture change. By creating more knowledgeable employees, old hierarchical norms become counterproductive. This demands upgrading job descriptions, collaborative skills, cross-functional networking, pay and progression systems, and leadership styles.

Attitude↗

PubMed1994

Azithromycin prophylaxis against a chloroquine-resistant strain of Plasmodium falciparum.

Azithromycin has antimalarial activity and favourable pharmacokinetic properties for a prophylactic antimalarial agent. We investigated the ability of azithromycin to prevent malaria in volunteers infected with a chloroquine-resistant strain of Plasmodium falciparum. 4 volunteers received oral azithromycin 500 mg followed by 250 mg daily for 7 further days. Subjects were infected on the third day of azithromycin. 3 subjects were protected compared with none of 15 controls. The volunteer not protected by azithromycin had unquantifiable plasma levels of azithromycin, probably because of poor absorption. Azithromycin could be a promising prophylactic agent for P falciparum malaria.

Administration, Oral↗

PubMed1994

The development of D2 autoreceptor-mediated modulation of K(+)-evoked dopamine release in the neostriatum.

A within-subject dose-response analysis was conducted by locally perfusing increasing concentrations (0.1, 1, 10 and 100 microM) of the selective D2 agonist quinpirole via a microdialysis probe into the neostriatum of urethane-anesthetized rat pups 5, 10-11, 15-16 and 21-22 days of age and adult rats. In Expt. 1, K(+)-evoked dopamine release was significantly decreased by quinpirole relative to the vehicle control group for each age in a dose-dependent manner. The maximum effect of quinpirole was not influenced by acute tolerance or the length of the experiment (Expt. 2). Finally, the effect of quinpirole (10 microM) was blocked by the addition of the selective D2 antagonist (-)-sulpiride (100 microM) to the perfusion solution (Expt. 3). These results support and extend previous research that suggests that presynaptic D2 autoreceptors in the neostriatum are able to modulate K(+)-evoked dopamine release in vivo by postnatal day 5 in the rat.

Aging↗

PubMed1994

The ontogeny of apomorphine-induced alterations of neostriatal dopamine release: effects on potassium-evoked release.

The effects of apomorphine (0.05, 0.1, and 1.0 mg/kg, s.c.) on K(+)-evoked dopamine release were studied through the use of in vivo microdialysis in the neostriatum of developing and adult rats. Fifteen-minute samples were collected from urethane-anesthetized rats 5, 10-11, 21-22, 35-36 days of age, and adults, and quantified by high performance liquid chromatography with electrochemical detection. Apomorphine attenuated K(+)-evoked dopamine release in all age groups, suggesting that the dopamine autoreceptor modulating release in the neostriatum is functional by 5 days of age. A dose-response effect of apomorphine was observed in all age groups except at 5 and 10 days of age. Absolute levels of extracellular dopamine were significantly lower at 5 and 10 days of age compared with the other ages, and the effectiveness of a high-K+ artificial cerebrospinal fluid to evoke dopamine release increased with age.

Aging↗

PubMed1994

Calcium dependency and tetrodotoxin sensitivity of neostriatal dopamine release in 5-day-old and adult rats as measured by in vivo microdialysis.

The calcium dependency and tetrodotoxin sensitivity of extracellular dopamine levels were assessed by microdialysis in the neostriatum of 5-day-old rat pups and were compared with those obtained in adult rats. The removal of calcium from the dialysate reduced spontaneous levels of extracellular dopamine to 20% of normal in the 5-day-old pups and to 10% of normal in the adults. Calcium-free dialysate also decreased potassium-evoked dopamine release to approximately 20% of baseline in both ages. Furthermore, the addition of tetrodotoxin to the dialysate decreased spontaneous levels of extracellular dopamine to 10% of baseline in both ages. The effects of calcium removal and the addition of tetrodotoxin on extracellular levels of the dopamine metabolite 3,4-dihydroxyphenylacetic acid were less pronounced. The results of this study demonstrate that extracellular levels of dopamine sampled by microdialysis in rats as young as 5 days of age are both calcium dependent and tetrodotoxin sensitive; thus, they are derived from neuronal activity and not from injury caused by acute implantation of the probe. Other age-related differences support the hypothesis that dopamine release and turnover is greater in immature rats and may represent a form of compensation for incomplete dopamine nerve terminal ingrowth.

3,4-Dihydroxyphenylacetic Acid↗

PubMed1994

Antimalarial activity of WR 243251, a Dihydroacridinedione.

WR 243251 is a dihydroacridinedione that was evaluated for antimalarial blood schizonticidal activity in vitro and in vivo. The in vitro doses calculated to kill 50% of organisms were 11 nM for a chloroquine-susceptible, mefloquine-resistant standard strain and 25 nM for a chloroquine- and pyrimethamine-resistant standard strain. The total dose needed to cure 100% of mice infected with a drug-susceptible strain of Plasmodium berghei was 12 to 20 mg/kg of body weight for both oral and subcutaneous administration. The regimen needed to cure 100% of Aotus monkeys infected with Plasmodium falciparum was 8 mg/kg/day for 3 days (chloroquine-susceptible strain) and 16 mg/kg/day for 3 days (chloroquine-resistant strain). The 100% curative doses for Aotus monkeys did not increase for parasites previously exposed to subcurative doses. The absolute value of the curative doses of WR 243251 was comparable to or lower than the values for clinical antimalarial agents. The high absolute activity, comparability of activities against susceptible and resistant parasites, and inability to induce resistance by exposure to subcurative doses suggest that WR 243251 has strong potential as a blood schizonticidal agent.

Acridines↗

PubMed1994

Efficacy of azithromycin as a causal prophylactic agent against murine malaria.

The efficacy of the newly marketed azalide azithromycin was compared with that of the clinical agent doxycycline in a murine model of sporozoite-induced malaria. Drug was administered once; Plasmodium yoelii sporozoites were administered 2 h later; survival at day 60 was determined. For parenterally administered drug, 160 mg of azithromycin or doxycycline per kg of body weight was 100% effective; 40 mg of azithromycin per kg was 80% effective, but 40 mg of doxycycline per kg was 40% effective. Orally administered azithromycin was somewhat less effective than parenterally administered drug, consistent with the 37% clinical oral bioavailability of this agent. For orally administered azithromycin, 160 mg/kg was 100% effective and 40 mg/kg was 40% effective. The efficacy of azithromycin in comparison with that of doxycycline and the known prolonged levels of azithromycin in the livers of humans suggest that azithromycin has potential as a clinical causal prophylactic agent for malaria.

Animals↗

PubMed1994

In vitro activity of bisquinoline WR268,668 against African clones and isolates of Plasmodium falciparum.

The in vitro activity of a new bisquinoline, WR268,668, was determined against chloroquine-susceptible and chloroquine-resistant African clones and isolates of Plasmodium falciparum using an isotopic semimicro drug susceptibility assay. The chloroquine-resistant clone (mean 50% inhibitory concentration [IC50] = 61.2 nM) was 11 times less susceptible to WR268,668 than the chloroquine-susceptible clone (IC50 = 5.75 nM). A similar result was obtained with fresh clinical isolates, with the chloroquine-susceptible isolates (IC50 = 5.36 nM, n = 11) being significantly (P < 0.05) more susceptible to WR268,668 than the chloroquine-resistant isolates (IC50 = 16.1 nM, n = 18). The compound WR268,668 exhibited a high activity against some moderately chloroquine-resistant isolates. There was a significant positive correlation between the in vitro responses to chloroquine and WR268,668 (r = 0.904, P < 0.05). Combinations of WR268,668 and desipramine, a chloroquine efflux inhibitor, showed that resistance to WR268,668 can be reversed against the chloroquine-resistant clone and that desipramine has no effect on the activity of WR268,668 against the chloroquine-susceptible clone. The results of the study indicate the presence of cross-resistance between chloroquine and WR268,668, and suggest that the basis of resistance to WR268,668 may be similar to that of other 4-aminoquinolines.

Africa↗

PubMed1993

Mu and kappa opioid systems modulate responses to cutaneous perioral stimulation in the fetal rat.

The prenatal ontogeny of functional mu and kappa opioid systems was investigated in a series of four experiments conducted with rat fetuses on the last day of gestation (E21). Fetal motor activity and responsiveness to cutaneous stimulation were measured following administration of various opioid agonists, including morphine, DAMGO, U69,593, and U50,488. The effectiveness of selective mu (CTOP) and kappa (nor-binaltorphimine) antagonists to block the effects of opioid agonists, and the effects of combined administration of DAMGO and U69,593, also were assessed. These experiments provide evidence that both mu and kappa opioid systems are functional and are capable of modulating fetal behavior during the late prenatal period. The data also suggest that different subclasses of kappa receptors may mediate different aspects of fetal behavior. These findings suggest a role for endogenous opioids in regulating important aspects of perinatal behavior, including the development of suckling, maternal-infant interaction and early learning at the nipple.

Animals↗

PubMed1993

Modulation of dopamine binding in the fetal rat: effects of milk and exogenous opioid manipulation.

Presentation of milk to the newborn rat promotes changes in sensory and motor behavior and concomitant changes in both endogenous opioid and dopamine systems. The present study employed an in vivo binding technique with a tritiated ligand for the D2 receptor ([3H]raclopride) to examine the effects of intraoral milk infusion and opioid manipulations on dopamine activity in the term rat fetus (E21). In Experiment 1, fetuses received a series of milk infusion, which resulted in decreased occupancy at D2 receptors by the endogenous ligand, dopamine, in striatal, septal, and hypothalamic brain regions. In Experiment 2, fetuses were pretreated with morphine, the mu-agonist [D-Ala2,NMe-Phe4,Gly5-ol]-enkephalin (DAMGO), the kappa-agonist U50,488, or saline. Opioid manipulations had no effect on binding at D2 receptors. These results confirm that intraoral milk infusion can modulate activity in the dopamine system of the near-term fetal rat.

Animals↗