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S L Andersen

Publications and source records attributed to S L Andersen.

At least 19 recordsLinked to original sources
PubMed2001

Maturational increases in c-fos expression in the ascending dopamine systems.

The unique maturational period of adolescence is replete with numerous changes in anatomy and function that may yield clues as to why drug abuse emerges at this stage. The behavioral effects of amphetamine are diminished during periadolescence (35 days) relative to younger (21 days) and older (>60 days) rats, prompting us to examine amphetamine effects on neuronal activation with the immediate early gene, c-fos. Amphetamine (1 and 5 mg/kg, i.p.) increased c-fos immunoreactivity in rats 21, 35, and 60 days of age in a dose-dependent manner. When expressed as a percentage of vehicle for each age, amphetamine-induced effects on c-fos immunoreactivity were higher at 21 days of age compared with the effects at 35 and 60 days of age in the nucleus accumbens core and shell, striatum, and prefrontal cortex. These data provide a possible reason as to why stimulants produce dysphoria in children, before transitioning to euphoria during adolescence. Implications of these results are discussed for stimulant use in a pediatric population and the development of drug abuse.

Age Factors↗
PubMed2000

Synthesis and antimalarial activity of sixteen dispiro-1,2,4, 5-tetraoxanes: alkyl-substituted 7,8,15,16-tetraoxadispiro[5.2.5. 2]hexadecanes.

Sixteen alkyl-substituted dispiro-1,2,4,5-tetraoxanes (7,8,15, 16-tetraoxadispiro[5.2.5.2]hexadecanes) were synthesized to explore dispiro-1,2,4,5-tetraoxane SAR and to identify tetraoxanes with better oral antimalarial activity than prototype tetraoxane 1 (WR 148999). The tetraoxanes were prepared either by peroxidation of the corresponding cyclohexanone derivatives in H(2)SO(4)/CH(3)CN or by ozonolysis of the corresponding cyclohexanone methyl oximes. Those tetraoxanes with alkyl substituents at the 1 and 10 positions were formed as single stereoisomers, whereas the five tetraoxanes formed without the stereochemical control provided by alkyl groups at the 1 and 10 positions were isolated as mixtures of diastereomers. Three of the sixteen tetraoxanes were inactive (IC(50)'s > 1000 nM), but five (2, 6, 10, 11, 12) had IC(50)'s between 10 and 30 nM against the chloroquine-sensitive D6 and chloroquine-resistant W2 clones of Plasmodium falciparum compared to corresponding IC(50)'s of 55 and 32 nM for 1 and 8.4 and 7.3 nM for artemisinin. We suggest that tetraoxanes 13, 16, and 17 were inactive and tetraoxanes 4 and 7 were weakly active due to steric effects preventing or hindering peroxide bond access to parasite heme. Tetraoxanes 1, 10, 11, and 14, along with artemisinin and arteether as controls, were administered po b.i.d. (128 mg/kg/day) to P. berghei-infected mice on days 3, 4, and 5 post-infection. At this dose, tetraoxanes 10, 11, and 14 cured between 40% and 60% of the infected animals. In comparison, artemisinin and tetraoxane 1 produced no cures, whereas arteether cured 100% of the infected animals. There was no apparent relationship between tetraoxane structure and in vitro neurotoxicity, nor was there any correlation between antimalarial activity and neurotoxicity for these seventeen tetraoxanes.

Alkanes↗
PubMed2000

Sex differences in dopamine receptors and their relevance to ADHD.

Gender differences in ADHD may be attributable to gender differences in dopamine receptor density. Striatal male D2 receptor density increases 144+/-26% between 25 and 40 days (the onset of puberty), while female D2 receptor density increases only 31+/-7%. Male receptor density is then sharply eliminated by 55% by adulthood. Periadolescent females show little overproduction and pruning of striatal D1 and D2 receptors, though adult density is similar to males. The rise of male, but not female, striatal dopamine receptors parallels the early developmental appearance of motor symptoms of ADHD and may explain why prevalence rates are 2-4 fold higher in men than women. Pruning of striatal dopamine receptors coincides with the estimated 50-70% remission rate by adulthood. Transient lateralized D2, dopamine receptors (left > right) in male striatum may increase vulnerability to ADHD. More persistent attentional problems may be associated with the overproduction and delayed pruning of dopamine receptors in prefrontal cortex. Differences in D1 receptor density in nucleus accumbens may have implications for increased substance abuse in males.

Aging↗
PubMed2000

Assessment of the antimalarial potential of tetraoxane WR 148999.

The antimalarial peroxide, dispiro-1,2,4,5-tetraoxane WR 148999, was synergistic with chloroquine, quinine, mefloquine, and artemisinin against both D6 and W2 clones of Plasmodium falciparum. In consideration of the contrasting antagonism between artemisinin and chloroquine, these drug combination data imply that WR 148999 and artemisinin may not share a common mechanism of action. For Plasmodium berghei-infected mice given oral, subcutaneous, and intraperitoneal doses of WR 148999 ranging from 2 to 1024 mg/kg in the Thompson test, median survival times were 8.8, 11.8, and 27.5 days, respectively, compared to 8 days for control animals. Using subcutaneous administration, WR 148999 had a considerably longer duration of action than did artemisinin against P. berghei. WR 148999 did not significantly inhibit cytochrome P450 isozymes CYP 2C9, 2C19, 2D6, 2E1, or 3A4 (IC50 >500 microM) but did inhibit CYP 1A2 with an IC50 value of 36 microM, suggesting that WR 148999 may be metabolized by the latter CYP isozyme. These results combined with previous observations that formulation strategies and incorporation of polar functional groups in a series of WR 148999 analogs both failed to enhance tetraoxane oral antimalarial activity suggest that oral bioavailability of tetraoxane WR 148999 is more likely a function of extensive first-pass metabolism rather than solubility-limited dissolution.

Animals↗
PubMed1999

Serotonin laterality in amygdala predicts performance in the elevated plus maze in rats.

Behavior in the elevated plus maze was correlated with hemispheric asymmetries in neurotransmitter content in limbic brain regions assayed with HPLC-EC in adult rats. A strong (r=0.86, p < 0.003) correlation exists between increased anxiety (more time spent in the closed arm) and the lateralization of serotonin in the amygdala. Greater serotonin in the right versus left amygdala relates to greater anxiety. In addition, increased dopamine in right prefrontal cortex is strongly correlated with anxiety (r=0.84, p < 0.01). No such correlations were observed for accumbens, hippocampus, or striatum. These data support the hypothesis that the right hemisphere is involved in emotional states: increased serotonin in the right amygdala is related to anxiety, while cortical dopamine may be associated with attention to the environment.

Amygdala↗
PubMed1999

Degree of neuronal activation following FG-7142 changes across regions during development.

We report that FG-7142 (20 mg/kg) differentially increased c-fos in the prefrontal cortex, nucleus accumbens, and striatum of rats 10, 18, 45, and 100 days of age. FG-7142 selectively activated the cortex in adults (70.7+/-3.0%), but the pattern was stronger in nucleus accumbens (83.4+/-9.8%) in younger subjects. These results are consistent with the delayed maturation of the cortex, and show that stress produces more diffuse effects early in life.

Animals↗
PubMed1999

Influence of body temperature on the development of fatigue during prolonged exercise in the heat.

We investigated whether fatigue during prolonged exercise in uncompensable hot environments occurred at the same critical level of hyperthermia when the initial value and the rate of increase in body temperature are altered. To examine the effect of initial body temperature [esophageal temperature (Tes) = 35.9 +/- 0.2, 37.4 +/- 0. 1, or 38.2 +/- 0.1 (SE) degrees C induced by 30 min of water immersion], seven cyclists (maximal O2 uptake = 5.1 +/- 0.1 l/min) performed three randomly assigned bouts of cycle ergometer exercise (60% maximal O2 uptake) in the heat (40 degrees C) until volitional exhaustion. To determine the influence of rate of heat storage (0.10 vs. 0.05 degrees C/min induced by a water-perfused jacket), four cyclists performed two additional exercise bouts, starting with Tes of 37.0 degrees C. Despite different initial temperatures, all subjects fatigued at an identical level of hyperthermia (Tes = 40. 1-40.2 degrees C, muscle temperature = 40.7-40.9 degrees C, skin temperature = 37.0-37.2 degrees C) and cardiovascular strain (heart rate = 196-198 beats/min, cardiac output = 19.9-20.8 l/min). Time to exhaustion was inversely related to the initial body temperature: 63 +/- 3, 46 +/- 3, and 28 +/- 2 min with initial Tes of approximately 36, 37, and 38 degrees C, respectively (all P < 0.05). Similarly, with different rates of heat storage, all subjects reached exhaustion at similar Tes and muscle temperature (40.1-40.3 and 40. 7-40.9 degrees C, respectively), but with significantly different skin temperature (38.4 +/- 0.4 vs. 35.6 +/- 0.2 degrees C during high vs. low rate of heat storage, respectively, P < 0.05). Time to exhaustion was significantly shorter at the high than at the lower rate of heat storage (31 +/- 4 vs. 56 +/- 11 min, respectively, P < 0.05). Increases in heart rate and reductions in stroke volume paralleled the rise in core temperature (36-40 degrees C), with skin blood flow plateauing at Tes of approximately 38 degrees C. These results demonstrate that high internal body temperature per se causes fatigue in trained subjects during prolonged exercise in uncompensable hot environments. Furthermore, time to exhaustion in hot environments is inversely related to the initial temperature and directly related to the rate of heat storage.

Adult↗
PubMed1998

Bisquinolines. 2. Antimalarial N,N-bis(7-chloroquinolin-4-yl)heteroalkanediamines.

N,N-Bis(7-chloroquinolin-4-yl)heteroalkanediamines 1-11 were synthesized and screened against Plasmodium falciparum in vitro and Plasmodium berghei in vivo. These bisquinolines had IC50 values from 1 to 100 nM against P. falciparum in vitro. Six of the 11 bisquinolines were significantly more potent against the chloroquine-resistant W2 clone compared to the chloroquine-sensitive D6 clone. For bisquinolines 1-11 there was no relationship between the length of the bisquinoline heteroalkane bridge and antimalarial activity and no correlation between in vitro and in vivo antimalarial activities. Bisquinolines with alkyl ether and piperazine bridges were substantially more effective than bisquinolines with alkylamine bridges against P. berghei in vivo. Bisquinolines 1-10 were potent inhibitors of hematin polymerization with IC50 values falling in the narrow range of 5-20 microM, and there was a correlation between potency of inhibition of hematin polymerization and inhibition of parasite growth. Compared to alkane-bridged bisquinolines (Vennerstrom et al., 1992), none of these heteroalkane-bridged bisquinolines had sufficient antimalarial activity to warrant further investigation of the series.

Animals↗
PubMed1998

Progressive accumbens degeneration after neonatal striatal 6-hydroxydopamine in rats.

Parkinson's disease is associated with progressive loss of nigrostriatal dopamine (DA). Models of the disorder, produced with neurotoxins (N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine or 6-hydroxydopamine) that selectively lesion DA neurons, are characterized by acute removal and gradual recovery of DA. We report slowly progressive loss of DA in ipsilateral nucleus accumbens following profound (>90%) acute unilateral depletion of DA in the caudate-putamen of neonatal rats, from 50% at age 27 days to 94% by 100 days. Metabolic turnover of DA markedly increased in ipsilateral accumbens, and may yield tissue-damaging neurotoxic by-products. This paradigm may help in elucidating mechanisms responsible for gradual degeneration of DA neurons and for screening potential neuroprotective agents.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1998

Successful double-blinded, randomized, placebo-controlled field trial of azithromycin and doxycycline as prophylaxis for malaria in western Kenya.

Azithromycin prevents malaria in animal models and early clinical trials. We determined the prophylactic efficacy of three antibiotic regimens given for 10 weeks (azithromycin, 250 mg daily; azithromycin, 1,000 mg weekly; and doxycycline, 100 mg daily) relative to that of placebo for 232 adult volunteers residing in an area of intense malaria transmission. Any confirmed parasitemia during the study was considered a prophylactic failure. Two hundred thirteen volunteers (92%) completed the study. The prophylactic efficacies were as follows: daily azithromycin, 82.7% (95% confidence interval [CI], 68.5%-91.1%); weekly azithromycin, 64.2% (95% CI, 47.1%-77.1%); and daily doxycycline, 92.6% (95% CI, 79.9%-97.5%). All regimens were well tolerated. We concluded that both 100 mg of doxycycline and 250 mg of azithromycin, given daily, were effective as prophylaxis for malaria in this setting. If studies with nonimmune volunteers confirm these results for semi-immune volunteers, a daily azithromycin regimen may have special utility for individuals with contraindications to treatment with doxycycline or other antimalarial agents.

Adolescent↗
PubMed1997

Lack of effect of chronic clorgyline or selegiline on dopamine and serotonin transporters in rat caudate-putamen or nucleus accumbens septi.

Rats were injected intraperitoneally thrice weekly for 4 weeks with doses of selective inhibitors of monoamine oxidase type A (clorgyline, 1 mg/kg) or B ((-)-selegiline, 10 mg/kg), or saline. Both treatments produced sustained elevations of concentrations of dopamine and serotonin, and decreased their deaminated metabolites in forebrain tissue. Nevertheless, no change in binding of [3H]GBR-12935 to the dopamine transporter or of [3H]paroxetine to the serotonin transporter in caudate-putamen or nucleus accumbens septi was found with quantitative autoradiography. These results support the impression that transporter proteins for these monoamines are not regulated by increased ligand abundance.

Animals↗
PubMed1997

The effects of bupropion in vivo in the neostriatum of 5-day-old and adult rats.

Infusion of six concentrations of the dopamine uptake inhibitor bupropion into the neostriatum increased extracellular dopamine in a dose-dependent manner in 5-day-old and adult rats. There was no age-related difference when calculated as a percentage of predrug dopamine baseline levels, but the absolute increase of dopamine was greater in the adult rats. Bupropion had only a minor effect on extracellular levels of DOPAC.

Aging↗
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↗