Biomedical subjects

John F Bowyer

Publications and source records attributed to John F Bowyer.

3 recordsLinked to original sources

PubMed2003

Plasma levels of parent compound and metabolites after doses of either d-fenfluramine or d-3,4-methylenedioxymethamphetamine (MDMA) that produce long-term serotonergic alterations.

Plasma levels of parent compounds and metabolites were determined in adult rhesus monkeys after doses of either 5mg/kg d-fenfluramine (FEN) or 10mg/kg d-3, 4-methylenedioxymethamphetamine (MDMA) i.m. twice daily for four consecutive days. These treatment regimens have been previously shown to produce long-term serotonin (5-HT) depletions. Peak plasma levels of 2.0+/-0.4 microM FEN were reached within 40min after the first dose of FEN, and then declined rapidly, while peak plasma levels (0.4+/-0.1 microM) of the metabolite norfenfluramine (NFEN) were not reached until 6h after dosing. After the seventh (next to last) dose of FEN, peak plasma levels of FEN were 35% greater than after the first dose while peak NFEN-levels were 500% greater. The t(1/2) for FEN was 2.6+/-0.3h after the first dose and 3.2+/-0.2h after the seventh. The estimated t(1/2) for NFEN was more than 37.6+/-20.5h. Peak plasma levels of 9.5+/-2.5 microM MDMA were reached within 20min after the first dose of MDMA, and then declined rapidly, while peak plasma levels (0.9+/-0.2 microM) of the metabolite 3,4-methylenedioxyamphetamine (MDA) were not reached until 3-6h after dosing. After the seventh (next to last) dose of MDMA, peak plasma levels of MDMA were 30% greater than the first dose while peak MDA levels were elevated over 200%. The t(1/2) for MDMA was 2.8+/-0.4h after the first and 3.9+/-1.1h after the seventh dose. The estimated t(1/2) for MDA was about 8.3+/-1.0h. Variability in plasma levels of MDMA and MDA between subjects was much greater than that for FEN and NFEN. This variability in MDMA and MDA exposure levels may have lead to variability in the subsequent disruption of some behaviors seen in these same subjects. There were 80% reductions in the plasma membrane-associated 5-HT transporters 6 months after either the FEN or MDMA dosing regimen indicating that both treatments produced long-term serotonergic effects.

Animals↗

PubMed2003

A statistical approach in using cDNA array analysis to determine modest changes in gene expression in several brain regions after neurotoxic insult.

Modest changes in gene expression of three-fold or less might be expected after mild to moderate neurotoxic exposure to classes of compounds, such as the substituted amphetamines, or at time points that are weeks after more severe neurotoxic exposures. When many genes appear to change expression by less than two-fold, it is crucial to run several pairs of arrays and use statistical analysis to determine which genes are really changing. This limits the number of genes that have to undergo the time consuming task of performing RT-PCR to validate change in expression levels. We describe here methods for statistically determining which genes are being expressed above background levels. These methods are used to compare expression differences among the striatum, parietal cortex, posterior lateral amygdaloid nucleus, and substantia nigra brain regions, all of which differ significantly in their gene expression profiles. In these comparisons, it was possible to distinguish differences among hundreds of genes with manageable estimated false discovery rates. The effect of amphetamine treatment on gene expression in posterior lateral amygdaloid nucleus was also evaluated. The expression data indicate that many genes have changed, but in this case it is more difficult to separate affected genes from false positives. The optimum list has 50 genes, of which 32% are expected to be false positives.

Amphetamine↗

PubMed2002

Parvalbumin neuron circuits and microglia in three dopamine-poor cortical regions remain sensitive to amphetamine exposure in the absence of hyperthermia, seizure and stroke.

The dopamine-releasing and depleting substance amphetamine (AMPH) can make cortical neurons susceptible to damage, and the prevention of hyperthermia, seizures and stroke is thought to block these effects. Here we report a 2-day AMPH treatment paradigm which affected only interneurons in three cortical regions with average or below-average dopamine input. AMPH (six escalating doses/day ranging from 5 to 30 mg/kg for 2 days) was given at 17-18 degrees C ambient temperature (T) to adult male rats. During the 2-day AMPH treatment, peak body T stayed below 38.9 degrees C in 40% of the AMPH treated rats. In 60% of the rats, deliberate cooling suppressed (<39.5 degrees C) or minimized (<40.0 degrees C) hyperthermia. Escalation of stereotypes to seizure-like behaviors was rare and post-mortem morphological signs of stroke were absent. Neurons labeled with the anionic, neurodegeneration-marker dye Fluoro-Jade (F-J) were seen 1 day after dosing, peaked 3 days later, but were barely detectable 14 days after dosing. Only nonpyramidal neurons in layer IV of the somatosensory barrel cortex and in layer II of the piriform cortex and posterolateral cortical amygdaloid nucleus were labeled with Fluoro-Jade. Isolectin B-labeled activated microglia were only detected in their neighborhood. F-J labeled neurons were extremely rare in cortical regions rich in dopamine (e.g. cingulate cortex), and were absent in cortical regions with no dopamine (e.g. visual cortex). Parvalbumin was seen in some Fluoro-Jade-labeled neurons and parvalbumin immunostaining in local axon plexuses intensified. This AMPH paradigm affected fewer cortical regions, and caused smaller reduction in striatal tyrosine hydroxylase (TH) immunoreactivity than previous 1-day AMPH regimens generating seizures or severe (above 40 degrees C) hyperthermia. Correlation between peak or mean body T and the extent of neurodegeneration or microgliosis was below statistical significance. Astrogliosis (elevated levels of the astroglia-marker, glial fibrillary acidic protein (GFAP)) was detected in many brain regions. In the striatum and midbrain, F-J labeled neurons and activated microglia were absent, but astrogliosis, decreased TH immunolabel, and swollen TH fibers were detected. In sum, after this AMPH treatment, cortical pyramidal neurons were spared, but astrogliosis was brain-wide and some interneurons and microglia in three cortical regions with average or below-average dopamine input remained sensitive to AMPH exposure.

Amphetamine↗