Platelet 3H-paroxetine binding to the serotonin transporter is insensitive to changes in central serotonergic innervation in the rat

Moret, Chantal; Briley, Mike

doi:10.1016/0165-1781(91)90035-n

Cited by 36 publications

(10 citation statements)

References 31 publications

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“…The filters were then washed repeatedly, and radiolabeling was determined. For binding to the presynaptic 5HT transporter (5HTT) (McGrath et al 1997;Moret and Briley 1991;Slotkin et al 1999b;Xu et al 2001), the membrane suspension was incubated with 85 pM [ 3 H]paroxetine (specific activity, 19.4 Ci/mmol; Perkin-Elmer) with or without addition of 100 µM 5HT to displace specific binding. Incubations lasted 120 min at 20°C.…”

Section: Methodsmentioning

confidence: 99%

Developmental exposure to chlorpyrifos elicits sex-selective alterations of serotonergic synaptic function in adulthood: critical periods and regional selectivity for effects on the serotonin transporter, receptor subtypes, and cell signaling.

Aldridge

Seidler

Slotkin

2004

Environ Health Perspect

146

175

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During brain development, serotonin (5HT) provides essential neurotrophic signals, and in earlier work, we found that developmental exposure to chlorpyrifos (CPF) elicits short-term changes in 5HT systems. In the present study, we evaluated the effects in adulthood after CPF exposures from the neural tube stage [gestational days (GD) 9-12] and the late gestational period (GD17-20) through postnatal neuronal differentiation and synaptogenesis [postnatal days (PN) 1-4 and 11-14], using treatments below the threshold for systemic toxicity. With exposure on GD9-12, CPF elicited global elevations in 5HT 1A and 5HT 2 receptors and in the 5HT presynaptic transporter. The GD17-20 treatment elicited larger effects that displayed selectivity for regions with 5HT nerve terminals and that were preferential for males. Although similar receptor up-regulation was seen after PN1-4 exposure, the effects were larger in regions with 5HT cell bodies; in addition, the presynaptic transporter was down-regulated in the nerve terminal zones of females. The PN11-14 exposure had much smaller effects on receptors but still elicited transporter suppression with the same regional and sex selectivity. Although CPF exposure on GD17-20, PN1-4, or PN11-14 altered the ability of 5HT to modulate adenylyl cyclase, this change did not correspond with the effects on 5HT receptors, suggesting an additional set of effects on proteins that transduce the 5HT signal. Our results indicate that CPF elicits long-lasting changes in 5HT receptors, the presynaptic 5HT transporter, and 5HT-mediated signal transduction after exposure in discrete developmental windows that range from the neural tube stage through synaptogenesis. These effects are likely to contribute to neurobehavioral teratology of CPF. Key words: adenylyl cyclase, brain development, chlorpyrifos, organophosphate insecticides, serotonin receptors, serotonin transporter, sex-selective effects.

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Section: Methodsmentioning

confidence: 99%

Developmental exposure to chlorpyrifos elicits sex-selective alterations of serotonergic synaptic function in adulthood: critical periods and regional selectivity for effects on the serotonin transporter, receptor subtypes, and cell signaling.

Aldridge

Seidler

Slotkin

2004

Environ Health Perspect

146

175

View full text Add to dashboard Cite

show abstract

“…The filters were then washed repeatedly, and radiolabel was determined. For binding to the presynaptic 5HTT (Moret and Briley 1991;Slotkin et al 1997Slotkin et al , 1999bSlotkin et al , 2000Xu et al 2001), the membrane suspension was incubated with 85 pM [ 3 H]paroxetine (specific activity, 19.4 Ci/mmol; PerkinElmer) with or without addition of 100 µM 5HT to displace specific binding. Incubations lasted 120 min at 20°C.…”

Section: Methodsmentioning

confidence: 99%

Serotonergic systems targeted by developmental exposure to chlorpyrifos: effects during different critical periods.

Aldridge

Seidler

Meyer

et al. 2003

Environ Health Perspect

128

124

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During brain development, serotonin (5HT) provides essential neurotrophic signals. In the present study, we evaluated whether the developmental neurotoxicity of chlorpyrifos (CPF) involves effects on 5HT signaling, as a potential mechanism underlying noncholinergic neuroteratogenic events. We evaluated four different treatment windows ranging from the neural tube stage [gestational days (GD) 9-12] and the late gestational period (GD17-20) through postnatal phases of terminal neuronal differentiation and synaptogenesis [postnatal days (PN) 1-4, PN11-14]. Exposure to CPF on GD9-12 elicited initial suppression, immediately followed by rebound elevation, of 5HT 1A and 5HT 2 receptors as well as the 5HT transporter, all at doses below the threshold for cholinergic hyperstimulation and the resultant systemic toxicity. In contrast, with GD17-20 exposure, the initial effect was augmentation of all three components by low doses of CPF. Sensitivity of these effects declined substantially when exposure was shifted to the postnatal period. We also identified major alterations in 5HT-mediated responses, assessed for the adenylyl cyclase signaling cascade. Although GD9-12 exposure had only minor effects, treatment on GD17-20 elicited supersensitivity to both stimulatory and inhibitory responses mediated by 5HT. Our results indicate that CPF affects 5HT receptors, the presynaptic 5HT transporter, and 5HT-mediated signal transduction during a discrete critical gestational window. These effects are likely to contribute to the noncholinergic component of CPF's developmental neurotoxicity.

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“…The filters were then washed repeatedly and radiolabel was determined. For binding to the presynaptic 5HTT [46,70,71,76,90], the membrane suspension was incubated with 85 pM [ 3 H]paroxetine (PerkinElmer; specific activity 19.4 Ci/mmol) with or without addition of 100 μM 5HT to displace specific binding, and incubations lasted 120 min at 20° C. Binding was calculated relative to membrane protein.…”

Section: Assaysmentioning

confidence: 99%

Developmental neurotoxicity of low dose diazinon exposure of neonatal rats: Effects on serotonin systems in adolescence and adulthood

Slotkin

Ryde

Levin

et al. 2008

Brain Research Bulletin

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The developmental neurotoxicity of organophosphate pesticides targets serotonin (5HT) systems, which are involved in emotional and appetitive behaviors. We exposed neonatal rats to daily doses of diazinon on postnatal days 1-4, using doses (0.5 or 2 mg/kg) spanning the threshold for barelydetectable cholinesterase inhibition. We then evaluated the effects on 5HT 1A and 5HT 2 receptors, and on the 5HT transporter in cerebral cortical regions and the brainstem in adolescence through adulthood. Diazinon evoked a lasting deficit in 5HT 1A receptors in males only, whereas it caused a small but significant increase in 5HT transporters in females; neither effect showed a significant regional selectivity. This pattern differed substantially from that seen in earlier work with another organophosphate, chlorpyrifos, which at pharmacodynamically similar doses spanning the threshold for cholinesterase inhibition, evoked a much more substantial, global upregulation of 5HT receptor expression; with chlorpyrifos, effects on receptors were seen in females, albeit to a lesser extent than in males, and were also regionally distinct. The effects of diazinon were nonmonotonic, showing larger alterations at the lower dose, likely reflecting positive trophic effects of cholinergic stimulation once the threshold for cholinesterase inhibition is exceeded. Our results reinforce the idea that different organophosphates have fundamentally distinct effects on the developmental trajectories of specific neurotransmitter systems, unrelated to their shared action as cholinesterase inhibitors. The effects on 5HT circuits expands the scope of behavioral endpoints that need to be considered in evaluating the developmental neurotoxicity of organophosphates.

show abstract

Platelet 3H-paroxetine binding to the serotonin transporter is insensitive to changes in central serotonergic innervation in the rat

Cited by 36 publications

References 31 publications

Developmental exposure to chlorpyrifos elicits sex-selective alterations of serotonergic synaptic function in adulthood: critical periods and regional selectivity for effects on the serotonin transporter, receptor subtypes, and cell signaling.

Developmental exposure to chlorpyrifos elicits sex-selective alterations of serotonergic synaptic function in adulthood: critical periods and regional selectivity for effects on the serotonin transporter, receptor subtypes, and cell signaling.

Serotonergic systems targeted by developmental exposure to chlorpyrifos: effects during different critical periods.

Developmental neurotoxicity of low dose diazinon exposure of neonatal rats: Effects on serotonin systems in adolescence and adulthood

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