Neurotrophin‐3‐ and norepinephrine‐mediated adrenergic differentiation and the inhibitory action of desipramine and cocaine

Abstract

In the presence of neurotrophin-3 (NT-3), high-affinity norepinephrine (NE) uptake by quail neural crest cells was significantly increased as judged by in vitro colony assay of adrenergic differentiation. In the presence of the related neurotrophins nerve growth factor (NGF) or brain-derived neurotrophic (BDNF) factor, or of basic fibroblast growth factor (bFGF), there were no significant changes. When NE was added to the culture medium in addition to NT-3, more colonies contained dopamine-beta-hydroxylase (DBH)-immunoreactive cells, an enzyme that is characteristic for adrenergic cells. The NE-mediated increase in the portion of colonies that contained DBH-immunoreactive cells was prevented by the tricyclic antidepressant desipramine (DMI) and by cocaine, two types of drug that block cellular transport of NE. To further examine whether NE acts via uptake, colony assays were performed in the presence and absence of adrenergic antagonists and agonists. These would be expected to mimic the DMI and NE effects, respectively, if the mechanism of action involved activation of adrenergic autoreceptors. Neither class of drug showed a detectable effect within a wide range of concentrations. Immunocytochemistry using antibodies against beta 1 and beta 2 adrenergic receptors further supported the notion that DMI action and beta-receptor expression are not causally related. Ratio imaging was subsequently used in an attempt to elucidate the mechanism of NE action. Within a few minutes of addition of NE to the culture medium, there was an increase in intracellular free calcium in a subset of neural crest cells. Taken together, our data indicate that NT-3 is involved in the appearance of the NE transporter (NET) during embryonic development; internalized NE directly or indirectly increases adrenergic differentiation as measured by immunoreactivity of the adrenergic biosynthetic enzyme DBH; and norepinephrine uptake inhibitors have treatogenic potential.

Association between reported venlafaxine use in early pregnancy and birth defects, national birth defects prevention study, 1997–2007

“…Several animal studies have provided specific evi- dence for serotonin acting as a morphogen in craniofacial and cardiac development (Moiseiwitsch and Lauder, 1995;Choi et al, 1997;Moiseiwitsch, 2000;Nebigil et al, 2000;Nebigil and Maroteaux, 2001;Cô té et al, 2007). Studies have also shown that norepinephrine influences neural crest cell formation and differentiation during embryogenesis (Zhang et al, 1997;Sieber-Blum and Ren, 2000;Ren et al, 2001;Ren et al, 2003;Hu et al, 2009). Thus, if venlafaxine is taken during early pregnancy and interferes with these embryologic signaling pathways, it is plausible that venlafaxine could affect craniofacial and cardiac development.…”

Cardiac neural crest stem cells

“…Quail and mouse neural crest cells express NET protein even before onset of their emigration from the neural tube (Ren et al, 2003). NE transport promotes differentiation of neural crest cells (Zhang et al, 1997b) and locus ceruleus cells (Sieber-Blum and Ren, 2000) into noradrenergic neurons. Conversely, drugs that block NE uptake, such as tricyclic antidepressants or cocaine, block noradrenergic differentiation in vitro and in vivo (Sieber-Blum, 1989b;Zhang and Sieber-Blum, 1992;Zhang et al, 1997b;Sieber-Blum and Ren, 2000).…”

“…NE transport promotes differentiation of neural crest cells (Zhang et al, 1997b) and locus ceruleus cells (Sieber-Blum and Ren, 2000) into noradrenergic neurons. Conversely, drugs that block NE uptake, such as tricyclic antidepressants or cocaine, block noradrenergic differentiation in vitro and in vivo (Sieber-Blum, 1989b;Zhang and Sieber-Blum, 1992;Zhang et al, 1997b;Sieber-Blum and Ren, 2000). While NET may not be functional during early neural crest migration, it is known that neural crest cells are capable of NE transport during No NE is delivered to the mesenchymal cells that underlie the epithelium (Ren et al, 2003).…”

Mitogenic and anti‐proliferative signals for neural crest cells and the neurogenic action of TGF‐β1

“…3f). Most of these colonies also contained cells expressing the high affinity norepinephrine transporter Zhang et al, 1997). They are thus thought to be formed by neurogenic cells that reside in a more advanced compartment of differentiation than the colony-forming cells giving rise to flattened unpigmented and mixed colonies.…”