Comparison of the maturation of the adrenergic and serotonergic neurotransmitter systems in the brain: implications for differential drug effects on juveniles and adults.

Our understanding of the development of neurotransmitter systems in the central nervous system has increased greatly over the past three decades and it has become apparent that drug effects on the developing nervous system may differ considerably from effects on the mature nervous system. Recently it has become clear there are significant differences in the effectiveness of antidepressant drug classes in children and adolescents compared to adults. Whereas the selective serotonin reuptake inhibitors are effective in treating all ages from children to adults, the tricyclic antidepressants, many of which inhibit norepinephrine reuptake, have been shown to be ineffective in treating children and adolescents even though they are effective in adults. We review here the development of the noradrenergic and serotonergic nervous systems, both in terms of neurotransmitter system markers and function. Both of these neurotransmitter systems are primary targets of antidepressant medications as well as of central nervous system stimulants. It is clear from a comparison of their development that the serotonin system reaches maturity much earlier than the norepinephrine system. We suggest this may help explain the differences in response to antidepressants in children and adolescents compared to adults. In addition, these differences suggest that drugs acting preferentially on either neurotransmitter system may impact the normal course of CNS development at different time points. Consideration of such differences in the development of neurotransmitter systems may be of significance in optimizing treatments for a variety of centrally mediated disorders.

Analysis of brain adrenergic receptors in dopamine-beta-hydroxylase knockout mice.

The biosynthesis of norepinephrine occurs through a multi-enzymatic pathway that includes the enzyme dopamine-beta-hydroxylase (DBH). Mice with a homozygous deletion of DBH (Dbh-/-) have a selective and complete absence of norepinephrine. The purpose of this study was to assess the expression of alpha-1, alpha-2 and beta adrenergic receptors (alpha1-AR, alpha2-AR and beta-AR) in the postnatal absence of norepinephrine by comparing noradrenergic receptors in Dbh-/- mice with those in Dbh heterozygotes (Dbh+/-), which have normal levels of norepinephrine throughout life. The densities of alpha1-AR, alpha2-AR and beta-AR were assayed with [3H]prazosin, [3H]RX21002 and [125I]-iodo-pindolol autoradiography, respectively. The alpha2-AR agonist high affinity state was examined with [125I]-para-iodoclonidine autoradiography and alpha2-AR functionality by alpha2-AR agonist-stimulated [35S]GTPgammaS autoradiography. The density of alpha1-AR in Dbh-/- mice was similar to Dbh+/- mice in most brain regions, with an up-regulation in the hippocampus. Modest decreases in alpha2-AR were found in septum, hippocampus and amygdala, but these were not reflected in alpha2-AR functionality. The density of beta-AR was up-regulated to varying degrees in many brain regions of Dbh-/- mice compared to the heterozygotes. These findings indicate that regulation of noradrenergic receptors by endogenous norepinephrine depends on receptor type and neuroanatomical region.

A transient expression of functional alpha2-adrenergic receptors in white matter of the developing brain.

Norepinephrine is a neurotransmitter with peripheral and central actions mediated by alpha-1, alpha-2, and beta-adrenergic receptors. In this paper, we report an expression of alpha-2 adrenergic receptors in developing white matter tracts as revealed by [(3)H]RX821002 autoradiography. In rats, these receptors are present in the corpus callosum and anterior commissure at gestational day 20. Quantification of their postnatal expression reveals peak expression in the corpus callosum at postnatal day 1, which decreases with maturation and disappears by postnatal day 21. Expression in the anterior commissure is persistently elevated throughout the first ten days of postnatal development and then decreases to near background levels by postnatal day 21. Further characterization of the receptors by agonist-stimulated [(35)S]GTPgammaS binding verifies alpha-2 adrenergic receptors are functionally coupled to G proteins early in development and therefore are mature receptors. In situ hybridization did not detect mRNA for any of the alpha-2 adrenergic receptor subtypes (A, B, and C) in white matter tracts of postnatal day 5 brain. [(3)H]RX821002 emulsion autoradiography demonstrated autoradiographic grains that were of comparable density between cells and over cell bodies. Collectively, these data suggest that alpha-2 adrenergic receptors in neonatal commissures are synthesized at sites distant from their white matter expression and may be guiding the maturation of these brain commissures.