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  • We found that the postnatal absence of


    We found that the postnatal absence of norepinephrine yields differing effects depending on noradrenergic receptor type and 5-Formyl-CTP region. The density of α1-AR, indicated by [3H]prazosin binding was similar between Dbh+/− and Dbh−/− mice except for a significant increase in hippocampus in Dbh−/− mice, in contrast to α2-AR. The density changes in α2-AR, determined by [3H]RX821002 binding, also were relatively minor in the absence of norepinephrine. There were small decreases in α2-AR density in septum, hippocampus (slm) and amygdala. However, the agonist high-affinity state of α2-AR, examined with [125I]PIC binding, was decreased only in septum and the functional linkage of these receptors, measured by agonist-stimulated [35S]GTPγS binding, was not significantly altered in any brain region examined. These data suggest that the number of α2-AR linked to G proteins remained relatively constant in all brain regions, even though there were small changes in total α2-AR density. In contrast to α1-AR and α2-AR, Dbh−/− mice respond to the developmental absence of norepinephrine by increasing β-AR expression throughout the brain, with 30% increases in cortex and septum and a 50% increase in hippocampus. It is important to note that because DBH catalyzes the conversion of dopamine to norepinephrine, Dbh−/− mice produce and probably release dopamine from their noradrenergic terminals. Therefore, it is possible that dopamine is providing sufficient agonist activity in Dbh−/− mice to maintain normal α1- and α2-AR levels. For example, some α2-AR subtypes have an affinity for dopamine that is comparable to their affinity for norepinephrine (Zhang et al., 1999). In addition, the “ectopic” dopamine in Dbh−/− mice appears to help maintain normal expression of the norepinephrine transporter (Weinshenker et al., 2002b). However, a functional replacement of norepinephrine by dopamine in Dbh−/− mice is unlikely to explain the maintenance of α2-AR levels for three reasons. First, when the selective noradrenergic neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) was used to lesion central noradrenergic neurons in neonatal rats, there was no “ectopic” dopamine and no change in α2-AR density (Sanders et al., 2001) Second, Dbh−/− mice have phenotypes (e.g., seizure susceptibility) that are reversed by α2 agonists (Szot et al., 2004), which would not be expected if endogenous dopamine could bind to and activate α2-AR. Finally, locus coeruleus neurons from Dbh−/− mice completely lack the characteristic α2-AR-mediated autoinhibition observed in locus coeruleus neurons from normal mice, indicating that endogenously released dopamine does not activate α2-AR in locus caeruleus of Dbh−/− mice (C. Paladini and D. Weinshenker, unpublished observation). The affinity of α1-AR and β-AR for dopamine is much lower than for that of norepinephrine, making modulation of these receptors by dopamine highly unlikely (Zhang et al., 2004). Previous studies have investigated the role of norepinephrine in α1-AR, α2-AR and β-AR ontogeny by lesioning the noradrenergic fibers of neonatal rats with 6-hydroxydopamine (6-OHDA). One study found a ∼20% increase in adult α1-AR and α2-AR in cortical membranes (Dausse et al., 1982) and a separate study showed a dramatic increase in adult β-AR (Lorton et al., 1988). These studies have similarities and differences with our studies. These previous studies found that a neonatal 6-OHDA lesion of noradrenergic neurons lead to a detectable increase in α1-AR and 5-Formyl-CTP α2-AR within the cortex of mature rat brain, in contrast to our findings of no change in mouse brain. This may reflect species differences or the effects of the 10–15% of normal norepinephrine remaining following the lesions. Similar to what is found in Dbh−/− mice, neonatal 6-OHDA caused a persistent up-regulation of β-AR (Lorton et al., 1988). The general pattern of β-AR up-regulation being greater than the effects on α1-AR and α2-AR is consistent between neonatal 6-OHDA lesion studies in rats and the Dbh−/− mouse model.