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  • These data from developing brain are in contrast to noradren

    2019-11-20

    These data from developing 2×Taq PCR Master Mix(with dye) are in contrast to noradrenergic receptor regulation in the adult brain. In adult animals, a persistent increase in the α2-AR high affinity state is elicited as a result of DSP-4 lesion or reserpinization, as measured by [3H]clonidine binding to membrane preparations (Dooley et al., 1983, Ribas et al., 2001). It is generally found that adult noradrenergic lesions lead to moderate increases in β-AR density (Dooley et al., 1983, Zahniser et al., 1986). In contrast, we find a decrease or no change in total α2-AR number, high affinity state or linkage to G proteins following a developmental loss of norepinephrine. We and others have found a persistent increase in β-AR (Lorton et al., 1988) subsequent to a developmental deficiency in norepinephrine, in contrast to the transient increases found in DSP-4 lesioned adults. These findings indicate there are distinct differences in adrenergic receptor regulation in CNS during postnatal development compared to adult brain. The profile of adrenergic receptor changes in Dbh−/− mice differs from changes seen in mice with a homozygous deletion of the norepinephrine transporter (Net−/−) (Gilsbach et al., 2006, Dziedzicka-Wasylewska et al., 2006). Because NET functions to remove released norepinephrine from the synapse, Net−/− mice display elevated extracellular concentrations of norepinephrine (Vizi et al., 2004). Therefore, Net−/− mice serve as a model of high noradrenergic tone that differs from the Dbh−/− mouse model of loss of noradrenergic tone. Adrenergic receptors in Net−/− mice respond to elevated norepinephrine with decreases in α1-AR and β-AR and accompanying increases in α2-ARA and α2-ARC subtypes (Gilsbach et al., 2006). These changes are in the opposite direction to the elevated α1-AR and β-AR and decreased α2-AR we have detected in Dbh−/− mice. Taken together, these data suggest that α1-AR, α2-AR and β-AR may respond in an integrated and predictable way to variations in postnatal noradrenergic tone. The relatively small changes in α1-AR and α2-AR are consistent with the ability of exogenous adrenergic receptor agonists to modulate neuronal excitability and behavior in Dbh−/− mice (Szot et al., 1999, Weinshenker et al., 2001, Murchison et al., 2004). They contrast with the significant changes found in the dopamine system in Dbh−/− mice. Dbh−/− mice are hypersensitive to the behavioral effects of D2 agonists and exhibit large increases in the high affinity state of brain D1 and D2 receptors (Weinshenker et al., 2002a, Schank et al., 2005). Our data indicate that α1-AR and α2-AR are normal in the postnatal absence of norepinephrine and that β-AR expression responds normally to the lack of norepinephrine, whereas other neurotransmitter systems, such as the dopamine system, require norepinephrine for normal development and maintenance.
    Experimental procedure [3H]RX821002 (58 Ci/mmol) was obtained from Amersham (Arlington Heights, IL). Rauwolscine, isoproterenol, epinephrine bitartrate, RX821002, phentolamine, glycylglycine HCl and dithiothreitol (DTT) were purchased from Sigma-Aldrich (St. Louis, MO.) [35S]GTPγS (1000–1500 Ci/mmol), p-[125I]iodoclonidine (2200 Ci/mmol), [125I]-iodo-pindolol (2200 Ci/mmol) and [3H]prazosin (80.5 Ci/mmol) were purchased from Perkin Elmer (Boston, MA). Guanosine 5′-diphosphate sodium (GDP) was purchased from United States Biochemical (Cleveland, OH). All other chemicals were research grade.
    Acknowledgments
    Introduction Parkinson\'s disease (PD) is one of the most common progressive neurodegenerative disorders, affecting approximately 1% of the elderly population (de Lau and Breteler, 2006). Clinical symptoms of PD involve motor dysfunction featuring slowness or lack of movement, rigidity, postural instability, and resting tremor (Jenner and Olanow, 2006, Olanow and Tatton, 1999). The pathogenesis of the movement dysfunction in PD involves loss of dopaminergic (DArgic) neurons in the substantia nigra pars compacta (SNpc).