To determine how norepinephrine affects the basic physiological properties of catecholaminergic neurons, brain slices containing the Substantia Nigra Pars Compacta and Locus Coeruleus were studied with cell-attached and whole-cell recordings in control and dopamine β-hydroxylase knockout (Dbh −/−) mice that lack norepinephrine. In the cell-attached configuration, the spontaneous firing rate and pattern of Locus Coeruleus neurons recorded from Dbh −/− mice was the same as the firing rate and pattern recorded from heterozygous littermates (Dbh +/−). During whole-cell recordings, synaptic stimulation produced an α-2 receptor-mediated outward current in the Locus Coeruleus of control mice that was absent in Dbh −/− mice. Normal α-2 mediated outward currents were restored in Dbh −/− slices after pre-incubation with norepinephrine. Locus Coeruleus neurons also displayed similar changes in holding current in response to bath application of norepinephrine, UK 14304, and methionine-enkephalin. Dopamine neurons recorded in the Substantia Nigra Pars Compacta similarly showed no differences between slices harvested from Dbh −/− and control mice. These results indicate that endogenous norepinephrine is not necessary for the expression of catecholaminergic neuron firing properties or responses to direct agonists, but is necessary for auto-inhibition mediated by indirect α-2 receptor stimulation.
Keywordsdopamine β-hydroxylase knockout; locus coeruleus; substantia nigra pars compacta; cocaine The activity of norepinephrine (NE) neurons in the locus coeruleus (LC) has an important role in selective attention, general arousal, and stress reactions upon challenging environmental situations (Foote et al., 1983;Levine et al., 1990;Berridge and Waterhouse, 2003;Aston-Jones and Cohen, 2005), and NE depletion may underlie some affective disorders and disease states (Ressler and Nemeroff, 1999). In addition, the LC projects directly to, and modulates the activity of, midbrain dopamine (DA) neurons (Swanson and Hartman, 1975;Jones and Moore, 1977;Liprando et al., 2004), which are critical for reward and motor related behaviors (Girault and Greengard, 2004;Montague et al., 2004). In an intact animal, NE neurons recorded in vitro fire spontaneously in a single-spike Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. pattern at a rate of up to 5 spikes per second (Williams et al., 1984). However, it is not known whether NE depletion affects the basic physiological properties of NE or DA neurons.
NIH Public AccessDopamine β-hydroxylase knockout (Dbh −/−) mice completely lack NE and have many bra...