Norepinephrine Modulates Glutamatergic Transmission in the Bed Nucleus of the Stria Terminalis

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Abstract
The bed nucleus of the stria terminalis (BNST) and its adrenergic input are key components in stress-induced reinstatement and maintenance of drug use. Intra-BNST injections of either β-adrenergic receptor (β-AR) antagonists or α2-adrenergic receptor (α2-AR) agonists can inhibit footshock-induced reinstatement and maintenance of cocaine- and morphine-seeking. Using electrophysiological recording methods in an in vitro slice preparation from C57/Bl6j adult male mouse BNST, we have examined the effects of adrenergic receptor activation on excitatory synaptic transmission in the lateral dorsal supracommissural BNST (dBNST) and subcommissural BNST (vBNST). α2-AR activation via UK-14,304 (10 μM) results in a decrease in excitatory transmission in both dBNST and vBNST, an effect predominantly dependent upon the α2A-AR subtype. β-AR activation via isoproterenol (1 μM) results in an increase in excitatory transmission in dBNST, but not in vBNST. Consistent with the work with receptor subtype specific agonists, application of the endogenous ligand norepinephrine (NE, 100 μM) elicits two distinct effects on glutamatergic transmission. In dBNST, NE elicits an increase in transmission (62% of dBNST NE experiments) or a decrease in transmission (38% of dBNST NE experiments). In vBNST, NE elicits a decrease in transmission in 100% of the experiments. In dBNST, the NE-induced increase in synaptic transmission is blocked by β1/β2- and β2-, but not β1-specific antagonists. In addition, this increase is also reduced by the α2-AR antagonist yohimbine and is absent in the α2A-AR knockout mouse. In vBNST, the NE-induced decrease in synaptic transmission is markedly reduced in the α2A-AR knockout mouse. Further experiments demonstrate that the actions of NE on glutamatergic transmission can be correlated with β-AR function.