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

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 beta-adrenergic receptor (beta-AR) antagonists or alpha2-adrenergic receptor (alpha2-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). Alpha2-AR activation via UK-14,304 (10 microM) results in a decrease in excitatory transmission in both dBNST and vBNST, an effect predominantly dependent upon the alpha2A-AR subtype. Beta-AR activation via isoproterenol (1 microM) 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 microM) 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 beta1/beta2- and beta2-, but not beta1-specific antagonists. In addition, this increase is also reduced by the alpha2-AR antagonist yohimbine and is absent in the alpha2A-AR knockout mouse. In vBNST, the NE-induced decrease in synaptic transmission is markedly reduced in the alpha2A-AR knockout mouse. Further experiments demonstrate that the actions of NE on glutamatergic transmission can be correlated with beta-AR function.

Yohimbine impairs extinction of cocaine-conditioned place preference in an α2-adrenergic receptor independent process

“…Thus, we examined the effects of yohimbine and atipamezole on glutamatergic transmission in the dorsolateral (dl) BNST. We previously reported that the ␣ 2 -AR agonists clonidine and UK14,304 elicit an acute depression of glutamatergic transmission in this region (UK14,304, 41.7 ‫ע‬ 7.7% of baseline, P < 0.05) (Egli et al 2005). We have replicated these data and show a representative experiment for comparison (Fig.…”

“…7B). Further, while the effect of UK14,304 was absent in slices prepared from ␣ 2A -AR KO mice (Egli et al 2005), yohimbine still caused a decrease (42.6 ‫ע‬ 7.5% of baseline; t = 5.44, df = 5, P < 0.003) in glutamatergic transmission in the dlBNST of these mice (Fig. 7C).…”

Reciprocal Catecholamine Changes during Opiate Exposure and Withdrawal

“…Reciprocal catecholamine signaling has interesting implications in the context of the aversive stimulus of drug withdrawal, due to norepinephrine's possible influence on dopaminergic signaling. Glutamatergic inputs from the vBNST exert strong excitatory influence over VTA dopamine neurons (Georges and Aston-Jones, 2002), and norepinephrine's actions through α 2A receptors decrease excitatory transmission in the vBNST (Egli et al, 2004). Moreover, during acute opiate withdrawal, norepinephrine can act through β-receptors to increase GABA A inhibition of VTAprojecting BNST neurons (Dumont and Williams, 2004), leading to increased inhibition of the VTA.…”

α1-Adrenergic Receptor-Induced Heterosynaptic Long-Term Depression in the Bed Nucleus of the Stria Terminalis Is Disrupted in Mouse Models of Affective Disorders

“…Recording electrodes of approximately 1 MO resistance were pulled on a Flaming/Brown microelectrode puller (Sutter Instruments, Novato, CA) and filled with ACSF. A bipolar Nichrome (A-M Systems, Carlsborg, WA) stimulating electrode was placed dorsally to the recording electrode within the dlBNST such that stimulation of the field resulted in two distinguishable negative shifts in potential: N1 (the TTX sensitive fiber volley estimate) and N2 (CNQX sensitive synaptic response) as previously reported (Weitlauf et al, 2004;Egli et al, 2005;Grueter and Winder, 2005). The amplitude (voltage) of the N2 was measured at a stimulation intensity that resulted in a voltage approximately 50% of the maximum N2 response.…”

“…Moreover, blockade of excitatory transmission within this same region also disrupts anxiety-related behavior (Walker and Davis, 1997). Due to these observations, our group characterized NE modulation of glutamatergic signaling in the dorsal and ventral lBNST (dlBNST, vlBNST), focusing on a 2 -and b-AR signaling (Egli et al, 2005). Studies, however, have also suggested a role for a 1 -ARs in the BNST, demonstrating that blocking a 1 -ARs decreases anxiety responses concurrent with reductions in hypothalamicpituitary-adrenal (HPA) axis activation (Cecchi et al, 2002).…”