Double-dissociation of the catecholaminergic modulation of synaptic transmission in the oval bed nucleus of the stria terminalis

Abstract

The bed nucleus of the stria terminalis (BST) is a cluster of nuclei within the extended amygdala, a forebrain macrostructure with extensive projection to motor nuclei of the hindbrain. The subnuclei of the BST coordinate autonomic, neuroendocrine, and somato-motor functions and receive robust neuromodulatory monoaminergic afferents, including 5-HT-, noradrenaline (NA)-, and dopamine (DA)-containing terminals. In contrast to 5-HT and NA, little is known about how DA modulates neuronal activity or synaptic transmission in the BST. DA-containing afferents to the BST originate in the ventral tegmental area, the periaqueducal gray, and the retrorubral field. They form a fairly diffuse input to the dorsolateral BST with dense terminal fields in the oval (ovBST) and juxtacapsular (jxBST) nuclei. The efferent-afferent connectivity of the BST suggests that it may play a key role in motivated behaviors, consistent with recent evidence that the dorsolateral BST is a target for drugs of abuse. This study describes the effects of DA on synaptic transmission in the ovBST. Whole cell voltage clamp recordings were performed on ovBST neurons in brain slices from adult rats in the presence or absence of exogenous DA and receptor-targeted agonists and antagonists. The results showed that DA selectively and exclusively reduced inhibitory synaptic transmission in the ovBST in a dose-dependent and D2-like dopamine receptor-dependent manner. DA also modulated excitatory synaptic transmission in a dose-dependent dependent manner. However, this effect was mediated by α2-noradrenergic receptors. Thus these data reveal a double dissociation in catecholaminergic regulation of excitatory and inhibitory synaptic transmission in the ovBST and may shed light on the mechanisms involved in neuropathological behaviors such as stress-induced relapse to consumption of drugs of abuse.

FIG. 1

Anatomical localization of recordings and effects of agonists on passive electrophysiological properties of bed nucleus of the stria terminalis (BST) with dense terminal fields in the oval (ovBST) neurons. A: schematic illustrating the anatomical localization of recording pipettes and stimulating electrodes. ac: anterior commissure; ic: internal capsule. B: dot plot showing the effects of dopamine (DA) 30 μM (○) or noradrenaline (NA) 10 μM (△) on membrane holding current (Hc) and membrane input resistance (Rin).

FIG. 2

Effects of DA, D1R, and D2R agonists on the amplitude of evoked GABA_A-inhibitory postsynaptic current (IPSC) in the ovBST. A: representative traces showing the effects of bath application of DA on electrically evoked GABA_A-IPSC in the ovBST. Each trace is the average of 5 consecutive events. B: bar graph summarizing the effects of DA agonists on the peak amplitude and paired-pulse ratios of evoked GABA_A-IPSC in the ovBST. C: coefficient of variation analysis of the effects of DA (0.1–30 μM) on evoked GABA_A-IPSC in the ovBST. S1, stimulus 1; S2, stimulus 2. r, [(1/CV²_drug)/(1/CV²_baseline)]; Π, peak amplitude_drug/Peak amplitude_baseline. *, significantly different from 0; P < 0.01.

FIG. 3

Pharmacological characterization of the effects of DA on the amplitude of evoked GABA_A-IPSC in the ovBST. A: representative dot plot showing the time course of the effects of DA on evoked GABA_A-IPSC in the ovBST in the absence and the presence of the D1 dopamine receptor (D1R) antagonist SCH-23390 or the D2 dopamine receptor (D2R) antagonist sulpiride. B: bar chart summarizing the effect of monoaminergic agonists and antagonists on evoked GABA_A-IPSC in the ovBST. *, significantly different from 0; P < 0.01. †, significantly different from DA 30 μM; P < 0.05.

FIG. 4

Catecholaminergic modulation of evoked AMPA-excitatory PSC (EPSC) in the ovBST. A: representative traces showing the effects of bath application of DA on electrically evoked AMPA-EPSC in the ovBST. Each trace is the average of 5 consecutive events. A1: bar graph summarizing the effects of DA and 5-HT agonists on the peak amplitude and paired pulse ratio (PPR_{50 ms}) of evoked AMPA-EPSC in the ovBST. Inset: coefficient of variation (CV) analyses. B: representative traces showing the effects of bath application of noradrenergic agonists on electrically evoked AMPA-EPSC in the ovBST. Each trace is the average of 5 consecutive events. B1: bar graph summarizing the effects of noradrenergic agonists on the peak amplitude and PPR_{50 ms} of evoked AMPA-EPSC in the ovBST. Inset: CV analyses. *, significantly different from 0; P < 0.01.

FIG. 5

Pharmacological characterization of the effects of DA and NA on evoked AMPA-EPSC in the ovBST. A: representative dot plot showing the time course of the effects of DA on evoked AMPA-EPSC in the ovBST in the absence and the presence of the α2R antagonist yohimbine. B: representative dot plot showing the time course of the effects of NA on evoked AMPA-EPSC in the ovBST in the absence and the presence of the α2R antagonist yohimbine. C: bar chart summarizing the effects of noradrenergic antagonists on dopaminergic and noradrenergic modulation of evoked AMPA-EPSC in the ovBST. *, significantly different from 0; P < 0.01. †, P < 0.05.

FIG. 6

Immunohistochemical localization of D1R and D2R in the ovBST. Light micrographs of the rat brain immunostained to reveal immunoreactivity for D1R (A and A′) and D2R (B and B′). The black doted line delineates the anterior BST, whereas the red dotted line delineates the ovBST. ac, anterior commissure; ic, internal capsula; ov, oval nucleus. Scale bars: A and B, 0.3 mm; A′, 0.1 mm; B′, 50 μm.

FIG. 7

Double-dissociation of the catecholaminergic modulation of synaptic transmission in the ovBST. The ovBST receives robust glutamatergic projection from insular cortex, piriform cortex, ventral subiculum, and basolateral amygdala as well as DA inputs from the midbrain and NA inputs from the brain stem. GABAergic inputs to ovBST are from local short-axon GABAergic neurons or from the central nucleus of the amygdala. Functional evidences from this study demonstrate that release of DA in the ovBST could activate D2R and selectively reduce inhibitory influence to promote neuronal activation and release of NA could activate α2R and selectively inactivate excitatory drive to the ovBST. This functional double dissociation of the effects of DA and NA in the ovBST may be involved in processing both stress-and reward-related stimuli.