Elsevier

Neuropharmacology

Volume 47, Issue 5, October 2004, Pages 631-639
Neuropharmacology

Dopaminergic modulation of spontaneous inhibitory network activity in the lateral amygdala

https://doi.org/10.1016/j.neuropharm.2004.07.015Get rights and content

Abstract

There is converging evidence that dopamine (DA) receptor activation in the lateral amygdala (LA) is required for the acquisition of conditioned fear. Powerful inhibitory circuits exist in the LA shaping the activity of excitatory projection neurons and controlling the induction of associative plasticity, which is thought to underlie fear learning. In vivo and in vitro electrophysiological experiments indicate that DA suppresses inhibitory transmission triggered by excitatory afferent input. Conversely, DA increases the excitability of inhibitory interneurons in the LA. However, the mechanisms by which DA modulates inhibitory transmission are poorly understood. Using whole-cell recordings from LA projection neurons in coronal mouse brain slices, we found that DA strongly increased the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs). In addition, DA application induced low-frequency (2–6 Hz) oscillatory activity of inhibitory circuits in the absence of excitatory input. The increase in sIPSC frequency required activation of D1-like receptors. Unlike D1 receptor-mediated transmission in other brain areas, this effect was independent of the cAMP/PKA signal transduction cascade, but involved activation of the protein tyrosine kinase Src. This indicates that DA orchestrates the activity of populations of interneurons in the LA by a D1-dependent, non-canonical signal transduction pathway.

Introduction

The amygdala, a group of interconnected nuclei in the temporal lobe, plays a central role for attributing and adjusting emotional valence to sensory inputs (Le Doux, 2000, Davis, 2000). In particular, there is compelling evidence that during classical fear conditioning, information about the conditioned (CS) and unconditioned (US) stimuli are converging at the level of the lateral nucleus of the amygdala (LA; Sah et al., 2003). In the LA, induction of associative synaptic plasticity by converging CS and US inputs is thought to underlie, at least in part, the acquisition and storage of fear learning (Maren, 2001, Rosenkranz and Grace, 2002a, Goosens et al., 2003). The activity of LA projection neurons and the induction of synaptic plasticity in the LA are strongly regulated by local inhibitory interneurons (Li et al., 1996, Lang and Paré, 1997, Bissière et al., 2003). Consistent with these physiological findings, behavioral experiments indicate that the acquisition and expression of different measures of conditioned and unconditioned fear are under the control of GABAergic inhibition (Davis, 2000). Converging evidence indicates that neuromodulators, such as dopamine (DA), affect amygdala-dependent fear learning by targeting inhibitory circuits in the basolateral amygdala. DA is released in the amygdala upon stress (Inglis and Moggadham, 1999), and intra-amygdala injection of DA receptor antagonists prevents the acquisition of conditioned fear (Lamont and Kokkinidis, 1998, Guarracci et al., 1999, Guarracci et al., 2000, Greba and Kokkinidis, 2001, Greba et al., 2001). The effects of locally released DA on inhibitory circuits in the LA appear to be complex. In vivo and in vitro electrophysiological experiments indicate that DA suppresses inhibition triggered by stimulation of excitatory afferents from the medial prefrontal cortex (mPFC) or from the thalamus thereby facilitating the induction of synaptic plasticity (Rosenkranz and Grace, 2001, Rosenkranz and Grace, 2002b, Bissière et al., 2003). Conversely, recordings from anaesthetized rats have demonstrated that DA receptor activation increases the firing rate of putative interneurons (Rosenkranz and Grace, 1999).

DA receptors are generally grouped into two subfamilies, the D1-like and the D2-like receptors (Missale et al., 1998). Both receptor subfamilies seem to be involved in regulating amygdala-dependent fear learning (Guarracci et al., 1999, Guarracci et al., 2000) and are expressed in the basolateral amygdala (Boyson et al., 1986, Meador-Woodruff et al., 1991). Whereas the attenuation of inhibition triggered by stimulation of mPFC afferents has been shown to involve activation of D1-like receptors (Rosenkranz and Grace, 2002a, Rosenkranz and Grace, 2002b), suppression of feedforward inhibition upon stimulation of thalamic afferents is mediated by D2-like receptor activation (Bissière et al., 2003). In contrast, the mechanism underlying the DA-induced increase in interneuron firing rate is poorly understood. The present study was designed to investigate the impact of DA receptor activation on spontaneous inhibitory network activity in vitro, and to elucidate the underlying signaling mechanisms.

Section snippets

Slice preparation

Standard procedures were used to prepare 350 μm thick coronal slices from 3 to 4 week old male C57BL/6J mice following a protocol approved by the Veterinary Department of the Canton of Basel-Stadt. Briefly, the brain was dissected in ice-cold artificial cerebrospinal fluid (ACSF), mounted on an agar block and sliced with a vibratome at 4 °C. Slices were maintained for 45 min at 35 °C in an interface chamber containing ACSF equilibrated with 95% O2/5% CO2 and containing (in mM): 124 NaCl, 2.7

DA increases spontaneous inhibitory network activity

To address the effect of DA on spontaneous inhibitory network activity in the LA we have obtained whole-cell voltage-clamp recordings from LA projection neurons that were located in the dorsal subdivision of the LA. Spontaneous inhibitory postsynaptic currents (sIPSCs) were recorded at −70 mV using a CsCl-based filling solution. sIPSCs were pharmacologically isolated by application of the AMPA/kainate receptor antagonist CNQX (20 μM) and the NMDA receptor antagonist CPP (10 μM). As previously

Discussion

Consistent with in vivo studies showing an increase in the spontaneous firing rate of putative interneurons upon systemic administration of DA receptor agonists (Rosenkranz and Grace, 1999), the present study demonstrates that spontaneous inhibitory network activity is strongly increased by DA. This effect involved the activation of somatodendritic DA receptors on LA interneurons since DA application did not affect mIPSC frequency, and directly depolarized interneurons in the LA. Indeed,

Acknowledgements

We thank all members of the Lüthi lab for helpful discussions and comments on the manuscript. This work was supported by the Swiss National Science Foundation, the Borderline Personality Disorder Research Foundation, and the Novartis Research Foundation.

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    These authors contributed equally to this work.

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