Individual differences in the locus coeruleus-norepinephrine system: Relevance to stress-induced cardiovascular vulnerability

Abstract

Repeated exposure to psychosocial stress is a robust sympathomimetic stressor and as such has adverse effects on cardiovascular health. While the neurocircuitry involved remains unclear, the physiological and anatomical characteristics of the locus coeruleus (LC)-norepinephrine (NE) system suggest that it is poised to contribute to stress-induced cardiovascular vulnerability. A major theme throughout is to review studies that shed light on the role that the LC may play in individual differences in vulnerability to social stress-induced cardiovascular dysfunction. Recent findings are discussed that support a unique plasticity in afferent regulation of the LC, resulting in either excitatory or inhibitory input to the LC during establishment of different stress coping strategies. This contrasting regulation of the LC by either afferent regulation, or distinct differences in stress-induced neuroinflammation would translate to differences in cardiovascular regulation and may serve as the basis for individual differences in the cardiopathological consequences of social stress. The goal of this review is to highlight recent developments in the interplay between the LC-NE and cardiovascular systems during repeated stress in an effort to advance therapeutic treatments for the development of stress-induced cardiovascular vulnerability.

Keywords: Corticotropin-releasing factor; Individual differences; Locus coeruleus; Neuroinflammation; Opioid; Social stress.

Figure 1

Schematic depicting afferent and efferent communication of the LC with brain regions involved in the regulation of the cardiovascular system. Opposing CRF excitatory afferents from the CNA and ENK inhibitory afferents from the PGi regulate the function of the LC. In addition, LC efferents inhibit parasympathetic/cardioinhibitory centers (DMV and Amb) and excite the sympathoexcitatory preganglionic sympathetic neurons (PSN) and CNA. Recent findings indicate that during social defeat stress, adopting an active coping strategy (resulting in a long latency to defeat, LL) biases the LC towards PGi-ENK inhibitory afferents and a decrease in CRF afferent activation of the LC from the CNA. On the other hand, when a passive coping response (short latency to be defeated, SL) is adopted this afferent regulation of the LC is shifted towards the CNA-CRF excitatory influence and reduced PGi-ENK afferents. These data lead us to hypothesize that a bias towards either an excitatory or inhibitory input to the LC may in part underlie the basis for the individual differences in cardiovascular susceptibility seen during social defeat stress. Excitatory and inhibitory projections are denoted by a (+) or a solid line perpendicular to the projection (−).

Figure 2

Effect of LC-NE lesion on IL-1β induced pressor response. Rats were implanted with cardiovascular transmitters (HD-S11, Data Sciences Intl.) and an intracerebroventricular (icv) cannula and injected with N-[2-chloroethyl]-N-ethyl-2-bromobenzylamine hydrochloride (400 ug/rat/4min, icv, DSP-4; R & D Systems) or vehicle 30 mins after citalopram hydrobromide (10mg/kg, IP; AK Scientific). One-week later rats were injected with IL-1β (5ng, icv) and the change in mean arterial pressure (MAP, mmHg) from the pre-IL-1β injection baseline was quantified. Rats with a DSP-4 induced LC-NE lesion lacked the IL-1β-induced pressor response. 2-way ANOVA significant interaction: F(2,4)=7.9; p=0.04; Bonferroni post-hoc *p<0.05 vs. DSP-4 treated rat at 90 mins post injection.