Activation of 5-hydroxytryptamine-1A receptors suppresses cardiovascular responses evoked from the paraventricular nucleus

School of Medical Sciences (Physiology) and Bosch Institute, University of Sydney, New South Wales, Australia.
AJP Regulatory Integrative and Comparative Physiology (Impact Factor: 3.11). 07/2011; 301(4):R1088-97. DOI: 10.1152/ajpregu.00144.2011
Source: PubMed


Activation of central 5-hydroxytryptamine-1A (5-HT(1A)) receptors powerfully inhibits stress-evoked cardiovascular responses mediated by the dorsomedial hypothalamus (DMH), as well as responses evoked by direct activation of neurons within the DMH. The hypothalamic paraventricular nucleus (PVN) also has a crucial role in cardiovascular regulation and is believed to regulate heart rate and renal sympathetic activity via pathways that are independent of the DMH. In this study, we determined whether cardiovascular responses evoked from the PVN are also modulated by activation of central 5-HT(1A) receptors. In anesthetized rats, the increases in heart rate and renal sympathetic nerve activity evoked by bicuculline injection into the PVN were greatly reduced (by 54% and 61%, respectively) by intravenous administration of (±)-8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), an agonist of 5-HT(1A) receptors, but were then completely restored by subsequent administration of WAY-100635, a selective antagonist of 5-HT(1A) receptors. Microinjection of 8-OH-DPAT directly into the PVN did not significantly affect the responses to bicuculline injection into the PVN, nor did systemic administration of WAY-100635 alone. In control experiments, a large renal sympathoexcitatory response was evoked from both the PVN and DMH but not from the intermediate region in between; thus the evoked responses from the PVN were not due to activation of neurons in the DMH. The results indicate that activation of central 5-HT(1A) receptors located outside the PVN powerfully inhibits the tachycardia and renal sympathoexcitation evoked by stimulation of neurons in the PVN.

Full-text preview

Available from:
  • [Show abstract] [Hide abstract]
    ABSTRACT: Clinical studies have established an inherent comorbidity between depression and the development of cardiovascular disease (CVD). Furthermore, this comorbidity seems to be more amplified in women than in men. To further investigate this comorbidity, a thorough literature review was conducted on studies from 1992 to date. The PubMed database was accessed using the keywords: cardiovascular disease, inflammation, depression, and sex differences. Both human and animal studies were considered. This review takes the standpoint that depression and CVD are both inflammatory disorders, and that their co-occurrence may be related to how the hypothalamic-pituitary-adrenal axis, serotonergic transmission and circulation, and the renin-angiotensin-aldosterone system via angiotensin II are affected by the excess secretion of proinflammatory cytokines. More recently, preliminary research attributes this systemic inflammation to a global deficiency in CD4+CD25+FOXP3 regulatory T cells. 17-β estradiol and progesterone mediated modulation of cytokine secretion may partially explain the sex differences observed. These hormones and reproductive events associated with hormonal fluctuations are discussed in depth, including the analysis of perinatal models of depression and CVD, including preeclampsia. However, as evidenced by this review, there is a need for mechanistic research in humans to truly understand the nature and directionality of the relationship between depression and CVD.
    No preview · Article · Feb 2014 · Therapeutic Advances in Cardiovascular Disease
  • [Show abstract] [Hide abstract]
    ABSTRACT: The dorsal raphe nucleus (DRN) is an important brainstem source of 5-hydroxytryptamine (5-HT), and 5-HT plays a key role in the regulation of panic attacks. The aim of the present study was to determine whether 5-HT1A receptor-containing neurons in the medial hypothalamus (MH) receive neural projections from DRN and to then determine the role of this neural substrate in defensive responses. The neurotracer biotinylated dextran amine (BDA) was iontophoretically microinjected into the DRN, and immunohistochemical approaches were then used to identify 5HT1A receptor-labelled neurons in the MH. Moreover, the effects of pre-treatment of the dorsomedial hypothalamus (DMH) with 8-OH-DPAT and WAY-100635, a 5-HT1A receptor agonist and antagonist, respectively, followed by local microinjections of bicuculline, a GABAA receptor antagonist, were investigated. We found that there are many projections from the DRN to the perifornical lateral hypothalamus (PeFLH) but also to DMH and ventromedial (VMH) nuclei, reaching 5HT1A receptor-labelled perikarya. DMH GABAA receptor blockade elicited defensive responses that were followed by antinociception. DMH treatment with 8-OH-DPAT decreased escape responses, which strongly suggests that the 5-HT1A receptor modulates the defensive responses. However, DMH treatment with WAY-100635 failed to alter bicuculline-induced defensive responses, suggesting that 5-HT exerts a phasic influence on 5-HT1A DMH neurons. The activation of the inhibitory 5-HT1A receptor had no effect on antinociception. However, blockade of the 5-HT1A receptor decreased fear-induced antinociception. The present data suggest that the ascending pathways from the DRN to the DMH modulate panic-like defensive behaviours and mediate antinociceptive phenomenon by recruiting 5-HT1A receptor in the MH.
    No preview · Article · Dec 2015 · European neuropsychopharmacology: the journal of the European College of Neuropsychopharmacology