Inhibition of the cardiovascular response to stress by systemic 5-HT_1A activation: sympathoinhibition or anxiolysis?

Abstract

5-HT1A agonists given systemically are known to produce anxiolytic effects. In addition, a growing body of research is showing that those compounds also have central sympathoinhibitory properties. Since emotional arousal gives rise to sympathetic activation, it is not clear whether systemic treatment with a 5-HT1A agonist reduces the sympathetic response to emotional stress primarily by a direct action on sympathetic-related sites in the brain or indirectly through reducing anxiety. To test this, we compared the effect of intraperitoneal injections of 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 0.05 and 0.25 mg/kg), a preferential 5-HT1A agonist, or vehicle on the cardiovascular responses to four stressors known to produce sympathetic activation, three being emotional stressors, and one physiological. In conscious rats, 30-min exposure to either a neutral context, a fear-conditioned context, or to restraint stress led to increases in heart rate and blood pressure, which were attenuated by 8-OH-DPAT. In contrast, the same treatment did not reduce the cardiovascular response to 30-min cold exposure (4°C). The results suggest that 8-OH-DPAT acts preferentially on limbic, rather than central, autonomic sites. Hence, doses of 5-HT1A agonists, which are just sufficient to produce anxiolysis, are not enough to cause true sympathoinhibition.

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

“…Furthermore, Vianna and Carrive (49) showed that systemic injections of 8-OH-DPAT, even at a higher dose (250 g/kg) than that used in the present study, did not reduce the pressor and tachycardic response to cold exposure in conscious rats. Therefore, the 5-HT 1A receptor-mediated inhibition of the PVN-evoked sympathoexcitation is not simply due to a nonspecific inhibition of sympathetic reactivity.…”

“…Methodological considerations. The dose of 8-OH-DPAT injected intravenously (100 g/kg) is within the range (30 -250 g/kg) that has been shown to reduce the tachycardia and pressor response induced by psychological stressors (restraint or novel environment) in conscious rats (35,49). This dose was also the same as that which in our previous study (24) powerfully suppressed DMH-evoked cardiovascular responses.…”

“…The effect of 8-OH-DPAT in reducing the PVN-evoked pressor and tachycardic response is not a consequence of this reduction in resting MAP and HR, however, because systemic injections of the same or a higher dose of 8-OH-DPAT did not affect the cardiovascular responses to chemoreceptor stimulation or to cold exposure (24,49).…”

“…Thus, the medullary raphé is one site at which 5-HT 1A receptors can suppress stress-evoked cardiac or cutaneous vasoconstrictor responses (33,35,38). At the same time, activation of 5-HT 1A receptors located in higher brain regions, such as limbic regions, may also reduce stress-evoked cardiovascular responses via an anxiolytic effect rather than via a direct effect on brainstem cardiovascular neurons (49).…”

Emotional Roles of Mono-Aminergic Neurotransmitters in Major Depressive Disorder and Anxiety Disorders

“…However, studies show a general reduction in the density of postsynaptic 5-HT1A receptors in depressed patients, which may result in poor response to antidepressant treatment ( Bhagwagar et al, 2004 ). Further, ligands with 5-HT1A agonist activity can produce both antidepressant ( Choi et al, 2012 ) and anxiolytic ( Vianna and Carrive, 2009 ) properties. Studies have also shown the aberrant sensitivity of postsynaptic 5-HT1D receptors and a distinctly higher distribution of 5-HT1D receptors in the globus pallidus in patients with MDD and/or suicide victims ( Lowther et al, 1997 ; Whale et al, 2001 ; Murrough et al, 2011 ).…”