5-HT2A/2C Receptor–Mediated Hypopnea in the Newborn Rat: Relationship to Fos Immunoreactivity

Abstract

Previous data derived from anesthetized, decerebrate, or in vitro preparations suggested that 5-HT 2 receptor activation might be responsible for respiratory dysfunction. Such a mechanism has not yet been documented in the intact animal, but might be of clinical relevance to the apneic spells of the premature infant. In the present investigation on conscious newborn rats we analyzed the respiratory response to the activation of 5-HT 2A/2C receptors by the agonist 1-(2.5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI), and we delineated central structures possibly involved in this response, using Fos expression as a marker of neuronal activation. We demonstrated that intraperitoneal injection of 5 mg/kg DOI produced a long-lasting decrease in respiratory frequency and tidal volume, which could be blocked by the antagonist ritanserin. Fos immunohistochemistry suggested that the rostral ventrolateral medulla and the lateral paragigantocellular nucleus might have a key role in the respiratory response to 5-HT 2 receptor activation. In addition, double immunostaining for Fos and tyrosine hydroxylase suggested that the contribution of catecholaminergic neurons to this response might be modest and indirect. Serotonin (5-hydroxytryptamine; 5-HT) acting at 5-HT 2 receptors has been involved in the neuromodulation of a broad spectrum of functions ranging from mental processing to autonomic regulation (1). 5-HT also interferes with breathing control, via central and peripheral 5-HT 2 receptors, and variable responses have been reported. In vitro studies on brain stem-spinal cord preparations isolated from the newborn rat indicated that central 5-HT 2A receptor mechanisms may exert facilitating influences on respiration, by activating spinal respiratory motoneurons (2) and increasing the frequency of rhythmic respiratory discharge (3). In contrast, in adult anesthetized rats, the activation of 5-HT 2 receptors located at the periphery has been involved in decreases in phrenic nerve activity and lung compliance observed during apnea induced by 5-HT (4). In decerebrate newborn rats, the application of 5-HT 2A/2C receptor agonists to the floor of the fourth ventricle elicited a bradypnea (5), reminiscent of the decrease in frequency of respiratory-like activity that followed bath application of 5-HT 2C receptor agonists to in vitro preparations (3). Furthermore, the finding that 5-HT 2A/2C receptor agonists inhibit hypoglossal inspiratory activity in isolated brain stemspinal cord preparations led to the hypothesis that 5-HT 2 receptors may be involved in the genesis of obstructive apneas in newborns with increased 5-HT biosynthesis (2, 6). Nevertheless, the depressant influence of 5-HT 2 receptor activation on hypoglossal activity has not been confirmed on medullary rhythmic slice (7). Altogether, those findings suggest that 5-HT 2 receptor mechanisms might influence the network devoted to respiratory control at multiple levels and that the response to 5-HT 2 receptor activation in the intact animal may not be definitely deduced...

The serotonin 2A receptor agonist 25CN-NBOH increases murine heart rate and neck-arterial blood flow in a temperature-dependent manner

“…The tachycardic effect of 25CN-NBOH at the increased pad temperature was quickly reversed as pulse distention rose, which is in line with the proposed opponency. Apart from its effect on pulse distention and heart rate, 25CN-NBOH facilitated the development of bradypnea, which mirrors findings for DOI ( Cayetanot et al, 2001 ; Khater-Boidin et al, 1999 ) and might be due to 5-HT 2 R-mediated inhibition of phrenic nerve activity ( King and Holtman, 1990 ). Interestingly, phrenic inhibition induced by the psychedelic 5-MeO-DMT could be overcome by ambient heat ( Lalley, 1982 ), which fits wells with the rapid reversal of 25CN-NBOH’s bradypneic effect at the increased pad temperature.…”

Association of the –1438G/A Polymorphism of the 5-HT_2AReceptor Gene with Obstructive Sleep Apnea Syndrome

“…In contrast, in adult anesthetized rats, activation of 5-HT 2 receptors located at the periphery has been involved in decreases in phrenic nerve activity and lung compliance observed during apnea induced by 5-HT. The 5-HT 2 receptor mechanisms might infl uence the network devoted to respiratory control at multiple levels [14] .…”

Individual differences in the sensitivity to serotonergic drugs: a pharmacobehavioural approach using rats selected on the basis of their response to novelty

“…All drugs were dissolved in saline. Ritanserin was dissolved in saline with a drop of acetic acid, and the pH was adjusted with sodium hydroxide (Schreiber et al 1998 ; Cayetanot et al 2001 ). In order to maintain the levels of stress as low as possible, rats received their injection only once before the first trial and not prior to every trial (Viana et al 1994 ; Graeff et al 1996a , b ).…”