Serotonergic mechanisms on breathing modulation in the rat locus coeruleus

Abstract

The locus coeruleus (LC) is a noradrenergic nucleus that plays an important role in the ventilatory response to hypercapnia. This nucleus is densely innervated by serotonergic fibers and contains high density of serotonin (5-HT) receptors, including 5-HT(1A) and 5-HT(2). We assessed the possible modulation of respiratory response to hypercapnia by 5-HT, through 5-HT(1A) and 5-HT(2) receptors, in the LC. To this end, we determined the concentrations of 5-HT and its metabolite 5-hydroxyindole-3-acetic acid (5-HIAA) in the LC after hypercapnic exposure. Pulmonary ventilation (VE: , plethysmograph) was measured before and after unilateral microinjection (100 nL) of WAY-100635 (5-HT(1A) antagonist, 5.6 and 56 mM), 8-OHDPAT (5-HT(1A/7) agonist, 7 and 15 mM), Ketanserin (5-HT(2A) antagonist, 3.7 and 37 mM), or (+/-)-2,5-dimethoxy-4-iodoamphetaminehydrochloride (DOI; 5-HT(2A) agonist, 6.7 and 67 mM) into the LC, followed by a 60-min period of 7% CO(2) exposure. Hypercapnia increased 5-HTIAA levels and 5-HIAA/5-HT ratio within the LC. WAY-100635 and 8-OHDPAT intra-LC decreased the hypercapnic ventilatory response due to a lower tidal volume. Ketanserin increased CO(2) drive to breathing and DOI caused the opposite response, both acting on tidal volume. The current results provide evidence of increased 5-HT release during hypercapnia in the LC and that 5-HT presents an inhibitory modulation of the stimulatory role of LC on hypercapnic ventilatory response, acting through postsynaptic 5-HT(2A) receptors in this nucleus. In addition, hypercapnic responses seem to be also regulated by presynaptic 5-HT(1A) receptors in the LC.

Ventilatory, metabolic, and thermal responses to hypercapnia in female rats: effects of estrous cycle, ovariectomy, and hormonal replacement

“…In many species, a decrease in Tb is observed during hypercapnia, including rats (19). Nevertheless, previous studies from our laboratory did not observe a Tb alteration during CO 2 challenge in male Wistar rats (6,13,14,31).…”

Orbitofrontal cortex 5-HT2A receptor mediates chronic stress-induced depressive-like behaviors and alterations of spine density and Kalirin7

“…The 5-HT 2A R antagonist Ketanserin (+)-tartrate salt (Ket, Sigma, catalog #S006, 5 µg/0.5 µL) was dissolved in sterile saline containing 15% dimethyl sulfoxide (de Souza Moreno et al, 2010). Similar to saline, 15% DMSO did not alter animal behaviors (Fig.…”

The locus coeruleus and central chemosensitivity

“…Another possible explanation could be that most of the previous cited studies were performed using anesthetized rats (Guyenet et al ., 1993; Jodkowski et al ., 1997; Dawid-Milner et al ., 2001) or neonatal preparations (Oyamada et al ., 1998; Shirasawa et al ., 2000; Hilaire et al ., 2004) whereas we used unanesthetized and adult animals. Whatever the explanation, in all of our lesion or microinjection studies using animals with manipulations specifically performed in the LC, no difference in basal ventilation has been observed (Biancardi et al ., 2008; Biancardi et al ., 2010; de Souza-Moreno, 2010; Carvalho et al ., in press ). …”

“…In fact, hypercapnia induced an increase in 5-hydroxyindole-3-acetic acid (5-HIAA) levels and serotonergic turnover (5-HTTIA/5-HT ratio) in the LC (de Souza Moreno et al ., 2010). In this study, WAY-100635 (a 5-HT 1A receptor antagonist), 8-OHDPAT (5-HT 1A/7 agonist), Ketanserin (5-HT 2A antagonist), or DOI (5-HT 2A agonist) were microinjected into the LC of conscious, freely behaving rats to determine what 5-HT receptors were involved in the ventilatory response to CO 2 .…”

“…The LC is implicated in the control of many homeostatic functions including maintenance of attention, motivation, arousal states (Svensson and Thorén, 1979; Bhaskaran and Freed, 1988), sleep (Aston-Jones and Bloom, 1981), circadian regulation of arousal and performance (Aston-Jones et al ., 2001), cognitive behaviors (for review see Sara, 2009), fever response (Almeida et al ., 2004), control of breathing (Oyamada et al 1998; Fabris et al ., 1999; Hilaire et al 2004; Putnam et al , 2004; Viemari et al 2004, Biancardi et al ., 2008; de Souza-Moreno et al, 2010), and cardiovascular function (Sved and Felsten, 1987). This nucleus is involved in some pathophysiological states as well, such as panic disorder (Charney et al ., 1990; Kaplan, 1992; Sullivan et al ., 1999; Bailey et al ., 2003; Griez and Schruers, 2003) and Rett syndrome (RTT) (Taneja et al ., 2009).…”