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The aim of the present study was to specifically investigate the involvement of serotonin [5-hydroxytryptamine (5-HT(2))] receptors in 5-HT-mediated respiratory recovery after cervical hemisection. Experiments were conducted on C(2) spinal cord-hemisected, anesthetized (chloral hydrate, 400 mg/kg ip), vagotomized, pancuronium- paralyzed, and artificially ventilated female Sprague-Dawley rats in which CO(2) levels were monitored and maintained. Twenty-four hours after spinal hemisection, the ipsilateral phrenic nerve displayed no respiratory-related activity indicative of a functionally complete hemisection. Intravenous administration of the 5-HT(2A/2C)-receptor agonist (+/-)-2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) induced respiratory-related activity in the phrenic nerve ipsilateral to hemisection under conditions in which CO(2) was maintained at constant levels and augmented the activity induced under conditions of hypercapnia. The effects of DOI were found to be dose dependent, and the recovery of activity could be maintained for up to 2 h after a single injection. DOI-induced recovery was attenuated by the 5-HT(2)-receptor antagonist ketanserin but not with the 5-HT(2C)-receptor antagonist RS-102221, suggesting that 5-HT(2A) and not necessarily 5-HT(2C) receptors may be involved in the induction of respiratory recovery after cervical spinal cord injury.

The present study investigates the role of serotonin in respiratory recovery after spinal cord injury. Experiments were conducted on C(2) spinal cord hemisected, anesthetized, vagotomized, paralyzed, and artificially ventilated rats in which end-tidal CO(2) was monitored and maintained. Before drug administration, the phrenic nerve ipsilateral to hemisection showed no respiratory-related activity due to the disruption of the descending bulbospinal respiratory pathways by spinal cord hemisection. 5-Hydroxytryptophan (5-HTP), a serotonin precursor, was administrated intravenously. 5-HTP induced time- and dose-dependent increases in respiratory recovery in the phrenic nerve ipsilateral to hemisection. Although the 5-HTP-induced recovery was initially accompanied by an increase in activity in the contralateral phrenic nerve, suggesting an increase in descending respiratory drive, the recovery persisted well after activity in the contralateral nerve returned to predrug levels. 5-HTP-induced effects were reversed by a serotonin receptor antagonist, methysergide. Because experiments were conducted on animals subjected to C(2) spinal cord hemisection, the recovery was most likely mediated by the activation of a latent respiratory pathway spared by the spinal cord injury. The results suggest that serotonin is an important neuromodulator in the unmasking of the latent respiratory pathway after spinal cord injury. In addition, the results also suggest that the maintenance of 5-HTP-induced respiratory recovery may not require a continuous enhancement of central respiratory drive.

We used bispectral analysis to characterize the nonlinear interactions of the respiratory-related (RR), cardiac-related (CR), or 10-Hz rhythms in sympathetic nerve discharge (SND) of urethan-anesthetized cats. Bispectral analysis investigates relationships among frequency triples in the same signal (inferior cardiac postganglionic SND) where the third frequency is the sum of the other two due to quadratic nonlinear coupling. Coupling of the RR and CR rhythms leading to the generation of new components (i.e., modulated frequencies) in SND occurred in 84% of the total cases, whereas the incidence was 71% for the RR and 10-Hz rhythms. The occurrence of such nonlinear interactions implies that the RR, CR, and 10-Hz rhythms are carried to common targets by the same postganglionic sympathetic neurons. Furthermore, we suggest that nonlinear interactions leading to the generation of new frequencies in SND may affect end-organ function beyond the level expected in simple cases of linear superposition of the primary rhythms. This suggestion is supported by our observation that strong coupling of the RR and CR rhythms resulted in appreciable power at the modulated frequencies.

We used phase plane analysis to identify modes of frequency locking of the 10-Hz rhythm in sympathetic nerve discharge (SND) to the cardiac cycle in urethan-anesthetized, baroreceptor-innervated cats. Frequency locking occurred in rational ratios predicted by a generic mathematical construct called the Farey tree. Both simple harmonic ratios (e.g., 1:3) and complex ratios (e.g., 2:5) comprised of relatively prime integers (no common divisor) were identified under natural conditions. Frequency locking in such ratios is attributed to forcing of the 10-Hz oscillator by pulse-synchronous baroreceptor afferent nerve activity (BNA). Ventricular pacing changed the frequency of the 10-Hz rhythm as well as heart rate so as to maintain or change the ratio of frequency locking in a predictable way. Intriguingly, frequency locking of the 10-Hz rhythm to medullary raphe sympathoinhibitory stimuli in simple harmonic ratios was accompanied by increased power in the 10-Hz band of SND, whereas locking in complex ratios led to decreased 10-Hz power. These findings raise the possibility that pulse-synchronous BNA also exerts divergent actions on the 10-Hz rhythm depending on the ratio of frequency locking. Augmented 10-Hz power can be attributed to the resonant properties of oscillators that are periodically forced at the same phase in their cycle.