Response to Systemic Administration of 5-HT2 Receptor Active Agents
The study have shown that systemic administration of both agonist and antagonist of 5-HT2 receptors caused parallel, prominent, and immediate changes in the phrenic and hypoglossal activity and EEG activity. Both respiratory and cortical effects of 5-HT2A/2C receptors agonist were reversed by 5-HT2A/2C antagonist.
The effects of systemic administration of DOI during eupneic ventilation consisted of diminution of phasic phrenic and hypoglossal nerve activity, an augmentation or appearance of tonic hypoglossal nerve activity and an increase in bursts frequency. In general, this respiratory response elicited in anesthetized, artificially ventilated animals corresponded to that evoked in the brainstem-spinal cord preparation [13, 14] and following DOI application on the ventral surface of the medulla . Stimulatory effects of a 5-HT2 agonist on respiratory activity concerned only the respiratory frequency in the present experimental conditions.
In the physiological state, serotonin increases EEG desynchronization and produces an increase in the vigilance level and motor activity by tonic activation of 5-HT2 receptors . Similarly to unanesthetized conditions, in anesthetized and paralyzed animals EEG reflects changes in the brain state. A decrease in total EEG power density and strong depression of delta power density elicited by 5-HT2 receptor agonist DOI corresponded to desynchronization of EEG. Conversely, ketanserin increased EEG activity, thus it caused EEG synchronization. Similar effects were reported in anesthetized animals following ritanserin administration, another 5-HT2 antagonist . DOI-induced reduction in the power of EEG low frequency band oscillations was reversed by ketanserin. It is interesting that DOI did not change significantly the baseline level of alpha band activity, while ketanserin increased it mostly as it does when 5-HT2 receptors are not activated earlier by an agonist .
Beside cortical and respiratory effects, a third prominent effect of systemic administration of 5-HT2A/2C receptors acting agents were changes in the arterial blood pressure; DOI increased while ketanserin decreased the arterial blood pressure. Ketanserin is not only a serotonin antagonist, but additionally an alpha-1 adrenoreceptor antagonist  and a strong hypotension evoked by ketanserin might result from a blocking action of both types of receptors. DOI does not express alpha-1 adrenergic action. An analysis of EEG power spectra and arterial blood pressure changes in the time course of hypoxia showed a correlation between these two parameters. Such a correlation was present in all studied conditions. Whether the EEG changes evoked by serotonin active agents, DOI and ketanserin, during eupneic ventilation could, in part, reflect changes in arterial blood pressure is difficult to speculate. Hypotension alone induced, for instance, by hypovolemia, when blood gases remain constant, does not affect the EEG amplitude, until a fall of arterial blood pressure bellow 30 mmHg .
DOI and Ketanserin Effects on Responses to Hypoxia
A previous study has demonstrated that the respiratory response to hypoxia was accompanied by changes in EEG activity . The results of the present experiments show that modulation of serotoninergic neurotransmission by DOI and ketanserin altered the response profile to hypoxia of the phrenic and hypoglossal nerve activity. The time course of changes in the total power of EEG signal was related to that of the respiratory response to hypoxia. The EEG power density during the stimulatory phase of the hypoxic response altered slightly, but it became strongly depressed during apnea and then increased during recovery.
An increased hypoxic respiratory response occurred when exogenously activated 5-HT2 receptors induced the EEG desynchronization. After DOI, when EEG activity was already desynchronized, the initial hypoxic response was associated with only slight EEG changes. Activation of EEG may facilitate a significant decrease in the delta band and total EEG power density that accompanied a decline of hypoxic response, suggesting some further increase of cortical desynchronization. Such an effect may be supportive in terms of mobilization of the system to improve general oxygenation. A depression of respiratory activity during hypoxia is of central origin . This part of the hypoxic cortical response was modulated by 5-HT2 active agents. A probable contribution of cortical 5-HT2 receptors to augmented hypoxic respiratory response following DOI may ensue from an increase in glutamate in the cortex, since systemic DOI increases glutamate concentrations in the ventral tegmental area  and cortical Fos expression .
The question arises of whether there is a common source of 5-HT2 receptors involved in a relative interaction of cortical and respiratory output. Projections from serotoninergic raphe nuclei to cortical and respiratory structures originating from different parts of raphe nuclei do not designate these midline structures. A more probable site for initiating the serotonin-dependent relationship of cortical and respiratory activity seems the nucleus tractus solitarii (NTS). There are anatomical projections with reciprocal relation between the cortex and the NTS [21, 22] and it concerns also serotoninergic cells and terminals. During the respiratory response to hypoxia, information from the carotid body reaches the NTS, releasing glutamate which stimulates ventilation. A recent study has revealed that 5-HT released in the dorsomedial medulla during hypoxia acts on 5-HT2 receptors and contributes to the initial hypoxic hyperventilation and subsequent respiratory decline .
Systemic application of 5-HT2 receptor active agents evokes a generalized response in several systems in which 5-HT2 receptors are present. It affects both central and peripheral mechanisms. The present results and hypothetical explanation suggest a necessity of further studies to differentiate between the peripheral and central serotonin 5-HT2 receptors contributing to the relationship between cortical activity and responses to hypoxia.
In conclusion, serotoninergic neurotransmission through 5-HT2 receptors modulates the respiratory and EEG activity in eupneic breathing and during episodic hypoxia. Alterations in the cortical state through 5-HT2 receptor active agents may influence the profile of the hypoxic respiratory response.