Chronic serotonin-norepinephrine reuptake transporter inhibition modifies basal respiratory output in adult mouse in vitro and in vivo

Abstract

Respiratory disturbances are a common feature of panic disorder and present as breathing irregularity, hyperventilation, and increased sensitivity to carbon dioxide. Common therapeutic interventions, such as tricyclic (TCA) and selective serotonin reuptake inhibitor (SSRI) antidepressants, have been shown to ameliorate not only the psychological components of panic disorder but also the respiratory disturbances. These drugs are also prescribed for generalized anxiety and depressive disorders, neither of which are characterized by respiratory disturbances, and previous studies have demonstrated that TCAs and SSRIs exert effects on basal respiratory activity in animal models without panic disorder symptoms. Whether serotonin-norepinephrine reuptake inhibitors (SNRIs) have similar effects on respiratory activity remains to be determined. Therefore, the current study was designed to investigate the effects of chronic administration of the SNRI antidepressant venlafaxine (VHCL) on basal respiratory output. For these experiments, we recorded phrenic nerve discharge in an in vitro arterially-perfused adult mouse preparation and diaphragm electromyogram (EMG) activity in an in vivo urethane-anesthetized adult mouse preparation. We found that following 28-d VHCL administration, basal respiratory burst frequency was markedly reduced due to an increase in expiratory duration (T(E)), and the inspiratory duty cycle (T(I)/T(tot)) was significantly shortened. In addition, post-inspiratory and spurious expiratory discharges were seen in vitro. Based on our observations, we suggest that drugs capable of simultaneously blocking both 5-HT and NE reuptake transporters have the potential to influence the respiratory control network in patients using SNRI therapy.

Figure 1. Effects of chronic (28-d) SAL and VHCL treatment on phrenic nerve discharge in the in vitro arterially-perfused adult mouse preparation

Example traces of integrated (Int) and raw phrenic nerve discharge observed in SAL-treated (upper panel) and VHCL-treated (lower panel) mouse preparations. In VHCL-treated mice, phrenic nerve discharge was regular but slower than that seen in SAL-treated mice. Post-inspiratory discharge was also observed in VHCL-treated mice. Both 30-s duration traces (left) and expanded 1-s traces (right) are shown.

Figure 2. Effects of chronic (28-d) SAL and VHCL treatment on timing and patterning of phrenic nerve discharge

Summary data showing that VHCL-treated mice exhibited a significant reduction in burst frequency, a substantial prolongation of T_E, and a significant decrease in T_I/T_tot. No significant differences in T_I or T_peak/T_I were noted. Asterisks denote a statistically significant difference (P<0.05) between SAL- and VHCL-treated mice.

Figure 3. Effects of chronic (28-d) SAL and VHCL treatment on diaphragm EMG activity in the in vivo urethane-anesthetized mouse preparation

Example traces of integrated (Int) and raw diaphragm EMG activity observed in SAL-treated (upper panel) and VHCL-treated (lower panel) mouse preparations. In VHCL-treated mice, respiratory burst frequency was regular but slower than that seen in SAL-treated mice. Both 10-s duration traces (left) and expanded 250-ms traces (right) are shown.

Figure 4. Effects of chronic (28-d) SAL and VHCL treatment on timing and patterning of diaphragm EMG bursts

Summary data showing that VHCL-treated mice exhibited a reduced breathing frequency, which resulted from a significant prolongation of T_E. A significant decrease in T_I/T_tot was also observed. No significant differences in T_I or T_peak/T_I were noted. Asterisks denote a statistically significant difference (P<0.05) between SAL- and VHCL-treated mice.