Atomoxetine changes rat's HR response to stress from tachycardia to bradycardia via alterations in autonomic function

Abstract

Atomoxetine is a central norepinephrine reuptake inhibitor used to treat attention deficit hyperactivity disorder. We tested the effects of atomoxetine upon the heart rate (HR) and mean arterial blood pressure (mBP) response to aversive conditioning. In Protocol 1 the mBP and HR responses to a stress (15s tone followed by shock) were tested in 8 Sprague-Dawley rats given saline pretreatment for 3 days; the rats' responses were then tested for 3 additional days following atomoxetine (1mg/kg, sc). Atomoxetine decreased (p<0.05) baseline mBP from 128+/-11 mm Hg (mean+/-SD) to 117+/-19 mm Hg; baseline HR slowed from 380+/-23 bpm to 351+/-21 bpm. The mBP increase to acute stress was similar after saline vs. after drug, but the peak was attained more slowly. After atomoxetine HR tended to slow during stress rather than accelerate. In Protocol 2 the cardiovascular responses were tested (n=6) for 3 days post-saline and for 3 days after a higher dose of atomoxetine (2mg/kg, sc). The average HR acceleration during the last 10s of the stress after saline (+7.5+/-14.7 bpm) was replaced by a HR slowing (-6.2+/-10.5 bpm). We conclude that drug treatment (a) decreases baseline sympathetic tone and/or elevates cardiac parasympathetic tone; (b) slows sympathetic arousal to acute stress without changing its magnitude; and, (c) enables the emergence of elevated parasympathetic tone during the stress. These autonomic consequences are consistent with atomoxetine's anxiolytic and transient sedative effects.

Figure 1

Group average (n=8 rats) of change (△) in mean arterial blood pressure (mBP; top panel) and in heart rate (HR, bottom panel) before (0-15 sec), during CS+ tone (15-30 sec.; dark bar on abscissa) and after ½ second shock (given at 30 sec.) in Protocol 1 rats following saline on days 1, 2 and 3 (black) and again following saline on days 4, 5 and 6 (blue). For each rat mBP and HR data files from each of 15 CS+ trials were ensembled to create a “high resolution file” for that animal. The high resolution files were then ensembled across the 8 animals. For C_1, the point where mBP initially peaks (pk C₁) and the time span over which the change in mBP is averaged (avg C₁) are indicated. The thin blue arrow extending downward to the X-axis from pk C₁ (i.e., blue line: days 4,5 and 6) indicates the time at which peak C₁ was attained (t_pkC1) for the second set of trials; this value was not significantly different for the two sets of trials (see Table 1). The time range for the C₂ components of the mBP conditional response and the C₂ component of the HR response are also demarcated, as is the unconditional response (UR) to the shock. Note that there were no significant changes in the response pattern across time.

Figure 2

Baseline mean arterial blood pressure (mBP, left) and heart rate (HR, right) during 15 sec. preceding tone for trials conducted in each of the 8 rats in Protocol 1. Data are taken after saline and after atomoxetine administration. Atomoxetine induced a significant decrease in both baseline mBP and in HR. * = p < 0.05, saline vs. atomoxetine

Figure 3

Baseline mean arterial blood pressure (mBP, left) and heart rate (HR, right) during 15 sec. preceding tone for trials conducted in each of the 6 rats in Protocol 2. Data are taken after saline and after atomoxetine administration. Atomoxetine induced a significant decrease in baseline HR; change in mBP was not statistically significant. * = p < 0.05, saline vs. atomoxetine.

Figure 4

Group average (n=6 rats) of actual values of mean arterial blood pressure (mBP; top panel) and of heart rate (HR, bottom panel) before (0-15 sec), during CS+ tone (15-30 sec.; dark bar on abscissa) and after ½ second shock (given at 30 sec.) in rats in Protocol 2 following saline (S; black) on days 1, 2 and 3 (S; black) and following drug (D; blue) on days 4, 5 and 6 (D, 2 mg/kg; blue). Overall mBP was lower following atomoxetine, but there were no significant differences in the amplitudes of the components of the conditional or unconditional arterial blood pressure response. Conversely, it is clear that the initial peak in mBP was attained later after drug (blue) than after saline (black). In addition, HR was significantly lower following drug, and HR slowed during last 10 seconds of tone (dark bar, abscissa) after atomoxetine (blue), rather than the usual acceleration (black).

Figure 5

Average (n=6 rats) ± SD change in mean arterial blood pressure (mBP, top panel) and in heart rate (HR, bottom panel) during C₂ component for CS+ (black) and CS− (cross hatched) trials. Data on left are for rats in Protocol 2 after saline administration; data on right are after atomoxetine (2 mg/kg, right). Drug had no effect on discrimination between shock reinforced CS+ tone and neutral CS− tone. * = p < 0.05, CS+ vs. CS−.