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. 2018 Nov 26;19(12):3748.
doi: 10.3390/ijms19123748.

Cognitive Deficits Following a Post-Myocardial Infarct in the Rat Are Blocked by the Serotonin-Norepinephrine Reuptake Inhibitor Desvenlafaxine

Mandy Malick  1   2 , Kim Gilbert  3   4 , Jonathan Brouillette  5   6 , Roger Godbout  7   8 , Guy Rousseau  9
Affiliations

Cognitive Deficits Following a Post-Myocardial Infarct in the Rat Are Blocked by the Serotonin-Norepinephrine Reuptake Inhibitor Desvenlafaxine

Mandy Malick et al. Int J Mol Sci. .

Abstract

Myocardial infarction (MI) in animal models induces cognitive deficits as well as the activation of caspase in the limbic system; both can be blocked by 2 weeks of treatment following MI using tricyclic antidepressants or selective serotonin uptake blockers. Here we used three different treatment schedules to test the short- and long-term effects of the combined serotonin-norepinephrine reuptake inhibitor desvenlafaxine on post-MI-associated cognitive deficits and caspase activation. MI was induced in 39 young adult rats, and 39 rats served as sham-operated controls. Desvenlafaxine (3 mg/kg/day, i.p.) or saline was administered according to one of three schedules: (1) for 2 weeks, starting right after surgery; (2) for 16 weeks, starting 2 weeks after surgery; (3) for 16 weeks, starting right after surgery. Behavior was tested 2 weeks (social interaction, passive avoidance) and 16 weeks (forced swimming, Morris water maze) after surgery. Caspase-3 and caspase-6 activities were measured 16 weeks after surgery. At 2 and 16 weeks post-surgery, saline-treated MI rats displayed performance deficits compared to desvenlafaxine-treated rats, regardless of the treatment schedule. Caspase-3 activity was higher in the amygdala (medial and lateral) and hippocampal CA3 region in untreated MI rats, whereas caspase-6 activity was higher in the CA1 region. Caspase-6 activity correlated positively with deficits in the Morris water maze. These results indicate that, independently of treatment schedules, various treatment schedules with desvenlafaxine can prevent MI-associated cognitive deficits and decrease caspase activities in the limbic system.

Keywords: behavior; caspase-3; caspase-6; desvenlafaxine; limbic system; memory; myocardial infarction.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Social interaction. MI rats treated with the vehicle interacted less with other rats than Sham rats treated with the vehicle. MI rats treated with DV performed at the same level as sham rats treated with the vehicle or with DV. n = 10–18/group. * p < 0.05. MI: myocardial infarction; Veh: vehicle; DV: Desvenlafaxine.
Figure 2
Figure 2
Passive-avoidance step-down test. Left panel: Time to success refers to the time spent by the rats on the platform they should not escape from. Right panel: Number of trials required before learning the task. The performance of MI rats treated with the vehicle was impaired compared to the other groups of rats. MI rats treated with DV performed at the same level as sham rats treated with the vehicle or with DV. n = 9–16 per group. * p < 0.05. MI: myocardial infarction; Veh: vehicle; DV: Desvenlafaxine.
Figure 3
Figure 3
Forced swimming test. MI rats treated with the vehicle were more immobile than the Sham rats treated with the vehicle and they swam less than the Sham rats treated with the vehicle or with DV. MI rats treated with DV performed at the same level as sham rats treated with the vehicle or with DV on measures of immobility and swimming. Escape trial duration was significantly longer in MI rats treated with the vehicle than the DV-treated Sham rats and MI rats. n = 9–12 per group. * p < 0.05. MI: myocardial infarction; Veh: vehicle; DV: Desvenlafaxine.
Figure 4
Figure 4
Morris Water Maze test. Left panel: Time needed to reach the target platform expressed as a percentage of time needed by sham rats treated with the vehicle. Right panel: Total number of quadrants crossed (6 trials per day) before finding the target platform. The dotted lines with triangle markers represent the results obtained by vehicle-treated MI rats. When tested 4 months after surgery, vehicle-treated MI rats took more time to find the platform and crossed more quadrants to find the platform compared to any of the other groups; n = 9–12 per group. (p < 0.05). The performance of the MI rats treated with DV was the same as that of the vehicle-treated sham rats. MI: myocardial infarction; Veh: vehicle; DV: Desvenlafaxine.
Figure 5
Figure 5
Caspase-3 activity. Casapse-3 activity in the CA3 region of the hippocampus, the medial amygdala, and the lateral amygdala of MI-Veh compared to Sham-Veh rats 4 months after surgery. Caspase-3 activity is higher in the vehicle-treated rats compared to any other group; caspase-3 activity is not different between DV-treated rats and vehicle-treated sham rats. n = 6–8 per group. * p < 0.05.
Figure 6
Figure 6
Caspase-6 activity in the CA1 region of the hippocampus 4 months after surgery. Caspase-6 activity in the CA1 region of the hippocampus is higher in vehicle-treated MI rats compared to any other group; caspase-6 activity is not different between DV-treated rats and vehicle-treated sham rats.; n = 6–8 per group (* p < 0.05).
Figure 7
Figure 7
Correlation between spatial memory performance and caspase-6 activity in the CA1 region of the hippocampus 4 months after surgery. Data are taken from day 3 With all groups of rats pooled together, the linear regression test showed a significant positive correlation between the time needed to reach the target platform (on day 3 of a 6 days series—see Figure 4). r2 = 0.36; p < 0.05.
Figure 8
Figure 8
Protocol timeline. Schematic representation of the treatment protocol. MI rats treated with DV were distributed in schedules 1, 2 and 3. Lines represent DV treatment. Sham rats treated with DV were distributed only in schedule 3. Other MI and sham rats received only vehicle. Behavioral test series #1: social interaction test and passive-avoidance step-down test; behavioral test series #2: forced swimming and Morris Water Maze (MWM) tests. “Water tests” were grouped at the end of the experiment.
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