Ivabradine Improves Cognitive and Behavioral Responses Following Traumatic Stress
Authors: Woodman Ryan , Student Jeffrey , Miller Coleman , Lockette Warren 
Published: June 2021

Background

Alpha‐2 adrenergic receptor (α2AR) agonists, such as clonidine or dexmedetomidine, can decrease the working memory acquisition of a traumatic event, and also, blocking the post‐synaptic action of the catecholamines with a β‐adrenergic receptor (β‐AR) antagonist, propranolol, can reduce the emotional response to memories of the traumatic event. α2ARs and β‐ARs divergently regulate neuronal intracellular cyclic adenosine monophosphate (cAMP) concentrations. It is suggested that other pharmacologic mechanisms that similarly lead to reductions in neuronal cAMP could also be salutary in the treatment of post‐traumatic stress (PTSD). In the central nervous system, hyperpolarization‐activated, cyclic nucleotide‐gated (HCN) “funny” channels are important for dendritic integration, synaptic transmission, setting membrane potential, and neuronal firing rate. These funny channels (HCN1 and HCN2) are expressed in the forebrain and pre‐frontal cortex where they are co‐located and cross talk with A2ARs that mediate intracellular cAMP concentrations and drive working memory and the emotional valence associated with memories. Also, targeted disruption of HCN gene expression, or inhibition of cyclic nucleotide binding to HCN channels in the brain, has been shown to result in antidepressant‐like behavior with improved coping in animal models of stress.

Hypothesis

We postulated that pharmacological inhibition of HCN channels would diminish the anxiolytic and cognitive decline that occurs in an animal model of PTSD.

Methods

We infused an HCN antagonist, ivabradine (10 mg/kg/day), subcutaneously or performed sham surgery in a mouse model of PTSD. After six days of random cued and contextual fear conditioning, mouse anxiety and cognition was assessed by their performance over five minutes on three standard behavioral challenges—Open Field Test (OFT), Elevated Plus Maze (EPM), and Object Recognition Test (ORT).

Results

During the OFT, ivabradine did not significantly affected the total exploratory distance traveled. However, ivabradine significantly increased the time the mice spent in the center of the field (all values expressed in sec ± SEM), from 19.0 ± 2.2 to 27.7 ± 3.2, p = 0.029. During EPM, ivabradine increased the time mice spent traversing the open arm from 66.8 ± 8.5 to 116 ± 11.5, p = 0.002, During the ORT, social isolation during PTSD reduced total exploratory time from 24.7 ± 4.9 to 13.1 ± 2.2, and the ivabradine group increased exploratory time to 30.0 ± 3.3 compared to the mice living in isolation with PTSD (p = 0.0004). Furthermore, when compared to the untreated PTSD mice living in social isolation, ivabradine significantly increased the exploratory times of both familiar (14.3 ± 1.9 vs. 5.6 ± 1.1, p=0.0008) and novel objects (15.8 ± 2.4 vs. 7.5 ± 1.6, p = 0.01).

Conclusion

Ivabradine may offer salutary advantage to men and women who experience PTSD.

Support or Funding Information

Department of Defense

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.