Effect of CB1 Receptor Antagonist, AM251, on Plasma Corticosterone levels and Anxious Behavior in Sprague-Dawley Rats

Benjamin, Cody

Effect of CB1 Receptor Antagonist, AM251, on Plasma Corticosterone levels and Anxious Behavior in Sprague-Dawley Rats

Persistent URL

http://hdl.handle.net/10456/34262

Author(s)

Benjamin, Cody

Date Issued

April 24, 2013

Abstract

Anxiety disorders are the most common mental illness in the United States. Debilitating symptoms relating to anxiety disorders affect over 40 million American adults, representing over 18 percent of the United States population (ADAA). Research suggests that methods of acute cortisol elevation may serve as therapy for some anxiety disorders (Wisloska-Stanek et al., 2012). Intraperitoneal administration of AM251, a CB1 antagonist, has been shown to elevate plasma corticosterone levels in rodents, as well as elevate behavioral depression in mice (Ginsberg et al., 2010 and Steiner et al., 2007). These findings suggest that, in addition to clinical treatment of depression, CB1 receptor modulating drugs may also have a clinical use in the treatment of anxiety disorders. Few studies have investigated intracranial routes of administration, however those that do suggest that AM251 may not be effective alone in initiating HPA hyperactivity, but instead prevent HPA suppression elicited by CB1 agonist administration. These findings develop a level of uncertainty regarding the mechanism by which CB1 mediated suppression of the HPA axis works (Evanson et al., 2010).The aim of the current experiment was to investigate the role of cannabinoid receptor signaling in the regulation of the HPA axis through the use of the CB1 antagonist AM251 to selectively block the function of retrograde CB1 signaling in the hypothalamic PVN. This molecule possesses an inverse agonist relationship with the CB1 receptor making it an ideal antagonist for experimentation (Steiner et al., 2007). Intracranial injections of two different concentrations of AM251 were administered unilaterally to the hypothalamic PVN in Sprague-Dawley rats, and compared to a control group through plasma corticosterone testing and elevated plus-maze testing. It has been demonstrated that CB1 signaling is significantly involved in the fast feedback response to HPA activation via glucocorticoid signaling (Evanson et al., 2010). This signaling pathway results in suppression and excitation of the HPA axis with regard to CB1 agonists and antagonists, respectively (Ginsberg et al., 2010). Therefore, the hypothesis was that administration of the antagonist AM251 would increase plasma corticosterone levels in a dose-dependent relationship, such that administration of a lower concentration of AM251 would increase time spent in open arms of an elevated plus maze and decrease other observable anxious behaviors compared to the control. Likewise, administration of a higher concentration of AM251 would increase time spent in enclosed arms of an elevated plus maze and increase other observable anxious behaviors compared to control. Other anxious behaviors to be noted included dips, entries (4 limbs), intermediate entries (2 limbs), and peeks. Results suggest no significant effect of drug concentration on plasma corticosterone levels, although marginal trends were observed for plasma corticosterone between groups. Results additionally suggest no significant effect of AM251 administration on anxious behavior, although high levels of behavioral anxiety were observed from all groups. This study presents several novelties. No study has investigated a dose-response relationship of intracranial AM251 administration to the hypothalamic PVN. Additionally, no study has examined intracranial AM251 administration to the PVN with regard to a behavioral test for anxiety. This study was the first examine both, and how a possible dose-response relationship correlates with anxious behavior.

First Reader(s)

Hollerman, Jeffrey R.