From non-pharmacological interventions to therapeutic targets for the treatment of PTSD

Abstract

Posttraumatic stress disorder (PTSD) is a severe anxiety disorder, which may develop after exposure to a traumatic event. PTSD gained a lot of attention in the media due to recent wars and the attack on the World Trade Centre in New York. Currently available pharmacological therapies are effective only in a subpopulation of patients. Therefore, better treatment options are needed. Development of new drugs starts with target discovery. A therapeutic target is a molecular switch, most often a protein, that, when triggered, selectively alleviates disease. Non-pharmacological therapies are relatively effective treatments for depressive and anxiety disorders. From studying the underlying mechanisms of the non-pharmacological interventions that lead to behavioral recovery, it may be possible to deduce novel therapeutic targets. In this thesis we have investigated the underlying mechanisms of the anxiolytic/antidepressive effects of environmental enrichment with or without voluntary exercise (EE/VE), re-exposure (RE) and food restriction (FR) in the inescapable foot shock (IFS) paradigm (an animal model for model PTSD in rats). Our aim was to identify pathways and proteins that can serve as therapeutic targets. EE, as opposed to standard housing, consisted of a larger cage with a shelter, large plastic tubes, gnaw-sticks, tissues, nesting materials, and sometimes a running-wheel. RE consisted of repeatedly placing the rat in the same box in which it received the IFS but without the shocks. Rats that were under the FR regime were provided with 60% of the amount of food the ad libitum fed control rats ate. We found that exposure to EE/VE or RE enhanced the recovery of the traumatized rats. However, FR did not attenuate the anxiogenic effects of IFS. We investigated these interventions to elucidate the molecular changes that might lead to recovery after IFS. Our discoveries that the neuropeptide Y1 receptor (Y1) and the corticotropin-releasing factor receptor 1 (CRFR1) are involved in this recovery are examples of therapeutic target discovery using non-pharmacological interventions. In conclusion we showed that EE and RE are very effective strategies to treat PTSD in an animal model. We hope that our experiments will contribute to the identification of therapeutic targets that, when activated, really cure patients suffering from PTSD or depression. Unfortunately, such targets have not yet been identified, which is why, until then, we really urge patients to exercise.