Preclinical Evaluation of Reconsolidation Blockade by Clonidine as a Potential Novel Treatment for Posttraumatic Stress Disorder

Abstract

Exposure to traumatic events can lead to posttraumatic stress disorder (PTSD). Current PTSD treatments typically only produce partial improvement. Hence, there is a need for preclinical research to identify new candidate drugs and to develop novel therapeutic approaches. Animal studies have indicated that fear memories can be weakened by blocking restabilization after retrieval, a process known as reconsolidation. Furthermore, evidence suggests that there are important alterations of the noradrenergic system in PTSD, and hence it may be of interest to study drugs that target this pathway. Here, we investigated the efficacy of clonidine, an a 2 -adrenoreceptor agonist, to block reconsolidation in an animal model of persistent traumatic memories. Using an auditory fear conditioning paradigm in rats, we tested the efficacy of clonidine to weaken fear memory retention when administered systemically after retrieval. We evaluated dosage, number of treatments, and specificity in reconsolidation blockade. We found that postretrieval administration of clonidine disrupts fear-related memories in a dose-dependent manner and that two treatments are sufficient for maximal memory impairment. Furthermore, we determined that this effect is long lasting and specific to reconsolidation processes as shown by the selectivity to affect reactivated memories and the absence of spontaneous recovery and of postreactivation short-term memory impairment. Our results demonstrate the efficacy of systemic administration of clonidine following retrieval to persistently disrupt fear memory retention through reconsolidation blockade. This study provides important preclinical parameters for future therapeutic strategies involving clonidine to block reconsolidation as a novel treatment for PTSD symptoms.

Enhanced noradrenergic activity potentiates fear memory consolidation and reconsolidation by differentially recruiting α1- and β-adrenergic receptors

“…It is also thought that neither sedation nor locomotor activity impairments were confounding effects of clonidine in the doserange tested because freezing time was reduced and not increased. The present results agree with those in which clonidine impaired consolidation of a two-way avoidance task (Gozzani and Izquierdo 1976) or reconsolidation of an auditory fear-conditioning (Gamache et al 2012), and support the premise that the facilitating role of yohimbine in both these memory phases is ultimately caused by enhanced noradrenergic transmission through blockade of a2-adrenergic receptors. If so, despite other effects of this drug being at least in part ascribed to its interaction with different receptors such as dopamine type 2 and serotonin type 1A (Holmes and Quirk 2010), one would anticipate a role for a1-and/or b-adrenergic receptors.…”

Human genome–guided identification of memory-modulating drugs

“…Additional studies are warranted to identify an optimal doseresponse relation and optimal timing of administration, to investigate the effects of diphenhydramine on the distinct memory phases of memory formation and retrieval, and to study whether the administration timed to traumatic reactivation is able to interfere with reconsolidation in patients suffering from PTSD (37,38). Our study also provides additional, potentially interesting compounds, which can be tested in following clinical trials.…”

Selective loss of dopaminergic neurons in the substantia nigra pars compacta after systemic administration of MPTP facilitates extinction learning

“…Different mice groups were used independently in the experiment of reconsolidation and extinction tests. To examine whether fear memory reconsolidation occurs after re-exposure (3 min) to CS, we examined the effect of clonidine, which can block reconsolidation [21], on fear memory reconsolidation. Clonidine hydrochloride (Wako, Tokyo, Japan) was dissolved in sterile saline (0.9% NaCl), and clonidine or its vehicle was administered by a single i.p.…”