title: Systemic mifepristone blocks reconsolidation of cue-conditioned fear; propranolol prevents this effect.
abstract: Reducing reconsolidation of reactivated traumatic memories may offer a novel pharmacological treatment for posttraumatic stress disorder (PTSD). Preclinical research is needed to identify candidate drugs. We evaluated the ability of postreactivation mifepristone (RU38486, a glucocorticoid antagonist), alone and in combination with propranolol (a beta-adrenergic blocker), both given systemically, to reduce cue-conditioned fear in rats. On Day 1, a 30-s tone conditioned stimulus (CS) was paired with an electric shock unconditioned stimulus (US). On Day 2, the CS was presented without the US (reactivation), and the freezing conditioned response (CR) was measured. This was immediately followed by subcutaneous injection of vehicle, mifepristone 30 mg/kg, propranolol 10 mg/kg, or both. On Day 3, the CR was again measured as a test of postreactivation long-term memory (PR-LTM). On Day 10, the CR was again measured to evaluate spontaneous recovery. On Day 11, the US was presented alone (reinstatement). On Day 12, the CR was again measured. A fifth group received mifepristone without the CS presentation (nonreactivation) on Day 2. A sixth group was tested four hours after the Day 2 mifepristone injection to measure postreactivation short-term memory. Postreactivation, but not nonreactivation, mifepristone produced a decrement in the CR that did not undergo spontaneous recovery and underwent only modest reinstatement. Mifepristone did not exert its effect when administered concurrently with propranolol. Postreactivation mifepristone did not impair short-term memory. Systemic mifepristone blocks the reconsolidation of cue-conditioned fear in rats. Concurrent administration of propranolol prevents this effect. Postreactivation mifepristone may be a promising treatment for PTSD, but not necessarily in combination with propranolol.
authors.affiliation: Department of Psychiatry, Massachusetts General Hospital, MGH-East, 120 Second Avenue, Charlestown, MA 02129, USA. roger_pitman@hms.harvard.edu
authors.forename: Roger K
authors.initials: RK
authors.lastname: Pitman
authors.forename: Mohammed R
authors.initials: MR
authors.lastname: Milad
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Igoe
authors.forename: Mark G
authors.initials: MG
authors.lastname: Vangel
authors.forename: Scott P
authors.initials: SP
authors.lastname: Orr
authors.forename: Alina
authors.initials: A
authors.lastname: Tsareva
authors.forename: Karine
authors.initials: K
authors.lastname: Gamache
authors.forename: Karim
authors.initials: K
authors.lastname: Nader
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D003213:Conditioning, Psychological / Q000187:drug effects*; D003463:Cues; D005239:Fear / Q000187:drug effects*; D005260:Female; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects; D006727:Hormone Antagonists / Q000008:administration & dosage*; D008297:Male; D057567:Memory, Long-Term / Q000187:drug effects; D015735:Mifepristone / Q000008:administration & dosage*; D011433:Propranolol / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: D000319:Adrenergic beta-Antagonists; D006727:Hormone Antagonists; D015735:Mifepristone; D011433:Propranolol