Differential effects of alpha 4 beta 2 nicotinic receptor antagonists and partial-agonists on contextual fear extinction in male C57BL/6 mice

作者：Kutlu Munir Gunes^*; Tumolo Jessica M; Cann Courtney; Gould Thomas J

来源：Psychopharmacology, 2018, 235(4): 1211-1219.

DOI：10.1007/s00213-018-4837-4

• Nicotinic receptors
• Fear extinction
• Spontaneous recovery
• PTSD

Numerous studies have attributed the psychopathology of post-traumatic stress disorder (PTSD) to maladaptive behavioral responses such as an inability to extinguish fear. While exposure therapies are mostly effective in treating these disorders by enhancing extinction learning, relapse of PTSD symptoms is common. Although several studies indicated a role for cholinergic transmission and nicotinic acetylcholine receptors (nAChRs) in anxiety and stress disorder symptomatology, very little is known about the specific contribution of nAChRs to fear extinction
In the present study, we examined the effects of inhibition and desensitization of alpha 4 beta 2 nAChRs via a full antagonist (Dihydro-beta-erythroidine (Dh beta E)) and two alpha 4 beta 2 nAChR partial-agonists (varenicline and sazetidine-A) on contextual fear extinction, locomotor activity, and spontaneous recovery of contextual fear in mice.
We trained and tested the subjects in a contextual fear extinction as well as an open field paradigm and spontaneous recovery following injections of Dh beta E, varenicline, and sazetidine-A.
Our results demonstrated that lower doses of Dh beta E (1 mg/kg) and sazetidine-A (0.01 mg/kg) enhanced contextual fear extinction whereas higher doses of varenicline (0.1 mg/kg) and sazetidine-A (0.1 mg/kg) resulted in impaired contextual fear extinction. However, the higher dose of sazetidine-A (0.1 mg/kg) decreased locomotor activity, which may contribute to increased freezing response observed during fear extinction. Finally, we found that the low dose of Dh beta E, but not sazetidine-A, also decreased spontaneous recovery of contextual fear following fear extinction.
Overall, these results suggest that inhibition and desensitization of alpha 4 beta 2 nAChRs enhance extinction of contextual fear memories. This suggests that modulation of alpha 4 beta 2 nAChRs may be employed as an alternative pharmacological strategy to aid exposure therapies associated with PTSD by augmenting contextual fear extinction processes.

• 出版日期2018-4