Cholinergic modulation of exposure disrupts hippocampal processes and augments extinction: proof-of-concept study with social anxiety disorder

Abstract Background In rodents context specificity of Pavlovian extinction is attenuated by manipulations that impair hippocampal function, including systemic administration of scopolamine, a muscarinic-cholinergic receptor antagonist. Context renewal translates into return of fear following exposure therapy to feared situations. We evaluated the effectiveness of scopolamine for attenuating context renewal of phobic fear. Method 60 participants (female = 35, male = 22, transgender = 1, undeclared = 2) with social anxiety disorder and fear of public speaking were randomized to placebo, .5mg or .6mg scopolamine. They completed seven exposure sessions in an exposure context and subsequently tested in the exposure context (extinction retest) versus a different context (context renewal test), counterbalanced. Testing one-month later occurred in the exposure context (long-term extinction retest). Fear measures included skin conductance and self-reported distress during speeches. Hippocampus dependent cognitive tasks were completed as well. Results Scopolamine augmented extinction across exposure sessions on skin conductance response and skin conductance level. Lower skin conductance response at context renewal in scopolamine groups relative to placebo was constrained to simple effects and complicated by unexpected outcomes within placebo and on self-reported fear. Scopolamine led to lower skin conductance response at long-term extinction retest. Scopolamine impaired performance on a cognitive task of hippocampal function. Conclusions Non-invasive and well-tolerated scopolamine impaired hippocampal processes and augmented extinction during exposure. Drug-free effects persisted one month later. Findings at context renewal were limited and suggestive only. Further investigation is warranted with varying scopolamine dosages.