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 in humans.

Methods: A total of 60 participants (35 female, 22 male, 1 transgender, 2 undeclared) with social anxiety disorder and fear of public speaking were randomized to placebo, 0.5 mg scopolamine, or 0.6 mg 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), which were counterbalanced. Testing 1 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 the placebo group 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: Noninvasive and well-tolerated scopolamine impaired hippocampal processes and augmented extinction during exposure. Drug-free effects persisted 1 month later. Findings at context renewal were limited and suggestive only. Further investigation is warranted with varying scopolamine dosages.

Trial registration: ClinicalTrials.gov NCT01900301.

Keywords: Context renewal; Extinction; Fear; Hippocampus; Public speaking; Scopolamine.

Copyright © 2019 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1.

Flow chart for seven exposure sessions, each including seven speeches to a virtual reality (VR) audience, context renewal and extinction retest, and long-term extinction retest. (Session 1 included a baseline speech before drug administration.) ITI, intertrial interval.

Figure 2.

(A) Skin conductance response-to-conditional stimulus (SCR-to-CS) onset across extinction. Multilevel modeling time points included first speech of first exposure session (drug free) and last (seventh) speech of exposure sessions 2 through 7. Compared with placebo, both scopolamine 0.5 mg (SCOP 0.5 mg) and 0.6 mg (SCOP 0.6 mg) demonstrated significantly lower SCR-to-CS onset on average across extinction (ps < .01). There were no differences between SCOP 0.5 mg and SCOP 0.6 mg. (B) SCR-to-CS termination across extinction. Multilevel modeling time points included first speech of first exposure session (drug free) and last (seventh) speech of exposure sessions 2 through 7. Compared with placebo, both SCOP 0.5 mg and SCOP 0.6 mg demonstrated significantly lower SCR-to-CS termination on average across extinction (ps < .01). There were no differences between SCOP 0.5 mg and SCOP 0.6 mg.

Figure 3.

(A) Skin conductance level (SCL) anticipation across extinction. Multilevel modeling time points included first speech of first exposure session (drug free) and last (seventh) speech of exposure sessions 2 through 7. Compared with placebo, both scopolamine 0.5 mg (SCOP 0.5 mg) and 0.6 mg (SCOP 0.6 mg) demonstrated significantly lower SCL anticipation on average across extinction (ps < .01). There were no differences between SCOP 0.5 mg and SCOP 0.6 mg. (B) SCL recovery across extinction. Multilevel modeling time points included first speech of first exposure session (drug free) and last (seventh) speech of exposure sessions 2 through 7. Compared with placebo, both SCOP 0.5 mg and SCOP 0.6 mg demonstrated significantly lower SCL recovery on average across extinction (ps < .05). There were no differences between SCOP 0.5 mg and SCOP 0.6 mg.

Figure 4.

(A) Skin conductance response-to-conditional stimulus (SCR-to-CS) onset across end of extinction (Ext), renewal, and retest. Multilevel modeling time points included first speech of first exposure session (drug free) (not depicted), last (seventh) speech of exposure sessions 2 through 7, context (Ctx) renewal, and extinction retest (counterbalanced) in participants who extinguished. +p = .10, ++p = .06. There were no group differences at end of extinction (session 7). At context renewal, scopolamine 0.5 mg (SCOP 0.5 mg) (p = .10) and 0.6 mg (SCOP 0.6 mg) (p = .06) showed trends for lower SCR-to-CS onset than placebo did, and there were no differences between SCOP 0.5 mg and SCOP 0.6 mg. There were no group differences at extinction retest. There were no significant differences between context renewal and extinction retest within any group. (B) SCR-to-CS termination across end of extinction, renewal, and retest. Multilevel modeling time points included first speech of first exposure session (drug free) (not depicted), last (seventh) speech of exposure sessions 2 through 7, context renewal, and extinction retest (counterbalanced) in participants who extinguished. *p < .05, **p < .01. Compared with placebo, SCOP 0.5 mg (p < .05) and SCOP 0.6 mg (p < .01) demonstrated significantly lower SCR-to-CS termination at end of extinction (session 7). At context renewal, SCOP 0.6 mg, compared with placebo, demonstrated significantly lower SCR-to-CS termination (p < .05) with no differences between SCOP 0.5 mg and SCOP 0.6 mg. There were no group differences at extinction retest. SCOP 0.6 mg demonstrated higher scores at extinction retest than context renewal (p < .05), whereas there were no differences within either SCOP 0.5 mg or placebo.

Figure 5.

Skin conductance response-to-conditional stimulus (SCR-to-CS) termination across end of extinction (session 7) and long-term extinction retest (1 month follow-up [FU]). Multilevel modeling time points included first speech of first exposure session (drug free), last (seventh) speech of exposure sessions 2 through 7, and long-term extinction retest. *p < .05, **p < .01. SCR-to-CS termination increased from end of extinction to long-term extinction retest (p < .001). Scopolamine 0.6 mg (SCOP 0.6 mg) and 0.5 mg (SCOP 0.5 mg), compared with placebo, demonstrated significantly lower SCR-to-CS termination at long-term extinction retest. There were no differences between SCOP 0.5 mg and SCOP 0.6 mg.