Emotional learning and glutamate: translational perspectives

Abstract

Anxiety disorders are a common focus of clinical concern and certain forms of anxiety may be conceptualized as disorders of emotional learning. Behavior therapies effective in the treatment of anxiety are modeled on extinction training as a means of reducing pathological anxiety. The present understanding of human anxiety has been informed by preclinical research using rodent models to study the acquisition and extinction of fear. Glutamate appears to have a central role in both of these processes. The authors review this literature and discuss novel applications of D-cycloserine, a partial N-methyl-D-aspartate agonist, for the treatment of anxiety.

FIGURE 1. Acrophobia within the virtual environment is improved with D-Cycloserine

A. Change in SUDS from pre- to post-test following two therapy sessions that occurred ~1 week prior to this short-term follow-up assessment. Decrease in SUDS level (y axis) is shown for each floor (1–19) of the virtual glass elevator. Overall ANOVA was performed using pre-post difference and floor as within subjects variables and drug group as between subjects variable. Significant overall pre-post changes were seen: F(1,25)=38, P<.001. Significant effect of floor was found: F(6,150)=89, P<.001. Most importantly, significant effect of pre-post X floor X drug interaction was found: F(6,150)=3.8, P<.001. B. Change in SUDS from pre to post-test at the 3-month long-term follow-up assessment. Statistics were performed as above. Significant overall pre-post changes were seen: F(1,17)=21, P<.001. Significant effect of floor was found: F(6,102)=81, P<.001. Most importantly, significant effect of pre-post X floor X drug interaction was found: F(6,102)=2.4, P<.05. Ressler KJ, Rothbaum BO, Tannenbaum L, et al. Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear. Arch Gen Psychiatry. 2004;61:136-144. SUDS=subjective units of discomfort; ANOVA=analysis of variance.

FIGURE 2. Reduction in acrophobia in the real world with DCS augmentation of virtual reality therapy. Assessment scores of acrophobia measures are shown at 3-month follow-up

A. AAQ Pre-post difference score, t(19)=2.4; P<.05 B. AAVQ Pre-post difference score, t(19)=2.4; P<.05 C. Self-report of number of in vivo exposures to heights since the treatment, t(17)=3.0; P<.01 D. Self-report of CGI (scale: “1”=very much improved, “4”=no change) t(19)=2.3; P<.05 * P<.05 Ressler KJ, Rothbaum BO, Tannenbaum L, et al. Cognitive enhancers as adjuncts to psychotherapy: use of D-cycloserine in phobic individuals to facilitate extinction of fear. Arch Gen Psychiatry. 2004;61:136-144. AAQ=Acrophobia Anxiety Questionnaire; DCS=D-cycloserine; AAVQ=Acrophobia Avoidance Questionnaire; CGI=Clinical Global Improvement.