Current behavioral therapy procedures for these disorders are somewhat effective, but their efficacy could be substantially improved. Because these procedures are largely based on the process of extinction, manipulations that enhance extinction may lead to improvements in treatment effectiveness. Although only a few studies have examined the effects of DCS on extinction of learned fear, this work suggests that this drug may have a number of potential clinical benefits.
Ravikumar Ponnusamy ,1 Helen A. Received Dec 7; Accepted Jun 7. Abstract Extinction of conditioned fear in animals is the explicit model of behavior therapy for human anxiety disorders, including panic disorder, obsessive-compulsive disorder, and post-traumatic stress disorder.
Based on previous data indicating that fear extinction in rats is blocked by quinpirole, an agonist of dopamine D2 receptors, we hypothesized that blockade of D2 receptors might facilitate extinction in mice, while agonists should block extinction, as they do in rats.
One day after fear conditioning mice with three pairings of a white noise conditional stimulus CS with moderate footshock, we injected the D2 antagonist, sulpiride, the D2 agonist, quinpirole, or vehicle, just before repeated CS presentations to generate extinction.
We assayed fear by measuring behavioral freezing during extinction presentations and then drug-free during CS presentations 1 d later. We found that sulpiride injections before extinction training facilitated extinction memory 24 h later, while quinpirole partially blocked extinction memory compared with vehicle-injected controls.
Notably, sulpiride treatment yielded significant extinction after spaced CS presentations, which yield no extinction at all in vehicle-treated mice. These findings suggest that dopamine D2-mediated signaling contributes physiological inhibition of extinction, and that D2 antagonists may be useful adjuncts to behavior therapy of human anxiety disorders.
Extinction of conditioned fear in mammals is an important pre-clinical model of behavior therapy, one of the most effective treatments for human anxiety disorders Wolpe ; Craske Despite the efficacy of behavior therapy for human anxiety disorders, extinction-like treatments require repeated cue exposures and are vulnerable to reversal by a number of environmental factors.
Thus, a deeper understanding of the synaptic mechanisms of extinction may permit the development of adjunctive medications to facilitate extinction learning, and perhaps, to make it more permanent. The rate of PTSD may well go higher in the context of current wars and terrorist acts.
Given the enormous burden of such anxiety disorders, we are fortunate in having a reasonable animal model for the acquisition of some of these fears, that is, classically conditioned fear, and an even better animal model of an effective treatment method for those disorders, extinction of conditioned fear.
Pavlovian, or classical, fear conditioning has long been an important model both of associative learning and of the etiology of human anxiety Watson and Rayner ; Eysenck ; Wolpe and Rowan Temporal pairing of a neutral conditional stimulus CS with an aversive unconditional stimulus US generates robust conditional fear responses upon subsequent presentations of the CS in experimental animals, including mice.
Fearful mice or rats show responses similar to those of human fear and anxiety, including increases of blood pressure and heart rate, changes in respiration, increased startle responses, and behavioral freezing Blanchard and Blanchard ; Archer ; Bolles and Fanselow ; Davis ; Blanchard et al.
Extinction of conditioned fear is the progressive decrease of the fear response generated by the repeated presentation of the CS without any US.
Considerable evidence indicates that extinction, like fear acquisition, is active learning, which inhibits rather than erases the original association. Thus, extinction appears only to inhibit the expression of an intact underlying fear, and extinction memory is labile and weak compared with fear conditioning itself.
It is likely that factors like these account for the inefficiency of behavior therapy for human anxiety.
Thus, the identification of pharmacological means of facilitating extinction, particularly using systemic administration, will likely yield effective adjunctive treatments to accelerate behavior therapy.
One group has already provided proof of this principle. Like many other forms of learning and synaptic plasticity, including fear acquisition, extinction depends on NMDA-type glutamate receptor activity Falls et al. Exploiting this dependence, several researchers have recently shown and confirmed that d-cycloserine, an agonist at the glycine-binding site of the NMDA receptor, facilitates both fear extinction Walker et al.
On the other hand, we and others have recently shown that extinction differs from fear acquisition at the molecular level, since extinction, but not acquisition or expression, of conditioned fear depends on L-type voltage-gated calcium channels LVGCCs Cain et al.D-Cycloserine and the Facilitation of Extinction of Conditioned Fear: Consequences for Reinstatement Lana Ledgerwood, Rick Richardson, and Jacquelyn Cranney University of New South Wales Several.
Facilitation of Extinction of Conditioned Fear by D-Cycloserine Implications for Psychotherapy Michael Davis,1,2,3,4 Karyn M. Myers,2,3,4 Kerry J. Ressler,2,3,4 Barbara O. Rothbaum2,3 Departments of 1Psychology and 2Psychiatry & Behavioral Sciences, 3Center for Behavioral Neuroscience, and 4Yerkes National Primate Research Center, Emory University ABSTRACT—Excessive fear and anxiety are.
neuroscience () – facilitation of conditioned fear extinction by d-cycloserine is mediated by mitogen-activated protein kinase and phosphatidylinositol 3-kinase cascades and requires de novo protein synthesis in basolateral nucleus of amygdala y.
l. yanga and k. ORIGINAL INVESTIGATION Amygdaloid zif participated in the D-cycloserine facilitation effect on the extinction of conditioned fear I-Tek Wu1,2 & Tso-Hao Tang1 & Meng-Chang Ko1 & Chen-Yu Chiu1 & Kwok-Tung Lu1 Received: 31 March /Accepted: 30 July /Published online: 19 August Cannabinoid facilitation of fear extinction memory recall in humans.
we found THC administration facilitates extinction of conditioned fear in participants with minimal or no previous history of marijuana usage; however we cannot generalize these findings to chronic marijuana users.
M. DavisFacilitation of conditioned fear extinction by. Extinction of conditioned fear in animals is the explicit model of behavior therapy for human anxiety disorders, including panic disorder, obsessive-compulsive disorder, and post-traumatic stress disorder.
Based on previous data indicating that fear extinction in rats is blocked by quinpirole, an.