Abstract
Avoidance and its perseveration represent key features of anxiety disorders. Both pharmacological and behavioral approaches (i.e., anxiolytics and extinction therapy) have been utilized to modulate avoidance behavior in patients. However, the outcome has not always been desirable. Part of the reason is attributed to the diverse neuropathology of anxiety disorders. Here, we investigated the effect of psychotropic drugs that target various monoamine systems on extinction of avoidance behavior using lever-press avoidance task. Here, we used the Wistar-Kyoto (WKY) rat, a unique rat model that exhibits facilitated avoidance and extinction resistance along with malfunction of the dopamine (DA) system. Sprague Dawley (SD) and WKY rats were trained to acquire lever-press avoidance. WKY rats acquired avoidance faster and to a higher level compared to SD rats. During pharmacological treatment, bupropion and desipramine (DES) significantly reduced avoidance response selectively in WKY rats. However, after the discontinuation of drug treatment, only those WKY rats that were previously treated with DES exhibited lower avoidance response compared to the control group. In contrast, none of the psychotropic drugs facilitated avoidance extinction in SD rats. Instead, DES impaired avoidance extinction and increased non-reinforced response in SD rats. Interestingly, paroxetine, a widely used antidepressant and anxiolytic, exhibited the weakest effect in WKY rats and no effects at all in SD rats. Thus, our data suggest that malfunctions in brain catecholamine system could be one of the underlying etiologies of anxiety-like behavior, particularly avoidance perseveration. Furthermore, pharmacological manipulation targeting DA and norepinephrine may be more effective to facilitate extinction learning in this strain. The data from the present study may shed light on new pharmacological approaches to treat patients with anxiety disorders who are not responding to serotonin re-uptake inhibitors.
Highlights
Anxiety disorders are the most common psychiatric disorder with a lifetime prevalence of over 15% in the U.S (Kessler et al, 2005; Somers et al, 2006)
ACQUISITION Avoidance responding In all respects, strain differences in avoidance learning in this study replicate what has been described previously (Servatius et al, 2008; Beck et al, 2010, 2011)
Consistent with our previous findings, the within-session acquisition learning is more obvious in Sprague Dawley (SD) rats as WKY rats emitted similar or greater avoidance responding on the first trial of a session compared to the last trial from the previous session, suggesting a lack of “warm-up” that plays a pivotal role in the development of avoidance perseveration during extinction phase in the WKY strain (Servatius et al, 2008) (Figure 1B)
Summary
Anxiety disorders are the most common psychiatric disorder with a lifetime prevalence of over 15% in the U.S (Kessler et al, 2005; Somers et al, 2006). The etiopathology of anxiety disorders remains elusive, the core characteristic of all anxiety disorders is pathological avoidance (American Psychiatric Association, 2000). Therapies targeting pathological avoidance are quite underdeveloped and problematic for people suffering clinical anxiety. Current treatment for anxiety disorder includes psychological [i.e., cognitive behavioral therapy (CBT)], pharmacological approaches, and the combination of both. Extinction-resistant avoidance is one of the target symptoms in CBT, which is largely based on changing behavior through different learning approaches (Holmes and Quirk, 2010; Nic Dhonnchadha and Kantak, 2011; Schneier, 2011; Melo et al, 2012). A large group of patients do not respond to SSRI treatment (>40%) or relapse after initial effective treatment (Pollack et al, 2006, 2008), providing a need for new therapeutic agents and strategies for refractory cases
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