Effects of Psychotropic Agents on Extinction of Lever-Press Avoidance in a Rat Model of Anxiety Vulnerability

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.

Avoidance expression in rats as a function of signal-shock interval: strain and sex differences

“…A stronger factor is temperament, represented by the inbred WKY rat, which shows robust patterns of avoidance responding. With regard to acquisition with a 60-s WS, several patterns noted previously were evident here (although not stressed in the results section): (1) WKY rats lacked warm-up, as acquisition progressed WKY rats avoided on the first trial of a session, whereas SD rats generally exhibited an escape response (Servatius et al, 2008 ), (2) WKY rats exhibited slower rates of extinction (Servatius et al, 2008 ; Jiao et al, 2014 ). In stark contrast to SD rats, WKY rats acquired with a 10-s WS with females WKY rats expressing avoidance to a higher degree than male WKY rats.…”

“…As an arbitrary response, rates of nonspecific responding are generally low enhancing sensitivity (Servatius et al, 2008 ; Avcu et al, 2014 ). An escape response is generally acquired early in training with avoidance emerging and reaching asymptotic performance over several sessions of training (Servatius et al, 2008 ; Jiao et al, 2011 , 2014 ; Pang et al, 2011 ; Avcu et al, 2014 ; Beck et al, 2014 ). Although avoidance is not expressed as quickly as other preparations (e.g., shuttle box), the slowness in acquisition is cited as a virtue (Bolles, 1970 ).…”

Differential effects of bupropion on acquisition and performance of an active avoidance task in male mice

“…In session 4, mice treated with 20 and 40 mg/kg showed shorter response latencies than controls. These results, which suggest an enhancement in acquisition of avoidance learning within some bupropion groups, confirm those of previous studies with this drug that indicated an improvement of other learning tasks, such as retrieval of inhibitory avoidance (Barros et al, 2002), lever-press avoidance active task (Jiao et al, 2014), conditioned place preference (Ortmann, 1985), conditioned emotional response (Lipina and Roder, 2010;Carmack et al, 2014), or novel object recognition (Kruk-Słomka et al, 2014). Moreover, present data agree with previous observations showing that bupropion reverses reserpineinduced impairment in a conditioned avoidance task (Nakagawa et al, 1997) and reverses nicotine withdrawal-associated deficits in contextual fear conditioning by enhancing retrieval processes (Portugal and Gould, 2007).…”

“…Given that previous data on the behavioural effects of bupropion in active avoidance tasks are limited (Jiao et al, 2014), we consider that present results add new information about the ability of bupropion to induce beneficial changes in the control of emotional responses. Considering that the active avoidance task is a relatively complex form of learning in which the animals have to learn a particular behavior in order to avoid the application of a stressor as a footshock, the performance displayed by animals treated with bupropion during sessions (jointly with the increase in the number of avoidances and the decrease in response latency observed here) suggests that this drug may improve the control of emotional responses.…”

“…There is, for example, evidence of the positive effects of antidepressant treatment on synaptic plasticity in cortical and subcortical brain circuits related with mood disorders and memory (Castrén and Hen, 2013;Sairanen et al, 2007). In animal models, bupropion has been found to induce place preference (Ortmann, 1985;Rauhut et al, 2008), to improve performance in a novel object recognition task (Kruk-Słomka et al, 2014), to disrupt latent inhibition measured in a conditioned emotional response (Lipina and Roder, 2010), to facilitate extinction of avoidance responses in a lever-press avoidance task in animals with innate vulnerability to anxiety (Jiao et al, 2014). Bupropion also improves the retrieval of an inhibitory avoidance response (Barros et al, 2002) and reverses the reserpine-induced impairment in conditioned avoidance response when administered at 40 mg/kg (Nakagawa et al, 1997), although this drug failed to alter the conditioned place preference induced by nicotine (Rauhut et al, 2008).…”