Seeking under threat of adversity: assessing control over reward pursuit in rats.

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Substance use disorder (SUD) is a chronic relapsing brain disorder that is characterised by loss of control over substance use. A variety of rodent models employing punishment setups have been developed to assess loss of control over substance use, i.e. persistent substance use despite negative consequences, to facilitate the translation of findings from animal studies to the human situation. Since the negative consequences of addictive behaviour are typically unpredictable, we here present the Seeking under Threat of Adversity (STA) task in rats, that incorporates cued, probabilistic and response-contingent punishment of reward seeking. Male rats were trained to lever press for sucrose, alcohol or cocaine and were subsequently tested in the STA task. In this task, a tone cue is presented during reward seeking which functions as a warning signal, since responding during tone presentation results in a probabilistic foot shock punishment. We first determined the optimal shock intensity to induce a moderate suppression of seeking. Next, we assessed the stability of punished reward seeking over repeated tests. Finally, we compared the development of loss of control over substance seeking for sucrose, alcohol and cocaine. (Loss of) control over substance seeking would be evident as the (in)ability to refrain from lever pressing to obtain a reward, despite the threat of a negative outcome. Parametric experiments revealed suppression of responding for both sucrose and alcohol in the STA task at shock intensities between 0.25 and 0.35mA. The suppression of responding was stable with repeated testing. Furthermore, less control over alcohol and cocaine seeking, when compared to sucrose seeking, was observed in male rats using the STA task. The STA task is a novel behavioural task that includes two important aspects of human substance use despite negative consequences, i.e. response contingency and unpredictability of adversity. Combined with other behavioural tasks and neural manipulations, the STA task can further our understanding of the psychopathology of substance use disorders.