Compulsive Coping Behavior, Developed Predominantly by Sign-Trackers, Is Exacerbated by Chronic Atomoxetine

Loss of control over coping strategies can result in the development of impulsive/compulsive spectrum disorders (ICSDs) such as obsessive-compulsive disorder or trichotillomania. Rats, like humans, show individual differences in their tendency to engage in and maintain control over coping behaviors. While most rats exposed to a schedule-induced polydipsia (SIP) procedure develop controlled, moderate, polydipsic coping, some vulnerable individuals engage in excessive, compulsive drinking, or hyperdipsia. The development of hyperdipsia depends in part on noradrenergic mechanisms, as it is prevented by the noradrenaline reuptake inhibitor atomoxetine (ATX) in highly impulsive vulnerable rats. However, whether noradrenergic mechanisms also underlie the expression of well-established hyperdipsia and whether other traits, such as the ICSD-relevant sign-tracking, confer vulnerability to its development are unknown.

In 2 longitudinal studies with male Sprague Dawley rats, we investigated whether well-established hyperdipsia was influenced by ATX and whether its development was predicted by sign-tracking.

Sign-tracking was associated with faster acquisition of SIP and the development of high or compulsive levels of SIP. Chronic ATX both exacerbated hyperdipsia and increased the messenger RNA levels of the markers of cellular activity and plasticity cFos and Zif268 across the dorsal striatum as revealed by quantitative polymerase chain reaction assays. ATX also altered the transcriptomic landscape of the nucleus accumbens shell and the pattern of cFos and Zif268 expression in the amygdalo-striatal system.

These results provide new insight into the biobehavioral basis of compulsive behaviors, revealing differential noradrenergic control of the development and expression of compulsive coping, with the latter involving recruitment of distinct striatal processes.