Noradrenergic and Pavlovian underpinnings of compulsive versus adaptive coping strategies

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 behaviours. While most rats exposed to a schedule-induced polydipsia (SIP) procedure develop a controlled coping response, namely polydipsic drinking, some engage in excessive, compulsive drinking, or hyperdipsia. The development of hyperdipsia, to which highly impulsive rats are particularly vulnerable, depends on noradrenergic mechanisms, as it is prevented by the noradrenaline reuptake inhibitor, atomoxetine. However, whether noradrenergic mechanisms also underlie the maintenance of hyperdipsia, or if other traits confer vulnerability to its development, are unknown. In two longitudinal studies in male Sprague Dawley rats, we investigated whether well-established hyperdipsia is influenced by atomoxetine and if its development is predicted by the ICSD-relevant sign-tracking trait. Sign-tracking predicted faster acquisition of adjunctive drinking but not the transition to hyperdipsia, while goal-tracking protected against the latter. Surprisingly, chronic atomoxetine exacerbated well-established hyperdipsia; post-mortem qPCR assays revealed that this was associated with increased cFos and Zif268 mRNA, markers of cellular activity and plasticity, across the dorsal striatum. Atomoxetine also altered the hyperdipsia-specific transcriptomic landscape of the nucleus accumbens shell and the pattern of cFos and Zif268 expression in the amygdalo-striatal system. These results provide new insights into the biobehavioural basis of compulsive behaviours, revealing a differential noradrenergic control of the development and the expression of compulsive coping.