Our results demonstrate that a brief stressor administered outside the self-administration environment is able to reinstate extinguished cocaine-seeking behavior after the stress itself had ended. This is the first time, to our knowledge, that a stressor both temporally and contextually separated from the drug-paired environment has been shown to induce reinstatement. The effects of cold swim stress on drug-seeking behavior persisted for up to three days after exposure to the stress. Swim stress did not increase responding in animals that had learned to self-administer saline, indicating that its effects were specific to cocaine.
Several types of stress-related stimuli are known to induce reinstatement of drug-seeking behavior. These include administration of the stress hormone corticosterone (8
), the peptide corticotrophin releasing factor (CRF) (10
), and the pharmacological stressor yohimbine (12
). Similarly, acute exposure to footshock and food deprivation reinstate drug-seeking behavior in self-administration models (6
), and cold swim stress reinstates seeking in a place preference paradigm (16
). However, the stressors utilized in these models were either on-board or were administered in close temporal proximity to the reinstatement test (for review, see 4
). Thus, these paradigms do not reproduce the common human situation, whereby stressors that are distinct from the experience of drugs can lead to relapse. Some studies have shown that either the pharmacological stressor CRF or intermittent footshock cause reinstatement even if a delay exists between exposure to stress and testing (5
). These studies also removed the animals from the drug taking context for a time between the exposure to the stressor and the reinstatement trial. However, despite achieving temporal separation, this delay was short, approximately three hours or less, and crucially, the stressor itself was still administered in the testing chamber. The stressor, therefore, remained contextually linked to experience of drugs. It was thus suggested that stress produces conditioned excitation to the context in which it is administered; this conditioned excitation overrides the inhibitory processes that govern reduced responding during extinction (5
). In the present study, however, the stressor was wholly separate from the drug-paired context and it caused reinstatement for up to three days after the stressor had ended. This suggests that the effects of cold swim stress are independent of such conditioned excitation. Although the effects of swim stress were significant, it should be noted that the magnitude of the effect was relatively small compared with other stressors, which produce higher levels of reinstatement (3
A number of candidate mechanisms could underlie this phenomenon. Elevation of the stress hormone corticosterone has been shown to produce reinstatement of seeking behavior (8
). One possibility is that swim stress leads to a persistent elevation of circulating corticosterone such that the animal remains in a “stressed” state until testing. However, this is unlikely to be the case because it has been shown that corticosterone returns to baseline levels two hours after the end of cold swim procedure (7
). Extra-hypothalamic corticotrophin releasing factor (CRF) and/or noradrenaline, have also been heavily implicated in stress-induced reinstatement of cocaine-seeking behavior (2
). These studies also involve the acute elevation of the modulator and the rapid production of a reinstatement response. Whether a prolonged elevation in either of these transmitters contributes to our effect is not certain as, to our knowledge, the length of time they remain elevated has not been studied after cold swim stress. Furthermore, this time course could be altered in cocaine-treated rats (18
). Therefore, although one possibility is that prolonged elevation of CRF and/or noradrenaline reinstates drug-seeking, the long delay between the stressor and reinstatement suggests a more complex explanation. One possibility is that the stressful experience could produce neuroadaptations that prime the system to respond more strongly when re-exposed to the drug-paired context at later time points. A key locus of such changes could be ventral tegmental area (VTA) dopamine neurons. Activation of VTA dopamine neurons has been linked to reinstatement of drug-seeking behavior (for review see (19
)). Importantly, a persistent long-term potentiation-like phenomenon can be induced in these cells by the same cold swim stress used in the current study (20
). This result suggests that exposure to cold stress may lead to a persistent elevation in synaptic strength in the VTA which, when paired with an increase in excitatory input caused by re-exposure to the drug-paired context, would lead to strong excitation of VTA dopamine neurons and re-instatement of drug-seeking behavior.
In conclusion, we show that reinstatement of drug-seeking behavior may be produced by a stressor that is both temporally and contextually distinct from the drug-paired environment. The relevance of this model to the human situation may make it useful for studying the mechanisms underlying stress-induced relapse with a view to creating better treatments.