Orexin neuropeptides contribute to the development and persistence of generalized avoidance behavior in the rat.

RATIONALE: Avoidance of contexts directly associated with fearful experiences represents an adaptive behavioral survival strategy. Over-interpretation of contextual cues leading to generalized avoidance of situations that are only remotely similar to the original fear context represents a pathologic process that contributes to anxiety disorders. Orexin neuropeptides modulate anxiety-like behavioral and physiological responses. OBJECTIVE: The objective of this paper was to investigate the impact of pharmacological orexin receptor blockade on generalized avoidance behavior. METHODS: Rats received a single electric foot-shock in the dark side of a two-compartment shuttle box followed by situational context reminders. After shock, rats were treated chronically (3 weeks) with the orexin receptor antagonist almorexant or with the selective serotonin reuptake inhibitor sertraline, used as positive anxiolytic control. In week 3, avoidance behavior was measured under conditions of high (dark-light (DL)-box) and low (elevated plus maze (EPM)) similarity to the original shock context. Avoidance behavior was re-assessed 5 and 17 weeks after treatment termination. RESULTS: Avoidance in the DL box (contextual fear memory) remained unaffected by any treatment and lasted 20 weeks post-shock exposure. Avoidance in the EPM (neophobic fear generalization) was partially attenuated during treatment with almorexant and sertraline at week 3. Following 5 and 17 weeks of drug washout, avoidance in the EPM was significantly reduced in almorexant- but not in sertraline-treated rats. Almorexant also reduced persistent avoidance in the EPM upon treatment initiation 3 weeks after shock exposure. CONCLUSION: Chronic orexin receptor blockade in rats reduces both the development and persistence of generalized avoidance in situations with low similarity to the initial shock context.

Sex comparison on long-lasting behavioral and physiological disturbances induced by single shock experience in rats.

Enhanced female vulnerability and symptom severity are described in post-traumatic stress disorder (PTSD). It remains largely unknown whether females present with more pronounced PTSD-like symptoms than males in rodent models of PTSD. A model of single electric foot-shock followed by situational reminders was used to investigate in rats the impact of sex on potential long-lasting changes in anxiety-like behavior, and in endocrine and physiological responses to stress and fearful situations. Three weeks after single shock exposure (in the dark side of a shuttle box) both male and female rats spent less time in the dark compartment of a dark-light box and in the closed arms of an elevated plus maze than non-shocked controls. Both behaviors were likely due to avoidance of places reminiscent of the initial shock context. The shock exposure had no long-term impact on social interaction behavior or on basal and restraint stress-induced increases in plasma corticosterone. Shock exposure increased sudden silence-induced freezing responses and hyperthermia during novelty stress and fear to a similar extent in both males and females and left heart rate responses unaffected. Non-shocked females generally showed a reduced response or faster recovery to baseline under stress- or fearful test conditions as compared to non-shocked males, which was likely due to differential sex-specific coping strategies. Taken together, our results suggest that, despite some baseline sex differences, both male and female rats are similarly affected in the long-term by the initial foot-shock exposure used in this particular simulation of PTSD.

Oxytocin selectively gates fear responses through distinct outputs from the central amygdala.

Central amygdala (CeA) projections to hypothalamic and brain stem nuclei regulate the behavioral and physiological expression of fear, but it is unknown whether these different aspects of the fear response can be separately regulated by the CeA. We combined fluorescent retrograde tracing of CeA projections to nuclei that modulate fear-related freezing or cardiovascular responses with in vitro electrophysiological recordings and with in vivo monitoring of related behavioral and physiological parameters. CeA projections emerged from separate neuronal populations with different electrophysiological characteristics and different response properties to oxytocin. In vivo, oxytocin decreased freezing responses in fear-conditioned rats without affecting the cardiovascular response. Thus, neuropeptidergic signaling can modulate the CeA outputs through separate neuronal circuits and thereby individually steer the various aspects of the fear response.

Opposite effects of oxytocin and vasopressin on the emotional expression of the fear response.

Oxytocin and vasopressin are two neuropeptides that have been extensively studied for their systemic and physiological roles. Studies in rodents show that oxytocin and vasopressin play an opposite role in several behavioural and physiological tests for anxiety and fear. Their effects on single cell activity in the central amygdala (CeA) triggered a number of electrophysiological studies that allowed us to develop a model of their opposing effects. In our model, GABAergic neurons in the lateral part of the central amygdala are excited by oxytocin and project to the medial part where they inhibit neurons that can be excited by vasopressin. Besides oxytocin and vasopressin, the CeA expresses a large number of other neuropeptide receptors and the question arises if a similar model can apply to their actions. We here develop a hypothesis in which neuropeptides, through their effects on distinct populations in the CeA, affect specific projections and specific physiological expressions of the fear response. Our hypothesis may be of importance for the current interest in neuropeptide receptors as therapeutic targets for neuropsychiatric disorders.