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Withdrawal and avoidance behavior are common symptoms of depression and can appear as a consequence of absence of reward, i.e. extinction-induced depression (EID). This is particularly relevant for the aged organism subjected to pronounced loss of former rewards. Avoidance of the former site of reward and increased withdrawal into a distant compartment accompany extinction of food-rewarded behavior in rodent models. During extinction, behavioral markers for re-learning dissociate from indicators of extinction-induced depression. Here we examined the effect of a chronic treatment with corticosterone (CORT), a well-known inducer of depression-related behavior, on EID in adult and aged rats. Adult (3-4months) and aged (18months) male rats were treated with CORT via drinking water for 3weeks prior to extinction of a cued food-reward task. CORT treatment increased the distance from the site of reward and decreased goal tracking behavior during extinction, especially in the aged rats. Plasma hormone levels measured before and after restraint stress showed a decline in basal ACTH- and CORT-levels after chronic CORT treatment in aged animals. The treatment significantly impaired the HPA-axis activation after acute stress in both, adult and aged animals, alike. Altogether, these findings show an enhancement of EID after chronic CORT treatment in the aged organism, which may be mediated by an impaired HPA-axis sensitivity. These findings may have special relevance for the investigation of human geriatric depression.

The withholding of expected rewards results in extinction of behavior and, hypothetically, to depression-like symptoms. In a test of this hypothesis, we examined the effects of extinction of food-reinforced lever-pressing on collateral behaviors that might be indices of depression. Operant extinction is known to be aversive to the organism and results in avoidance behavior. We hypothesized that avoidance of, or withdrawal from, the former source of reward may serve as a marker for “despair.” Adult male Wistar rats ( n =6–7 animals per group) were exposed to a Skinner box attached to a second compartment of the same size, providing opportunity for the animals to leave the operant chamber and to enter the “withdrawal” compartment. The animals spent a portion of the time during the extinction trials in this second chamber. To assess the predictive validity of this behavior as a potential marker of “despair,” we tested the effects of chronic administration of two common antidepressant drugs on this measure. The tricyclic antidepressant imipramine (20 mg/kg) as well as the selective serotonin reuptake inhibitor citalopram (20 mg/kg) reduced the number of entries and time spent in the withdrawal compartment. We propose that entries into and time spent in the withdrawal compartment may operationalize “avoidance,” a core symptom of major depression. Rearing as well as biting behaviors during the extinction trials were also attenuated by the antidepressant treatment. These results lend support to the hypothesis that extinction of positively reinforced operants evokes behaviors that reflect elements of “despair/depression” because these behaviors are modulated by antidepressant treatment. The avoidance of the operant chamber as a consequence of extinction, together with rearing and biting behaviors, may serve as useful measures for the testing of antidepressant treatments.

The androgenic steroid testosterone is well known for its function in reproduction, sexual differentiation and sexual behavior. A growing number of human and animal studies suggest a modulatory role of testosterone in the regulation of emotionality and associated psychiatric disorders, including depressive-like disorders. However, most of the studies have been carried out in subjects deficient in androgenic steroid levels. Here, we tested potential beneficial effects of subcutaneously applied testosterone on emotionality and depressive-like behavior in healthy male rats. For this purpose, male Wistar rats (3–4 months) received either vehicle or testosterone (1.0, 2.0, 4.0 mg/kg) subcutaneously and were tested for potential effects on motor activity and anxiety-like behavior in a novel open field and elevated plus-maze. The forced swim test was used for assessing potential beneficial effects of testosterone on depressive-like behavior. The results show, that, while subcutaneous application of testosterone failed to influence spontaneous motor activity as well as anxiety-like behavior in the open field, a trend for an increase in the time spent on the open arms in the elevated plus-maze with the highest dose was found. Furthermore, in the forced swim test, testosterone application induced a dose-dependent reduction of immobility behavior, indicating antidepressant-like action of testosterone in healthy animals.

Despair-related withdrawal behaviors are common symptoms of major depression (MD) and can be ascribed to a loss or absence of former rewarding events. Extinction of negatively reinforced escape behavior in the Morris Water Maze has been shown to induce despair-like behavior. A new animal model of depressive-like behavior is based on the extinction of positively reinforced behavior, which was shown to induce spatial avoidance of the former source of reward and biting of the operandum. Treatment with antidepressants attenuated these extinction-induced behaviors, suggesting that they reflect a depressive-like state. Here we present a methodological variation of this depression model. We employed an elongated operant chamber rather than a two-compartment procedure with the intent to establish a flowing gradient of withdrawal from the source of reward, rather than an all-or-none binary measure. Furthermore, instead of employing extinction of lever-pressing behavior, we applied a cued fixed-time food-delivery schedule. Sixty adult male Wistar rats ( n = 12/group) were trained to receive a food reward after appearance of a cue-light (fixed interval 90 s) in an elongated Skinner-box of 72 cm length. Prior to extinction, the animals were treated for 9 days with either 7.5 or 10 mg/kg of the tricyclic antidepressant clomipramine, 7.5 or 10 mg/kg of the selective serotonin reuptake inhibitor (SSRI) citalopram or vehicle. Subsequent testing in an open field was carried out to investigate potential effects of the antidepressants on locomotor- and anxiety-like behavior. An overall increase in distance from the feeder and biting behavior was found over the course of the extinction trials. Both, citalopram and clomipramine decreased the distance from the pellet feeder during the initial extinction trials compared to the vehicle-treated group. The attenuation of withdrawal behavior by the antidepressants supports the hypothesis that avoidance/withdrawal behavior during extinction trials can serve as a marker for extinction-induced depression and suggests the utility of this paradigm as a rodent model of depression.

Although cocaine induces several behavioral and hormonal effects, little is known about non-contingent repeated administrations in non-human primates. Therefore, we analyzed behavioral (locomotion, vigilance) and hormonal (cortisol) responses of adult black tufted-ear marmosets during repeated administrations and withdrawal trials. The subjects were divided into two groups (saline or cocaine 5 mg/kg, ip) and submitted to nine treatment trials and four withdrawal trials in the absence of any treatment in an open-field arena. Blood samples were obtained on five different time points of the procedure to evaluate the effects of repeated cocaine treatment on basal cortisol levels. Cocaine repeatedly administered to drug-naive marmosets induced a slow-onset hypervigilance effect (i.e., scan — long-lasting sweeping movements of the head directed at the environment; and glance — single rapid movement of the head directed at the environment), with no concomitant change in locomotion. Treatment cessation during withdrawal immediately reversed the cocaine-induced hypervigilance effect. Cortisol levels remained constant throughout the procedure. Therefore, marmosets seem to have a similar behavioral — but not hormonal — response as humans and other nonhuman primates repeatedly injected with cocaine, but differ from rats in their absence of hyperlocomotor activity. The development of hypervigilance with repeated application may constitute a unique measure to assess cocaine-induced changes in behavior in the marmoset and other nonhuman primates.