Cannabinoid type-1 receptor ligands, alone or in combination with cocaine, affect vigilance-related behaviors of marmoset monkeys.

Endocannabinoids (eCB) have been functionally linked to cocaine׳s rewarding effects. However, results differ at the behavioral level, with few reports in nonhuman primates (NHPs). Here we analyzed whether repeatedly administered cannabinoid type-1 receptor (CB1r) agonist WIN 55-212,2 (WIN) or antagonist AM 251 (AM) induce effects per se and if concurrent pre-treatments affect cocaine-induced changes in marmoset behavior. Six groups were tested: WIN-saline; WIN-cocaine; AM-saline; AM-cocaine; vehicle-cocaine; and vehicle-saline. Subjects were pre-treated with either WIN (1mg/kg), AM (2mg/kg) or vehicle and then injected with cocaine (5mg/kg) or saline. Six exposures were held at 48 h intervals. Behaviors were scored during 15-min in an open-field on days 1 and 6, as well as a withdrawal (WD) trial. Marmosets became hypervigilant during cocaine exposures, which did not condition to the injection context. CB1r activation induced an equivalent response, whereas AM had no effect on its own. However, when given as a pre-treatment to cocaine, CB1r blockade enhanced the former׳s hypervigilance effect and potentially conditioned this response to the exposure context. Enhancement may have resulted from AM׳s inhibition of eCB-potentiated cocaine-induced anxiogenesis and/or its action independent of the eCB system, or even CB1r-mediated changes in synaptic plasticity involved in cocaine reward-learning. All effects were independent of motor function. Thus, changes in CB1r function - alone and in combination with cocaine - affected stereotyped vigilance-related behaviors in this NHP, further implicating the eCB system in the neurobiological mechanisms of cocaine addiction.

Cannabinoid type 1 receptor ligands WIN 55,212-2 and AM 251 alter anxiety-like behaviors of marmoset monkeys in an open-field test.

Cannabinoid type 1 receptors (CB1r) are an important modulatory site for emotional behavior. However, little is known on the effects of CB1r ligands on emotionality aspects of primates, even with their highly similar behavioral response and receptor density/distribution as humans. Thus, we analyzed the effects of the CB1r agonist WIN 55,212-2 (WIN; 1mg/kg) and the antagonist AM 251 (AM; 2mg/kg), systemically administered prior to a single brief (15 min) exposure to a novel open-field (OF) environment, on the behavior of individually tested adult black tufted-ear marmosets. Both WIN- and AM-treated subjects, compared to vehicle controls, had significantly lower rates of long (contact) calls and exploration, while higher levels of vigilance-related behaviors (scan/glance); these are indicators of anxiolysis in this setup. Changes in locomotion were not detected. However, in the vehicle and AM-groups, sojourn in the peripheral zone of the OF was significantly higher than in its central region. WIN-treated marmosets spent an equivalent amount of time in both zones. Therefore, activation or blockade CB1r function prior to a short and individual exposure to an unfamiliar environment exerted a significant and complex influence on different behavioral indicators of anxiety in these monkeys (i.e., a partially overlapping anxiolytic-like profile). AM 251, however, has no anxiolytic effect when the time spent in the center of the OF is considered. This is a major difference when compared to the WIN-treated group. Data were compared to the response profile reported in other pre-clinical (rodent) and clinical studies.

Repeated cocaine administration in marmoset monkeys induces hypervigilance-related behaviors, but no changes in locomotion and cortisol levels.

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 5mg/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-naïve 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.

Diazepam-induced decrease in anxiety-like behaviors of marmoset monkeys exposed to a novel open-field.

Unfamiliar environments can be a source of stress, fear and anxiety for marmoset monkeys. In spite of existing data, the influence of putative anxiolytics on the effects of novel environments has yet to be tested in primates. Therefore, the behavior of adult black tufted-ear marmosets to a single brief (15 min) exposure to a novel environment was analyzed in the presence and absence of diazepam (DZP). Marmosets were pre-treated with vehicle (n=5) or diazepam (0.5 mg/kg, ip; n=5) and submitted to a 15 min free exploration trial within a rectangular open-field arena. DZP-treated subjects, compared to vehicle controls, demonstrated significantly lower rates of (phee) contact calls and exploration, while a higher scan duration. Sojourn time in the arena's central zone was also significantly higher in the former group and sedation was not observed. Thus, pre-treatment with the benzodiazepine DZP decreased several anxiety-related behaviors induced by subjecting the marmosets to a new environment. The results also indicate that, as with rodent subjects, the open-field may provide a useful simple paradigm for assessing anxiety-like behaviors in this primate and, as such, constitutes a unique opportunity for direct comparative studies between rodents and marmoset monkeys in terms of anxiety and/or sedation.

Immediate, but no delayed, behavioral response to a snake model by captive black tufted-ear marmosets.

Whether callitrichids are naturally capable of detecting and responding to predators - or if such skills are learned - remains a controversial issue, with results differing in terms of species, predator and encounter conditions. Therefore, the behavioral response of naïve adult captive black tufted-ear marmosets (Callithrix penicillata) was assessed before, during, 0 and 4 h after a 5-min encounter with a snake and flower model. Using a two-phase cross-over design, marmosets (n = 16) were submitted to one trial for each stimulus, divided into four 5-min intervals: pre-exposure, exposure and post-exposure observations held 0 and 4h later. The snake exposure increased the number of gazes made towards the stimulus and the time cage-mates spent close to each other, as well as induced tsik-tsik alarm/mobbing calls, while inhibiting foraging and decreasing the time spent near the snake's location. After the snake was removed, all changes were immediately reversed. Mobbing was not observed. The flower stimulus only increased direct gazes and time spent in proximity during its presentation. All marmosets were captive-born and snake-naïve yet had recently been confronted with a cat stimulus in a previous experiment. Thus, previous experiences with snakes may be required for marmosets to fully develop appropriate immediate and long-term responses.

Humans and natural predators induce different fear/anxiety reactions and response pattern to diazepam in marmoset monkeys.

The behavioral response of marmoset monkeys in the Human Threat (HT) test of anxiety, and the effects of diazepam (DZP), were compared to those in the Predator Confrontation (PC) procedure. Subjects (n=13) were initially submitted to four habituation trials, followed by four random confrontation sessions for each test (DZP 0, 1, 2 and 3 mg/kg). Each trial was divided into three consecutive 5-min intervals: pre-exposure, exposure (human observer, taxidermized oncilla cat) and post-exposure. As DZP induced sedation, marmosets (n=10) were re-tested in a second experiment, consisting of two habituation trials and four confrontation sessions per stimulus, with lower DZP doses (0, 0.10, 0.25 and 0.50 mg/kg). Exposure to both stimuli significantly increased direct gazes and alarm calls, being dose-dependently reduced by DZP only in the PC test. In the HT protocol, the significant decrease in aerial scans was not detected with 0.10 mg/kg DZP. Locomotion, proximity, displacement activities and vigilance were not consistently influenced by the stimuli and/or DZP. The results thus suggest that the HT test had a greater impact on the marmosets' behavior, while DZP was more effective on the reactions observed in the PC test, possibly due to the inherent nature of each stimulus, distinct threat levels and/or presentation order.