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

Abstract

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.

Temporal and dose-dependent differences in simultaneously-induced cocaine hypervigilance and conditioned-place-preference in marmoset monkeys

“…Rodents respond to repeated psychostimulant exposure with a hyperlocomotor effect that is: (1) very susceptible to behavioral sensitization (Vanderschuren and Kalivas, 2000); (2) inversely correlated with the initial cocaine response (Seymour and Wagner, 2008); (3) more pronounced in individuals that are highly explorative prior to drug exposure (Pierre and Vezina, 1997); and (4) strongly controlled by conditioned environmental stimuli (Mattson et al, 2008). Similar to previous reports from our group (Cagni et al, 2012(Cagni et al, , 2014Melamed et al, 2013), changes in locomotor activity were not detected in the marmosets. The hypervigilance effect was also not correlated with the initial response to cocaine or pre-drug vigilance, locomotion and exploratory levels, possibly an effect of the small sample size.…”

“…In humans, there is also a trend for the emergence of paranoid psychosis when higher doses of psychostimulants are used repeatedly (reviewed in Bradberry, 2007). As a matter of fact, it has been suggested that behavioral sensitization develops best in animals when moderately high doses are used (reviewed in Vezina and Leyton, 2009), with our present results and that of previous studies in NHPs corroborating this notion (Bradberry, 2007;Cagni et al, 2012Cagni et al, , 2014Melamed et al, 2013).…”

“…However, all marmosets were routinely submitted to prophylactic clinical treatment injections prior to the present study, which may have minimized the influence of this effect on the results. In marmosets, repeated injections of 5 and 7 mg/kg of cocaine have induced a slow-onset hypervigilance effect (Cagni et al, 2012(Cagni et al, , 2014Melamed et al, 2013). In rhesus and vervet monkeys, visual monitoring increased progressively after repeated cocaine exposure (4 mg/kg; Farfel et al, 1992), as well as with other psychostimulants Goldman-Rakic, 1999, 2003;Castner et al, 2000;Ridley et al, 1982).…”

“…Saline was used as vehicle control on alternating days with cocaine injections (see Section 2.4). The doses used were based on previous reports in the same species Cagni et al, 2012;Melamed et al, 2013). As subjects had been previously submitted to routine prophylactic clinical treatment injections for at least a 1-year period prior to the present study, a specific habituation protocol to the injection procedure was not currently adopted.…”

“…Among their most prominent and consistent behaviors are stereotyped psychotomimetic or hallucinatory-like responses, particularly those related to vigilance (Bradberry, 2007). This response becomes progressively enhanced in different NHP species after both repeated escalating or same-dose regimes (Cagni et al, 2012(Cagni et al, , 2014Goldman-Rakic, 1999, 2003;Castner et al, 2000;Farfel et al, 1992;Kleven and Woolverton, 1990;Melamed et al, 2013;Post et al, 1976;Ridley et al, 1982;Saka et al, 2004), and may persist for weeks or even months after administrations are discontinued (Castner and Goldman-Rakic, 1999). In terms of cocaine, NHPs will also exhibit hypervigilance when subsequently challenged with this drug some time later, independently from the enhanced locomotion typically seen in rodents (Melamed et al, 2013), with both profiles corresponding to a behavioral sensitization (Vezina and Leyton, 2009).…”