Oxytocin may have promise as a treatment for neuropsychiatric disorders. Its therapeutic effect may depend on its ability to enter the brain and bind to the oxytocin receptor. To date, the brain tissue penetrance of intranasal oxytocin has not been demonstrated. In this nonhuman primate study, we administer deuterated oxytocin intranasally and intravenously to rhesus macaques and measure, with mass spectrometry, concentrations of labeled (exogenously administered) and endogenous oxytocin in 12 brain regions two hours after oxytocin administration. Labeled oxytocin is quantified after intranasal (not intravenous) administration in brain regions (orbitofrontal cortex, striatum, brainstem, and thalamus) that lie in the trajectories of the olfactory and trigeminal nerves. These results suggest that intranasal administration bypasses the blood–brain barrier, delivering oxytocin to specific brain regions, such as the striatum, where oxytocin acts to impact motivated behaviors. Further, high concentrations of endogenous oxytocin are in regions that overlap with projection fields of oxytocinergic neurons.

Attentional set-shifting ability is an executive function underling cognitive flexibility in humans and animals. In humans, this function is typically observed during a single experimental session where dimensions of playing cards are used to measure flexibility in the face of changing rules for reinforcement (i.e., the Wisconsin Card Sorting Test (WCST)). In laboratory animals, particularly non-human primates, variants of the WCST involve extensive training and testing on a series of dimensional discriminations, usually in social isolation. In the present study, a novel experimental approach was used to assess attentional set-shifting simultaneously in 12 rhesus monkeys. Specifically, monkeys living in individual cages but in the same room were trained at the same time each day in a set-shifting task in the same housing environment. As opposed to the previous studies, each daily session began with a simple single-dimension discrimination regardless of the animal’s performance on the previous session. A total of eight increasingly difficult, discriminations (sets) were possible in each daily 45 min session. Correct responses were reinforced under a second-order schedule of flavored food pellet delivery, and criteria for completing a set was 12 correct trials out of a running total of 15 trials. Monkeys progressed through the sets at their own pace and abilities. The results demonstrate that all 12 monkeys acquired the simple discrimination (the first set), but individual differences in the ability to progress through all eight sets were apparent. A performance index (PI) that encompassed progression through the sets, errors and session duration was calculated and used to rank each monkey’s performance in relation to each other. Overall, this version of a set-shifting task results in an efficient assessment of reliable differences in cognitive flexibility in a group of monkeys.

Chronic alcohol abuse is frequently considered a habitual or inflexible behavior; however, measures of pre-existing cognitive flexibility prior to initiation of alcohol use are usually not available. This study used rhesus monkeys and an attentional set-shifting task to investigate whether pre-existing cognitive flexibility would predict increased risk for heavy alcohol drinking. As previously reported, monkeys were given 30 daily set-shifting sessions prior to alcohol access. These sessions consisted of the same sequence of eight unique visual discriminations (sets) of two objects that varied on two dimensions (shapes and colors). The ratio of errors per trials, session duration, and maximum set reached were primary dependent variables from each session and were used to compose a session performance index (PI) that ranged from a low performance PI of 31 to an optimal performance PI of 247. Here, animals underwent an alcohol induction period followed by 22 weeks of daily (22-h) self-administration sessions with free access to water and alcohol. Based on average daily alcohol intake during 22 weeks of 22-h/day access, the monkeys were categorized as non-heavy (mean = 2.0 ± 0.3 g/kg/day; n = 3) and heavy (mean = 3.3 ± 0.5 g/kg/day; n = 6) drinkers. The two groups diverged in performance on the set-shifting task across the 30 pre-alcohol sessions, and at the end of the pre-alcohol testing, the group average PI was 216 ± 27 and 137 ± 71 for the future non-heavy and heavy drinkers, respectively. The data show that low cognitive flexibility assessed with a set-shifting procedure was predictive of future classification as a heavy alcohol drinker. The data highlight individual differences in both cognitive flexibility and in alcohol self-administration in this population of rhesus monkeys.