Short-term testosterone manipulations do not affect cognition or motor function but differentially modulate emotions in young and older male rhesus monkeys.

Human aging is characterized by declines in cognition and fine motor function as well as improved emotional regulation. In men, declining levels of testosterone (T) with age have been implicated in the development of these age-related changes. However, studies examining the effects of T replacement on cognition, emotion and fine motor function in older men have not provided consistent results. Rhesus monkeys (Macaca mulatta) are excellent models for human cognitive aging and may provide novel insights on this issue. We tested 10 aged intact male rhesus monkeys (mean age=19, range 15-25) on a battery of cognitive, motor and emotional tasks at baseline and under low or high T experimental conditions. Their performance was compared to that of 6 young males previously tested in the same paradigm (Lacreuse et al., 2009; Lacreuse et al., 2010). Following a 4-week baseline testing period, monkeys were treated with a gonadotropin releasing hormone agonist (Depot Lupron, 200 µg/kg) to suppress endogenous T and were tested on the task battery under a 4-week high T condition (injection of Lupron+T enanthate, 20 mg/kg, n=8) or 4-week low T condition (injection of Lupron+oil vehicle, n=8) before crossing over to the opposite treatment. The cognitive tasks consisted of the Delayed Non-Matching-to-Sample (DNMS), the Delayed Response (DR), and the Delayed Recognition Span Test (spatial-DRST). The emotional tasks included an object Approach-Avoidance task and a task in which monkeys were played videos of unfamiliar conspecifics in different emotional context (Social Playbacks). The fine motor task was the Lifesaver task that required monkeys to remove a Lifesaver candy from rods of different complexity. T manipulations did not significantly affect visual recognition memory, working memory, reference memory or fine motor function at any age. In the Approach-Avoidance task, older monkeys, but not younger monkeys, spent more time in proximity of novel objects in the high T condition relative to the low T condition. In both age groups, high T increased watching time of threatening social stimuli in the Social Playbacks. These results suggest that T affects some aspects of emotional processing but has no effect on fine motor function or cognition in young or older male macaques. It is possible that the duration of T treatment was not long enough to affect cognition or fine motor function or that T levels were too high to improve these outcomes. An alternative explanation for the discrepancies of our findings with some of the cognitive and emotional effects of T reported in rodents and humans may be the use of a chemical castration, which reduced circulating gonadotropins in addition to T. Further studies will investigate whether the luteinizing hormone LH mediates the effects of T on brain function in male primates.

Testosterone modulation of anxiety in gonadally-suppressed male rhesus monkeys: a role for gonadotropins?

Testosterone (T) has repeatedly been shown to have anxiolytic properties in rodents, but findings in primates are more mixed. To examine the effects of exogenous T on anxiety, we tested pharmacologically-castrated adult male rhesus monkeys in a modified version of the Human Intruder Paradigm, which measured defensive responses to an unfamiliar human staring directly at them for 2 min. Monkeys were tested at 2 week intervals during 4 experimental conditions lasting 4 weeks each: at baseline, during treatment with the gonadotropin releasing hormone (GnRH) agonist leuprolide acetate (200 µg/kg; Lupron phase), during treatment with Lupron+T enanthate (TE, 5 mg/kg; TE phase) and during treatment with Lupron+oil vehicle (oil phase). We found that the number of anxious behaviors was lower during periods of low T (Lupron only and Lupron+oil phases) than during the Lupron+TE phase. No change in pacing or watching behavior was observed. Thus, in contrast to rodent data, we found no evidence for anxiolytic properties of T in male rhesus monkeys. Rather, T supplementation restored baseline levels of anxiety in Lupron-treated monkeys. These discrepant findings may be best explained by the low levels of gonadotropins achieved by the GnRH agonist. We suggest that Lupron-induced luteinizing hormone (LH) suppression reduced anxiety and that this effect was abolished by T administration. This interpretation is consistent with the view that T increases emotional reactivity to a potential threat and facilitates adaptive arousal response in face of immediate social challenge.

Short-term testosterone manipulations modulate visual recognition memory and some aspects of emotional reactivity in male rhesus monkeys.

The role of testosterone (T) in modulating cognitive function and emotion in men remains unclear. The paucity of animal studies has likely contributed to the slow progress in this area. In particular, studies in nonhuman primates have been lacking. Our laboratory has begun to address this issue by pharmacologically manipulating T levels in intact male rhesus monkeys, using blind, placebo-controlled, crossover designs. We previously found that T-suppressed monkeys receiving supraphysiological T for 4 weeks had lower visual recognition memory for long delays and enhanced attention to videos of negative social stimuli (Lacreuse et al., 2009, 2010) compared to when treated with oil. To further delineate the conditions under which T affects cognition and emotion, the present study focused on the short-term effects of physiological T. Six intact males were treated with the gonadotropin-releasing hormone antagonist degarelix (3 mg/kg) for 7 days and received one injection of T enanthate (5 mg/kg) followed by one injection of oil vehicle 7 days later (n=3), or the reverse treatment (n=3). Performance on two computerized tasks, the Delayed-non-matching-to-sample (DNMS) with random delays and the object-Delayed Recognition Span test (object-DRST) and one task of emotional reactivity, an approach/avoidance task of negative, familiar and novel objects, was examined at baseline and 3-5 days after treatment. DNMS performance was significantly better when monkeys were treated with T compared to oil, independently of the delay duration or the nature (emotional or neutral) of the stimuli. Performance on the object-DRST was unaffected. Interestingly, subtle changes in emotional reactivity were also observed: T administration was associated with fewer object contacts, especially on negative objects, without overt changes in anxious behaviors. These results may reflect increased vigilance and alertness with high T. Altogether, the data suggest that changes in general arousal may underlie the beneficial effects of T on DNMS performance. This hypothesis will require further study with objective measures of physiological arousal.