¹Asia University, Department of Psychology, Taichung, Taiwan, ²China Medical University Hospital, Department of Medical Research, Taichung, Taiwan

Background: Adolescents are often impulsive, and their behavior frequently lacks inhibitory control and temporal regulation. In the domain of impulsive action, sex differences have been demonstrated in waiting impulsivity, as measured by the five-choice serial reaction time task, in adolescent rats. However, it remains unclear whether sex differences exist in timing impulsivity.

Aims & Objectives: The differential reinforcement of low-rate (DRL) task, a validated operant conditioning paradigm, is increasingly used to study neuropsychopharmacological mechanisms underlying time-based impulsive action. In this task, subjects are required to withhold responding for a specified interval, set in seconds, and then respond to obtain a reinforcer. Any “premature” response made before the criterion time is not reinforced; moreover, the scheduled time interval is reset. The current study investigated sex differences during adolescence in the acquisition of a DRL task, followed by a dose-response assessment of MK-801, a non-competitive NMDA receptor antagonist.

Method: The subjects were male and female Wistar rats (n = 10 each), arriving at postnatal day (PD) 21. After adapting to a water-restriction regimen, followed by lever-press training on a fixed-ratio 1 schedule during PD 35-42, the subjects acquired a DRL 10-second task during PD 43-63. Subsequently, MK-801 was administered acutely (0, 0.05, 0.1, 0.15, and 0.2 mg/kg, IP) as pharmacological tests conducted during PD 64-68.

Results: The results indicated significant training-day effects and day-by-sex interactions on measures of total responses and non-reinforced responses. Compared to females, males exhibited higher levels of these two measures, particularly during the second and third days of acquisition; however, these differences gradually diminished across subsequent training days. In contrast, the other four behavioral measures, including reinforced responses, burst responses, peak rate, and peak time, remained stable across training days and did not differ by sex. The effects of MK-801 on DRL 10-second performance were both sex- and dose-dependent. A biphasic dose-response relationship was observed in males for total responses, non-reinforced responses, and peak rate, such that lower doses of MK-801 increased these measures, whereas the highest dose had the opposite effect, reducing them. In females, MK-801 produced dose-related decreases in total responses, non-reinforced responses, and peak rate. Post-hoc analyses following a significant sex-by-dose interaction revealed that, at 0.15 mg/kg MK-801, total responses, non-reinforced responses, and peak rate were significantly greater in males than in females.

Discussion & Conclusions: In summary, both the acquisition of the DRL 10-s task and the effects of MK-801 on task performance are sex-dependent during adolescence. Together, these data suggest that NMDA receptors contribute to time-based impulsive action in adolescent rats in a sex-dependent manner.