Sex differences, learning flexibility, and striatal dopamine D1 and D2 following adolescent drug exposure in rats

Abstract

Corticostriatal circuitry supports flexible reward learning and emotional behavior from the critical neurodevelopmental stage of adolescence through adulthood. It is still poorly understood how prescription drug exposure in adolescence may impact these outcomes in the long-term. We studied adolescent methylphenidate (MPH) and fluoxetine (FLX) exposure in rats and their impact on learning and emotion in adulthood. In Experiment 1, male and female rats were administered MPH, FLX, or saline (SAL), and compared with methamphetamine (mAMPH) treatment beginning in postnatal day (PND) 37. The rats were then tested on discrimination and reversal learning in adulthood. In Experiment 2, animals were administered MPH or SAL also beginning in PND 37 and later tested in adulthood for anxiety levels. In Experiment 3, we analyzed striatal dopamine D1 and D2 receptor expression in adulthood following either extensive learning (after Experiment 1) or more brief emotional measures (after Experiment 2). We found sex differences in discrimination learning and attenuated reversal learning after MPH and only sex differences in adulthood anxiety. In learners, there was enhanced striatal D1, but not D2, after either adolescent MPH or mAMPH. Lastly, also in learners, there was a sex x treatment group interaction for D2, but not D1, driven by the MPH-pretreated females, who expressed significantly higher D2 levels compared to SAL. These results show enduring effects of adolescent MPH on reversal learning in rats. Developmental psychostimulant exposure may interact with learning to enhance D1 expression in adulthood, and affect D2 expression in a sex-dependent manner.

Age- and sex-dependent effects of methamphetamine on cognitive flexibility and 5-HT2C receptor localization in the orbitofrontal cortex of Sprague-Dawley rats

“…Coupled with our analysis of 5-HT 2C R co-localization, this suggests that METH exposure may result in functional, but not structural changes to 5-HT 2C Rs in the OFC of adolescent females. In addition, the finding that no other METH exposed groups exhibited deficits in reversal learning is consistent with a recent report (Izquierdo et al, 2016), but inconsistent with many previous studies (Izquierdo et al, 2010; Parsegian et al, 2011; Hankosky et al, 2013; Ye et al, 2014; Cox et al, 2016). The inconsistent findings might be related to these studies differences in task difficulty, total drug intake, drug-free interval prior to testing, or the method of drug exposure (i.e., volitional vs. experimenter-administered).…”

Adolescent fluoxetine history impairs spatial memory in adult male, but not female, C57BL/6 mice

“…Preclinical studies indicate that psychotropic drug and/or stress exposure alter behavior differentially, as a function of sex (Izquierdo et al, 2016;Luine et al, 2017). Similarly, under normal conditions, male and female rodents display differences in memory-related performance across numerous behavioral tasks, including object recognition and MWM performance (Frick and Gresack, 2003).…”

“…Accumulating preclinical investigations on the enduring consequences of early-life drug treatment, specifically during adolescence, have started to question the safety of exposure to antidepressant medications. While results are not always conclusive (Izquierdo et al, 2016;Norcross et al, 2008), generally, juvenile exposure to FLX results in neurobiological and behavioral alterations in adulthood (Olivier et al, 2011;Shrestha et al, 2014). For example, adolescent exposure to FLX modifies the reward valence of both natural (Iñiguez et al, 2010) and drug (Flores-Ramirez et al, 2018;Iñiguez et al, 2015) rewards later in life; per the sucrose and cocaine place conditioning behavioral paradigms.…”

Sex chromosome complement affects multiple aspects of reversal‐learning task performance in mice

“…In studies of otherwise healthy subjects, evidence is highly inconsistent for sex differences in performance of the RLT or related tasks that include a reversal learning component (e.g., Wisconsin Card Sorting Task, attentional‐set shifting). Many studies detected no sex difference in either humans 21‐30 or animal models, 31‐43 and a minority finding that males performed better under reversal conditions in humans 44 and animal models 44‐48 …”