Recovery from behavior and developmental effects of chronic oral methylphenidate following an abstinence period

Abstract

Chronic oral methylphenidate (MP) exposure in rats is associated with numerous developmental and behavioral consequences. The present study investigated the persistence of the effects of chronic oral MP exposure after abstinence from MP use. Male and female rats were exposed to daily orally self-administered water, low dose MP (LD), or high dose (HD) MP for 13 weeks, followed by a 4-week abstinence period. Fluid, food consumption and bodyweights were monitored and animals were tested for locomotor activity, anxiety- and depressive-like symptoms, learning and memory, and social behavior during both the treatment and abstinence phases of the experiment. During treatment, MP attenuated bodyweight regardless of sex, but increased food and fluid consumption in females and males by 20.7% and 30.1%, respectively. MP also increased locomotor activity in both males and females observed as increased distance travelled in an open field. (59.1% and 95.9%, respectively) and increased locomotor activity in the home cage over a 24-hour circadian cycle (45.5% and 63.0%). Additionally, MP exerted an anxiolytic effect observed as increased time spent in the open arms of an elevated plus maze (31.1% in HD males, 59.2% in HD females), and an increased latency to immobility in a forced swim test (330% in HD males, 418% in HD females). The effects of MP (bodyweight, consumption, locomotion, anxiolytic, and anti-depressive) were, almost without exception, eliminated during the abstinence period. MP had no impact on learning and memory performance as measured by a T-maze, or social behavior during treatment. These findings suggest that the behavioral consequences of chronic oral MP treatment in our preclinical model are reversible in rats following an abstinence period from use of the drug.

Brief and extended abstinence from chronic oral methylphenidate treatment produces reversible behavioral and physiological effects

“…Previous studies reported a dose‐related locomotor‐increasing characteristic of chronic MP exposure (Griggs et al, ; Kuczenski & Segal, ; Penner, McFadyen, Carrey, & Brown, ; Yang, Swann, & Dafny, ). Indeed, similar to our previous reports following uninterrupted 13‐week daily MP exposure (Martin et al, ; Robison, Michaelos, et al, ) and 13‐week daily MP exposure with weekend abstinence periods (Carias et al, ), chronic MP consumption increased locomotor activity in this study. This effect was evident from the increased floor‐plane distance, floor plane move time, and center distance in the open field in the HD MP‐treated group compared to both LD and water groups during the treatment phase.…”

“…Similar to our previous findings following chronic uninterrupted exposure (Martin et al, ; Robison, Michaelos, et al, ) and chronic exposure with weekend abstinence periods (Carias et al, ), we observed attenuated anxiety‐like behaviors in the HD compared to both LD and water groups during the treatment phase. This finding corroborates existing evidence that MP administration exerts an anxiolytic effect on pre‐pubertal mice (Carrey, ), adult mice prenatally exposed to MP (McFadyen‐Leussis, Lewis, Bond, Carrey, & Brown, ) and on adult rats (Britton & Bethancourt, ).…”

“…The goal of this study was to use a rat model to examine the long-lasting physiological, behavioral and developmental effects of three consecutive cycles of a three-week daily MP consumption followed by 1-week abstinence, and the reversal of such effects during a 5-week abstinence period. We hypothesized that chronic MP exposure would be associated with hyperactivity and decreased anxiety, depressive-like symptoms, and social interaction as previously reported following weekday-only (Carias et al, 2019) and uninterrupted chronic 13-week daily MP use (Martin et al, 2018;Robison, Michaelos, et al, 2017) in adolescent rats. The current schedule of administration was chosen in order to supplement our previous report on weekday-only administration (Carias et al, 2019).…”

“…However, few clinical and preclinical studies on the behavioral and physiological impact of "drug holidays" have been conducted (Carias et al, 2019;Griggs, Weir, Wayman, & Koeltzow, 2010;Martins et al, 2004). Therefore, it is important to further understand the behavioral and developmental effects of interrupted schedules of MP use, in addition to the existing knowledge of uninterrupted chronic daily MP use (Martin et al, 2018;Robison, Ananth, Hadjiargyrou, Komatsu, & Thanos, 2017;Robison, Michaelos, et al, 2017;Thanos et al, 2015;Uddin et al, 2018).…”

Weekday-only chronic oral methylphenidate self-administration in male rats: Reversibility of the behavioral and physiological effects

“…We hypothesized that during the treatment phase, chronic MP exposure, regardless of weekend abstinence, would produce the same effects as we previously reported [11]. Furthermore, we expected the effects of chronic MP treatment to be generally reversed following prolonged abstinence, as our recent data indicated [23]. The present study examined the behavioral consequences of chronic weekday-only oral MP treatment in rats and revealed that HD MP exposure resulted in increased open field and circadian locomotor activity; increased latency to immobility and decreased time spent immobile in the forced swim test; increased center activity in the open field and percent of time spent in an open arm of the elevated-plus-maze; and increased social affiliation and memory in the Crawley’s three chamber sociability test.…”