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

Abstract

Methylphenidate (MP) is a commonly prescribed psychostimulant for Attention Deficit Hyperactivity Disorder (ADHD). We recently reported behavioral and developmental effects of chronic MP use in healthy rats. The current study investigated how interrupting chronic MP treatment with weekend abstinence altered the behavioral and physiological consequences of chronic MP treatment, and if prolonged abstinence would reverse the observed effects. Male Sprague Dawley rats were assigned to one of three treatment groups: water (W); low dose (LD) MP; and high dose (HD) MP. For 13 weeks, rats had access to drink from a bottle containing 4 mg/kg MP (LD), 30 mg/kg MP (HD) or water (W) for 1 hour, and 10 mg/kg MP (LD), 60 mg/kg MP (HD) or water (W) for the next 7 hours, each week day. During weekends, all animals received only water as well as throughout the 5-week-long abstinence phase, which immediately followed the treatment phase. Throughout the treatment phase, regardless of weekend abstinence, chronic MP resulted in significant decreased food and fluid intake and body weight. Also, HD MP exposure resulted in the following behavioral effects: 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. During the prolonged (5-week) abstinence phase, all these effects were reversed while HD treated rats increased their fluid intake. These results indicated that intermittent brief abstinence periods (weekend’s off-treatment) produced the same behavioral and developmental effects as those previously reported with chronic (7 days/week) MP treatment, but were reversible following a prolonged abstinence period (5 weeks).

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, ).…”

“…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, ) and uninterrupted chronic 13‐week daily MP use (Martin et al, ; Robison, Michaelos, et al, ) in adolescent rats. The current schedule of administration was chosen in order to supplement our previous report on weekday‐only administration (Carias et al, ). We expected these effects to persist regardless of the intermittent 1 week abstinence from MP, but to be reversed during the prolonged 5‐week abstinence period.…”

“…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).…”

“…The American Academy of Child and Adolescent Psychiatry (AACAP) recommends these breaks in order to test the need for continued pharmacotherapy in children and adolescents with ADHD (Ibrahim & Donyai, 2014;van de Loo-Neus, Rommelse, & Buitelaar, 2011;Pliszka, 2007), and parents tend to utilize these breaks in order to manage the negative side effects observed in their children, including suppressed appetite and stunted growth (Ibrahim & Donyai, 2014;Shyu et al, 2016). 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).…”