Cognitive and emotional behavioural changes associated with methylphenidate treatment: a review of preclinical studies

Abstract

There is evidence from animal studies that repeated exposure to methylphenidate (MPH), a widely used psychostimulant for the treatment of attention deficit hyperactivity disorder (ADHD), produces behavioural, structural and neurochemical changes that persist long after drug administration has ended. However, the translational utility of much of this work is compromised by the use of drug doses and routes of administration that produce plasma and brain MPH levels that fall outside the clinical range, i.e. experimental parameters more relevant to drug abuse than ADHD. We used PubMed to identify pre-clinical studies that employed repeated MPH administration at low doses in young rodents and examined long-term effects on cognition, emotion, and brain structure and function. A review of this work suggests that repeated MPH treatment during early development can modify a number of cognitive, behavioural and brain processes, but these are reduced when low therapeutic doses are employed. Moreover, MPH sites of action extend beyond those implicated in ADHD. Studies that combined neurobiological and behavioural approaches provide important insights into the mechanisms underlying MPH-produced effects on cognitive and behavioural processes, which may be relevant to MPH therapeutic efficacy. There is an emerging consensus that pharmacological treatment of childhood psychiatric disorders produces persistent neuroadaptations, highlighting the need for studies that assess long-term effects of early developmental pharmacotherapy. In this regard, studies that mimic clinical therapy with rodents are useful experimental approaches for defining the behavioural and neural plasticity associated with stimulant therapy in paediatric populations.

Co-segregation of hyperactivity, active coping styles, and cognitive dysfunction in mice selectively bred for low levels of anxiety

“…Clinical evidence points to sensitive phases in development (e.g., early childhood) when pharmacological treatment for ADHD is most efficient (Zito et al, 2000). Several studies have proposed that both the timing of treatment onset and treatment duration influence the therapeutic effects of the drugs (Andersen et al, 2002; Thanos et al, 2007; Britton, 2011). In our study, the timing of treatment may be too late to modify the cognitive deficits of adult subjects.…”

Changes in behavior as side effects in methylphenidate treatment: review of the literature

“…In 2012, Britton stated that until 2011, not a single study had been published on the long-term effects of treatment with methylphenidate. 1 Since then, preclinical research has identified possible changes in brain structure and function, which suggest that “early pharmacotherapy can produce neuroadaptations that can persist long after drug treatment has ended”. 1 …”

Neonatal methylphenidate does not impair adult spatial learning in the Morris water maze in rats

“…During juvenile periods of exposure, increases in CREB, an important transcription factor, can also be seen after MPD exposure [3]. Because of its integral role in synaptogenesis and maintenance [2, 24] regulating cellular processes and gene transcription[8], CREB may be part of a neuroadaptive developmental mechanism activated during developmental MPD exposure. This may partially explain a lack of detrimental effects on learning and memory, although more research into mechanisms and behavioral outcomes are clearly needed.…”