Abuse and dependence liability analysis of methylphenidate in the spontaneously hypertensive rat model of attention-deficit/hyperactivity disorder (ADHD): what have we learned?

Abstract

Methylphenidate is the most prescribed stimulant medication for attention-deficit/hyperactivity disorder (ADHD). Despite the well documented clinical benefits of the drug, several questions remain unanswered concerning the effects of extended methylphenidate use (e.g. can methylphenidate be abused by ADHD patients? does repeated methylphenidate treatment produce addiction?). Preclinical studies can help address the long-term safety of clinical treatments, moreover animal studies provide valuable information on the details of drug actions. The spontaneously hypertensive rat (SHR), bred from normotensive Wistar Kyoto rat strain, is considered as the best validated and the most widely used animal model of ADHD. We reviewed the findings of research reports that investigated the abuse and dependence liability of methylphenidate in SHR. In particular, we surveyed the studies which investigated the effects of methylphenidate pretreatment on subsequent methylphenidate-induced conditioned place preference or self-administration for they may give insights into the abuse or dependence liability of long-term methylphenidate treatment in ADHD.

Prefrontal cortical and striatal transcriptional responses to the reinforcing effect of repeated methylphenidate treatment in the spontaneously hypertensive rat, animal model of attention-deficit/hyperactivity disorder (ADHD)

“…We observed in this study that methylphenidate pretreatment produced reinforcing effects in SHRs, however, we also found comparable CPP scores and similar rates of methylphenidate self-administration in both saline- and methylphenidate-pretreated rats (cohort 1 and 2 rats, respectively). Investigating the mechanism that underlies differential behavioral responses of strains to the reinforcing effects of repeated methylphenidate treatment is beyond the scope of this study [ for review, however, see [38]]. Nevertheless, the present and the previous findings [19] appear to simulate the reported similarity in the rates of drug abuse or dependence to psychoactive substances in both ADHD and non-ADHD controls [39].…”

Sweat it out? The effects of physical exercise on cognition and behavior in children and adults with ADHD: a systematic literature review

“…Despite the existence of well-elaborated evidence-based guidelines (NICE Guidelines on ADHD 2008 ) and the fact that efficacy and safety of stimulants have been proved in a considerable number of studies and meta-analyses (e.g., Maia et al 2014 ; Rubia et al 2014 ; Thapar and Cooper 2016 ), uncertainties still exist concerning stimulant drug treatment for ADHD. These include sub-optimal treatment in clinical practice (Hodgkins et al 2013 ), uncertainty about the physical safety and potential long-term and side effects of stimulant medication (Biederman et al 1991 ; Buitelaar and Medori 2010 ; Dela Pena and Cheong 2013 ; Owens et al 2000 ; Sonuga-Barke et al 2009 ; Stein et al 2003 ; Taylor et al 2004 ; Van der Heijden et al 2006 ; Wilens et al 2008 ) and a relatively high non-response rate of 10–25 % (Banaschewski et al 2006 ; Taylor et al 2004 ). Besides pharmacological approaches to ADHD treatment, there are non-pharmacological treatment options, such as cognitive trainings, neurofeedback, and behavioral therapy, diets, and combined interventions.…”

Differential sensitivity to the acute and sensitizing behavioral effects of methylphenidate as a function of strain in adolescent and young adult rats

“…Rather, our results suggest that SHR rats are more vulnerable than other strains to methylphenidate-induced cross-sensitization to the locomotor-activating effects of cocaine when methylphenidate is administered in an environment other than home. While the present results are limited to cross-sensitization of the locomotor-activating effects of methylphenidate and cocaine, our findings suggest that individuals with ADHD that are treated with methylphenidate may have greater vulnerability to abuse illicit drugs than normal individuals, a possibility that has recently been supported [22], but see [23-25]. …”