Development of 5-HT transporter density and long-term effects of methylphenidate in an animal model of ADHD

Abstract

Although stimulants as the treatment of choice are widely prescribed in ADHD, little is known about their long-term neurobiological effects. Hence, for the first time the present study examined the long-term effects of chronic methylphenidate (MPH) administration on striatal 5-hydroxytryptamine transporter (5-HTT) densities in an animal model of ADHD. First, it compared the normal development of striatal 5-HTT densities of spontaneously hypertensive rats (SHR) as an animal model of ADHD and Wistar Kyoto (WKY) rats as controls; binding of the highly selective ligand of 5-HTT [(3)H]paroxetine was determined on membrane preparations of the striatum of SHR and WKY rats on postnatal days 25, 50, and 90, i.e. from the time of weaning until adulthood. Second, the long-term effect of chronic administration of 2 mg/kg per day MPH at two different developmental stages (days 25-39 or 50-64) on the striatal 5-HTT density was examined in both rat strains at day 90. Long-term effects of MPH treatment on striatal 5-HTT density in adulthood could be ruled out in both healthy (WKY) and "ADHD" rats (SHR). But a higher striatal 5-HTT density in older SHR versus WKY rats might indicate ADHD specific changes in the 5-HT system that needs further investigation not only in animals.

Adolescent methylphenidate treatment differentially alters adult impulsivity and hyperactivity in the Spontaneously Hypertensive Rat model of ADHD

“…Moreover, discontinuation of adolescent MPH treatment (2 mg/kg/day, i.p. ; either PND 25–39 or PND 50–64) did not result in long term alterations in striatal 5-HT transporter density in adult SHR and WKY (Roessner, Manzke et al 2009). Thus, 5-HT does not appear to play a critical role in strain differences with respect to impulsivity.…”

Effects of tryptophan depletion on reactive aggression and aggressive decision‐making in young people with ADHD

“…More recent research has suggested that a functional variant of the serotonin transporter gene moderates impulsivity in boys with ADHD (8). Regarding potential implications for treatment, the development of the density of the 5‐HT transporter (5‐HTT) and long‐term effects of methylphenidate were studied in an animal model of ADHD, suggesting that a higher striatal 5‐HTT density in older spontaneously hypertensive rats (serving as an animal model for ADHD) vs. Wistar Kyoto rats (control condition) might be indicative of ADHD‐specific changes in central nervous neurotransmission (9). Overall, it can be assumed that changes in central nervous serotonin function play an important role in ADHD, with aggression being a behavioural characteristic associated with ADHD because of its comorbidity with conduct disorder.…”

Postnatal Brain Development and Psychotropic Drugs. Effects on Animals and Animal Models of Depression and Attention-Deficit/Hyperactivity Disorder

“…from day P25-39 or from day P 50-64 had no significant longterm effect when 5-HTT density was measured at day 90 [84]. This underlines that MPH acts mainly within the DA-system.…”