Neurobehavioral adaptations to methylphenidate: The issue of early adolescent exposure

Abstract

Exposure to psychostimulants, including both abused and therapeutic drugs, can occur first during human adolescence. Animal modeling is useful not only to reproduce adolescent peculiarities but also to study neurobehavioral adaptations to psychostimulant consumption. Human adolescence (generally considered as the period between 9/12 and 18 years old) has been compared with the age window between postnatal days (pnd) 28/35 and 50 in rats and mice. These adolescent rodents display basal hyperlocomotion and higher rates of exploration together with a marked propensity for sensation-seeking and risk-taking behaviors. Moreover, peculiar responses to psychostimulants, including enhanced locomotor sensitization, no drug-induced stereotypy and reduced place conditioning have been described in adolescent rodents. During this age window, forebrain dopamine systems undergo profuse remodeling, thus providing a neuro-biological substrate to explain behavioral peculiarities observed during adolescence, as well as the reported vulnerabilities to several drugs. Further, methylphenidate (MPH, better known as Ritalin^®), a psychostimulant extensively prescribed to children and adolescents diagnosed with attention-deficit/hyperactivity disorder (ADHD), raises concerns for its long-term safety. Using magnetic resonance techniques, MPH-induced acute effects appear to be different in adolescent rats compared to adult animals. Moreover, adolescent exposure to MPH seems to provoke persistent neurobehavioral consequences: long-term modulation of self-control abilities, decreased sensitivity to natural and drug reward, enhanced stress-induced emotionality, together with an enhanced cortical control over sub-cortical dopamine systems and an enduring up-regulation of Htr7 gene expression within the nucleus accumbens (NAcc). In summary, additional studies in animal models are necessary to better understand the long-term consequences of adolescent MPH, and to further investigate the safety of the prescription and administration of such pharmacological treatment at early life stages.

Introduction

Adolescence is the period of transition between childhood and adult life. During adolescence, dramatic hormonal and physical changes occur. The adolescent brain undergoes notable plastic changes and important maturational rearrangements within major neurotransmitter systems, including the dopaminergic system (see review by Andersen and her group, this issue). Moreover, a particular behavioral repertoire is observed among human adolescents and in rodents at the age window broadly identified as adolescence, i.e. between postnatal days 28 and 50 (Spear, 2000, Laviola et al., 2003). Affiliative and playful behaviors are prevalent, together with a notable trend for sensation-seeking and risk-taking (Laviola et al., 2003, Tirelli et al., 2003). For these reasons, a particular interest has been devoted to the investigation of the dopaminergic system, and notable differences between adolescent versus adult animals have been described within the forebrain dopamine (DA) circuitry. Indeed, the developmental profile of the DAergic system during adolescence may contribute to specific behavioral patterns observed among adolescents (Andersen et al., 2002, Laviola et al., 1999, Teicher et al., 1995).

In humans, initial exposure to drugs of abuse including stimulants of the central nervous system – psychostimulants such as amphetamine, cocaine or methylphenidate (MPH) – commonly occurs during infancy or adolescence (Johanson and Fischman, 1989). An increasing body of evidence from human and animal studies supports the fact that adolescent subjects, compared to adults, may be differentially sensitive to some but not all effects of drugs of abuse (Badanich et al., 2006, Caster et al., 2007, Laviola and Adriani, 1998, Laviola et al., 1995, Laviola et al., 1999). However, much investigation is still needed to reveal whether this age difference (in sensitivity to drug-induced effects) may explain or reflect a well-documented increased vulnerability to move from excessive use and abuse up to addiction, and whether age-dependent developmental changes within the forebrain DAergic system may play a critical role. Therefore, the first aim of present review will be a focus on the peculiarities of adolescence, with an emphasis on the neurobehavioral responses to psychostimulant drugs, discussing evidence coming primarily from animal models.

Among psychostimulants, methylphenidate (MPH, commonly known as Ritalin^®) is the elective pharmacological therapy in the management of attention-deficit/hyperactivity disorder (ADHD) in children and adolescents (Scheffler et al., 2007). The pharmacological pathways and the psychotropic effects of MPH are similar, although not identical, to those produced by amphetamines and cocaine. Actually, all these compounds act mainly through the modification of the DAergic system, by blocking the dopamine transporter (DAT), and consequently by increasing meso-corticolimbic DA levels (Volkow et al., 2001, Volkow et al., 2002). Currently, there is great concern about the dramatic increase in the prescription of MPH for therapeutic purposes as well as in its off-label and/or illicit use by the young population. The annual prevalence of illicit MPH use, predominantly intranasal, is 4% in the USA and rising (Klein-Schwartz and McGrath, 2003, McCabe et al., 2004). College students and adolescents might be attracted to MPH for attention focusing, weight loss, or euphoric effects. Indeed, the majority of college students in the USA reported that the primary reason for use was to improve academic performance (Bogle and Smith, 2009). In spite of the fact that MPH has little abuse potential, especially if taken orally (as prescribed) (Svetlov et al., 2007, Volkow et al., 2002), the reinforcing effects of this compound (MPH) depend upon the route of administration. Intranasal MPH produces a euphoric sensation or “high” in humans (Volkow and Swanson, 2003), and laboratory rats readily self-administer this drug intravenously (Fletcher et al., 2007). Despite this, the potential long-term effects of recreational MPH use and abuse during adolescence are still unknown.

Given the extent of prescribed use of MPH (Bogle and Smith, 2009, Brown et al., 2005), exposure to MPH during early stages of brain development, i.e. childhood and adolescence, raises some concern for public health due to possible adverse long-term effects. Since MPH interacts with the same brain pathways activated by other drugs of abuse (i.e. cocaine and amphetamine), most research has focused on assessing the addictive properties of MPH and on its potential to alter an individual's risk for drug addiction. However, the alternative evaluation of long-term consequences following adolescent MPH administration is still lacking. Since stimulant drugs can cause enduring neurochemical and behavioral adaptations, we have examined in depth some of the neurobehavioral consequences due to adolescent exposure to MPH, by using animal models for a translational perspective.

In this review, as a second aim, we will focus on the short and long-term consequences of juvenile exposure to psychostimulants, particularly MPH. The focus on this specific drug was elicited due to public concern, at least in some sectors of Western society, raised for a number of reasons, particularly:

• the possibility of misdiagnosed ADHD in the management of problematic children, and hence the potential sequelae of inappropriate pharmacological therapy;

• the impact of MPH abuse during adolescence, at least in Western society.

In this regard, animal models become of critical relevance in order to better understand the determinants of adolescent vulnerability to MPH, thus providing ground to further investigate possibilities of intervention.