Nucleus accumbens lesions modulate the effects of methylphenidate

Abstract

The psychostimulant methylphenidate (MPD, Ritalin) is the prescribed drug of choice for treatment of ADHD. In recent years, the diagnosis rate of ADHD has increased dramatically, as have the number of MPD prescriptions. Repeated exposure to psychostimulants produces behavioral sensitization in rats, an experimental indicator of a drug’s potential liability. In studies on cocaine and amphetamine, this effect has been reported to involve the nucleus accumbens (NAc), one of the nuclei belonging to the motive circuit. The aim of this study was to investigate the role of the NAc on the expression of behavioral sensitization as a response to MPD exposure. In the present study, 20 male Sprague-Dawley rats were divided randomly into three groups: an intact control group, a sham operated group, and a NAc bilateral electrical lesion group. Locomotor activity was assessed for the first two hours following 2.5 mg/kg MPD injection, using open field monitoring systems. Recordings were made during six days of continuous MPD administration, and then upon re-challenge with the same dose following three days of washout. Acute MPD exposure elicited an increase in locomotor activity in all three groups. However, the NAc lesion group exhibited significantly increased locomotor activity in comparison to sham and control groups. Chronic MPD did not elicit sensitization in the NAc lesion group, while both sham and control groups did exhibit behavioral sensitization to repetitive MPD administration. These findings suggest that the NAc plays a significant role in eliciting locomotor activity as an acute effect of MPD, and in the expression of sensitization due to chronic MPD exposure.

Behavioral and neuronal recording of the nucleus accumbens in adolescent rats following acute and repetitive exposure to methylphenidate

“…The NAc has historically been considered a key center in the behavior response elicited by psychostimulants such as MPD (Kim et al 2009;Pierce and Kalivas 1997b;Podet et al 2010). For example, it has been demonstrated that MPD can act as a rewarding and reinforcing stimulus in inducing self-administrative behavior and conditioned place preference (Bergman et al 1989;Kollins et al 2001;Martin-Iverson et al 1985;Meririnne et al 2001;Mithani et al 1986).…”

“…HA represents overall locomotor activity as recorded by beam breaks from one beam to the next. NOS, on the other hand, counts the number of small, repetitive movement episodes during which an animal breaks the same beam repeatedly, with at least 1 s between each episode Eckermann et al 2001;Gaytan et al 2000aGaytan et al , 2000bPodet et al 2010). Thus, in general, as an animal increases (or decreases) its movements after drug administration, it also increases (or decreases) the number of beam breaks it performs.…”

“…This implies that when studying the effects of repetitive MPD administration on adolescent rats, it is advisable to simultaneously record both neuronal and behavioral activity and to evaluate all data based on the animals' behavioral response to the repetitive MPD exposure. methylphenidate; dose response; neuronal recording; freely behaving animal THE NUCLEUS ACCUMBENS (NAc) has often been studied as an important center with regards to the behavioral response elicited by psychostimulants (Kim et al 2009;Pierce and Kalivas 1997b;Podet et al 2010). For example, many studies have demonstrated that repeated administration of methylphenidate (MPD) in rats elicits behavioral sensitization, while others have in contrast shown that repeated administration can elicit behavioral tolerance (Askenasy et al 2007;Gaytan et al 1997a;Yang et al 2007).…”

“…In particular, modulation of dopaminergic transmission in the NAc has been widely investigated as a central process in the expression of behavioral sensitization to psychostimulants (Kim et al 2009;Pierce and Kalivas 1997a;Podet et al 2010;Rebec 2006). MPD has also been shown to act as a rewarding and reinforcing stimulus, as evidenced by its ability to induce and maintain self-administrative behavior (Bergman et al 1989;Kollins et al 2001), as well as induce conditioned placed preference (CPP) in rats (Martin-Iverson et al 1985;Mithani et al 1986;Meririnne et al 2001).…”

“…The present study focuses on the NAc of adolescent animals because of the NAc's well-established role in psychostimulant response in behavioral studies (Pierce and Kalivas 1997a;Podet et al 2010). Moreover, adolescent rats are employed to parallel the age in which MPD use is widespread and controversial in humans (Laviola et al 2003;Marco et al 2011) and because it has been shown that there is a difference in the response to MPD between adult and adolescent animals, particularly in that adolescent subjects are often more sensitive to psychostimulants than adults (Canese et al 2009;Marco et al 2011).…”