Vol.:(0123456789) 1 3 Journal of Neural Transmission https://doi.org/10.1007/s00702-018-1963-4 NEUROLOGY AND PRECLINICAL NEUROLOGICAL STUDIES - ORIGINAL ARTICLE Acute and chronic methylphenidate administration in intact and VTA- specifc and nonspecifc lesioned rats Stephanie A. Ihezie 1  · Ming M. Thomas 1  · Nachum Dafny 1 Received: 6 August 2018 / Accepted: 7 December 2018 © Springer-Verlag GmbH Austria, part of Springer Nature 2019 Abstract Methylphenidate (MPD) is a psychostimulant used for the treatment of ADHD and works by increasing the bioavailability of dopamine (DA) in the brain. As a major source of DA, the ventral tegmental area (VTA) served as the principal target in this study as we aimed to understand its role in modulating the acute and chronic MPD efect. Forty-eight male Sprague– Dawley rats were divided into control, sham, electrical lesion, and 6-OHDA lesion groups. Given the VTA’s implication in the locomotive circuit, three locomotor indices—horizontal activity, number of stereotypy, and total distance—were used to measure the animals’ behavioral response to the drug. Baseline recording was obtained on experimental day 1 (ED 1) followed by surgery on ED 2. After recovery, the behavioral recordings were resumed on ED 8. All groups received daily intraperitoneal injections of 2.5 mg/kg MPD for six days after which the animals received no treatment for 3 days. On ED 18, 2.5 mg/kg MPD was re-administered to assess for the chronic efect of the psychostimulant. Except for one index, there was an increase in locomotive activity in all experimental groups after surgery (in comparison to baseline activity), acute MPD exposure, induction with six daily doses, and after MPD re-challenge. Furthermore, the increase was greatest in the electrical VTA lesion group and lowest in the 6-OHDA VTA lesion group. In conclusion, the results of this study suggest that the VTA may not be the primary nucleus of MPD action, and the VTA plays an inhibitory role in the locomotive circuit. Keywords Behavior · Locomotion · Ritalin · CNS lesion · Psychostimulant · Sensitization Introduction Psychostimulants have historically been used in the treat- ment of Attention Defcit Hyperactivity Disorder (ADHD), a behavioral disorder linked to low dopamine activity in the brain (Kalivas 1993). Methylphenidate (MPD, Ritalin) has become the pharmacotherapy of choice for ADHD (Chall- man and Lipsky 2000; Swanson et al. 1991) since it indi- rectly increases levels of dopamine (DA) and norepinephrine (NE) by inhibiting their reuptake from the presynaptic cleft. A major source of dopamine in the rat midbrain is the A10 cells of the ventral tegmental area (VTA) which serve as the origin of the dopaminergic mesolimbic pathway (German and Manaye 1993; Kelly et al. 1975). Within the VTA there are GABAergic, glutamatergic, and dopamin- ergic neurons—mainly D1 DA which are excitatory and D2 DA which are inhibitory (Nair-Roberts et al. 2008; Olson and Nestler 2007; Ranaldi and Wise 2001). The glutamatergic aferents to the VTA originate from prefron- tal cortex (PFC) primarily but also from the subthalamic nucleus, the pedunculopontine- and laterodorsal-tegmen- tal nuclei, the bed nucleus of the stria terminalis, and the superior colliculus (Morikawa and Paladini 2011; Kita and Kitai 1987; Clements et al. 1991; Lavoie and Parent 1994; Charara et al. 1996; Georges and Aston-Jones 2002; Comoli et al. 2003; Dommett et al. 2005). The GABAergic aferents come from the nucleus accumbens (NAc), ventral pallidum, and rostromedial tegmental nucleus (Morikawa and Paladini 2011). As for output, the two major eferents from the VTA project back to the PFC and NAc though there are also projections to the amygdala, cingulate gyrus, hippocampus, and olfactory bulb (Malenka et al. 2009; Nechifor 2008). Given the heterogeneity in VTA com- position and connections, the outcome of glutamatergic inputs are not exclusively excitatory nor are the outcome * Nachum Dafny nachum.dafny@uth.tmc.edu 1 Department of Neurobiology and Anatomy, University of Texas Health Science Center at Houston, McGovern Medical School, 6431 Fannin Street, Houston, TX 77030, USA