Comparison of the VTA and LC response to methylphenidate: a concomitant behavioral and neuronal study of adolescent male rats

Abstract

Methylphenidate (MPD), also known as Ritalin, is a psychostimulant used to treat attention deficit hyperactivity disorder. However, it is increasingly being misused by normal adolescents for recreation and academic advantage. Therefore, it is important to elucidate the behavioral and neurophysiological effects of MPD in normal subjects. MPD inhibits the reuptake of catecholamines, mainly found in the ventral tegmental area (VTA) and locus coeruleus (LC). The VTA and LC normally mediate attention, motivation, and drug reward behaviors. Selective neuronal connections between the VTA and LC have been identified implicating regular interaction between the structures. The objective of this study was to compare the neuronal responses of the VTA and LC to MPD in normal adolescent rats. Animals were implanted with permanent electrodes in the VTA and LC, and neuronal units were recorded following acute and repetitive (chronic) saline or 0.6, 2.5, or 10.0 mg/kg MPD exposure. Animals displayed either behavioral sensitization or tolerance to all three doses of MPD. Acute MPD exposure elicited excitation in the majority of all VTA and LC units. Chronic MPD exposure elicited a further increase in VTA and LC neuronal activity in animals exhibiting behavioral sensitization and an attenuation in VTA and LC neuronal activity in animals exhibiting behavioral tolerance, demonstrating neurophysiological sensitization and tolerance, respectively. The similar pattern in VTA and LC unit activity suggests that the two structures are linked in their response to MPD. These results may help determine the exact mechanism of action of MPD, resulting in optimized treatment of patients. The same dose of 0.6, 2.5, and 10 mg/kg methylphenidate (MPD) elicits either behavioral sensitization or tolerance in adolescent rats. There is a direct correlation between the ventral tegmental area (VTA) and locus coeruleus (LC) neuronal response to chronic MPD exposure. Both the VTA and LC are involved in the behavioral and neurophysiological effects of chronic MPD.

Age, Sex and Strain Respond Differently to Acute Ritalin (Methylphenidate) Exposure

“…Although we found significant differences in just this first exposure, we believe much more can be gained from looking at a chronic exposure to MPD, as we would then be able to make conclusions about the differences in tolerance and sensitization in the various animal groups we studied. Additionally, many studies have shown the concordance between behavioral and electrophysiologic data from brain structures implicated in the reward pathway [41,4,5] . This presents another area for comparison between sex, age and strain.…”

“…Open field locomotion behaviors represent the interaction of the whole animal within the experimental situation. The details of the procedure are well established and previously published [41,42,4,5,43,36,40] . Each interruption from each sensor was counted and cumulative counts were compiled by the Accuscan Analyzer (Columbus, OH, USA).…”

“…Furthermore, there has been an increase in the number of preschoolers, adolescents and adults with and without a diagnosis of ADHD using MPD [2,3] . However, there have been few studies done on the possible adverse effects produced by psychostimulants on developing female and male brains [4,5,6,7] . Furthermore, there is a paucity of research when it comes to the effect of MPD on different strains.…”

Glutaminergic Signaling in the Nucleus Accumbens Modulates the Behavioral Response to Acute and Chronic Methylphenidate

“…Starting on experimental day 9 (ED 9-MPD), daily injections of 2.5 mg/kg MPD (Mallinckrodt, Hazelwood MO) dissolved in 0.8 mL of 0.9% saline were administer for 6 consecutive days (ED 9-MPD to ED 14-MPD), and activity recorded for 120 minutes post-injection. This dose of 2.5 mg/kg MPD has been shown to be sufficient to elicit behavioral sensitization in rats in previous doseresponse experiments [27][28][29]48,51,[61][62][63][64][65][66][67][68]. For the next 3 days (ED 15-17), animals received no injections (the washout period).…”

Amphetamine, but not methylphenidate, increases ethanol intake in adolescent male, but not in female, rats

“…Our aim was to test whether repeated treatment with these doses, which are commonly used in the literature of animal models of ADHD, would alter subsequent ethanol self-administration during adolescence and assess potential behavioral and neurochemical correlates of this effect. More in detail, the MPH dose employed is in the upper range of doses employed in animal models of ADHD (Karim, Reyes-Vazquez, & Dafny, 2017;Venkataraman, Claussen, & Dafny, 2017); and doses equal or lower than 10.0 mg/kg MPH have been found to evoke changes in MPH-induced motor activity (i.e., behavioral sensitization or tolerance; Chong, Claussen, & Dafny, 2012;Frolov, Reyes-Vasquez, & Dafny, 2015;Gaytan, Nason, Alagugurusamy, Swann, & Dafny, 2000;Gaytan, Yang, Swann, & Dafny, 2000). Similarly, we employed a dose of AMPH that has been repeatedly employed in the assessment of AMPH-induced behavioral sensitization and has been shown to yield this phenomenon in adolescent mice (Kameda et al, 2011).…”