Acute and chronic dose–response effect of methylphenidate on ventral tegmental area neurons correlated with animal behavior

Abstract

Methylphenidate (MPD) is used to treat ADHD and as a cognitive enhancement and recreationally. MPD's effects are not fully understood. One of the sites of psychostimulant action is the ventral tegmental area (VTA). The VTA neuronal activity was recorded from freely behaving rats using a wireless system. 51 animals were divided into groups: saline, 0.6, 2.5, and 10.0 mg/kg MPD. The same repetitive MPD dose can elicit either behavioral sensitization or tolerance, thus the evaluation of the VTA neuronal activity was based on the animals’ behavioral response to chronic MPD exposure: animals exhibiting behavioral tolerance or sensitization. Acute MPD elicits dose related increases in behavioral activity. About half of the animals exhibited behavioral sensitization or tolerance to each of the MPD doses. 361 units were recorded from the VTA and exhibited similar spike shape on experimental day 1 (ED1) and on ED10. 71%, 84%, and 79% of VTA units responded to acute 0.6, 2.5, and 10.0 mg/kg MPD respectively. The neuronal baseline activity at ED10 was significantly modified in 94%, 95%, and 100% of VTA units following 0.6, 2.5 and 10.0 mg/kg MPD respectively. Following chronic MPD exposure, 91%, 98%, and 100% exhibit either electrophysiological tolerance or sensitization of 0.6, 2.6, or 10.0 mg/kg MPD respectively. In conclusion, the chronic administration of the same dose of MPD caused some animals to exhibit behavioral sensitization and other animals to exhibit tolerance. The VTA units recorded from animals exhibiting behavioral sensitization responded significantly differently to MPD from animals that exhibited behavioral tolerance.

Methylphenidate dose–response behavioral and neurophysiological study of the ventral tegmental area and nucleus accumbens in adolescent rats

“…The main behavioral findings of this study were that the same chronic dose of 0.6, 2.5, and 10.0 mg/kg methylphenidate elicited in some animals behavioral sensitization, and in others behavioral tolerance. This is comparable to observations using similar protocols (Claussen & Dafny,; Frolov et al, ;Jones & Dafny, ; Tang & Dafny, ; Venkarataman, Claussen, Joseph, & Dafny, ). In general, the ventral tegmental area and nucleus accumbens units responded to MPD with dose‐response characteristics: with increased MPD dosage more units responded to the drug, from less than 50% of units responding following acute 0.6 mg/kg MPD exposure to more than 70% of units responding following acute 10.0 mg/kg MPD exposure.…”

“…Studies investigating the types of dopamine receptors in the ventral tegmental area and nucleus accumbens, as well as certain transcription factors, could help explain these behavioral findings. The VTA and NAc are part of the mesolimbic dopamine system of the central nervous system, or the “motive system.” This system participates in the induction of behavioral sensitization to psychostimulants and modulating reward processes (Yang et al ., ; Dafny & Yang, ; Tang et al ., ; Podet et al ., ; Calipari et al ., ; Jones & Dafny, ; Frolov et al ., ). Both the VTA and NAc contain D1 and D2 dopamine receptors (Missale, Nash, Robinson, Jaber, & Caron, ; Ranaldi & Wise, ); dopaminergic neurons in the VTA project to the medium‐sized spiny neurons in the NAc, which plays a role in modulating input from the prefrontal cortex (Chao & Nestler, ).…”

“…Electrodes were secured to the skull when at least a 3:1 signal to noise ratio was achieved. If a 3:1 ratio was not achieved, the electrode was lowered in increments of 5–10 μm until the desired ratio was obtained (Chong, Claussen, & Dafny, ; Claussen & Dafny, ; Jones & Dafny, ; Salek, Claussen, Pérez, & Dafny, ; Tang & Dafny, ). This procedure was repeated for all other electrodes implanted into each NAc and VTA bilaterally.…”

“…Current research has shown that repeated administration of psychostimulants such as methylphenidate in normal experimental animals can lead to altered patterns of behavioral and neuronal responses which include behavioral and neurophysiological sensitization and tolerance (Claussen, Chong, & Dafny, 2014;Dafny & Yang, 2006;Frolov, Reyes-Vasquez, & Dafny, 2015;Jones & Dafny, 2014;Tang, Wanchoo, Swann, & Dafny, 2009). Sensitization is a significant increase in neurophysiological and behavioral activities associated with repeated exposure to the same dose of the pharmacological agent as compared to the initial (acute) effect of the drug.…”

“…Studies have shown that the same dosage of repeated MPD in two different animals can cause behavioral sensitization in one animal or behavior tolerance in the other one; the expression of sensitization and tolerance potentially underlies the neural processes that form maladaptive relationships with substance use and has been used as an experimental biomarker of drug craving and dependency (Yang, Amini, Swann, & Dafny, 2003;Dafny & Yang, 2006;Frolov et al, 2015). Previous research of neuronal recordings in adult rats from the nucleus accumbens (NAc; Claussen & Dafny, 2015) and ventral tegmental area (VTA; Jones & Dafny, 2014) individually has demonstrated that chronic MPD exposure leads to behavioral and neuronal sensitization or tolerance. The VTA and NAc are part of the "motive system" of the brain and are involved in the induction of behavioral sensitization to psychostimulants and modulating reward processes (Yang et al, 2003;Dafny & Yang, 2006;Tang et al, 2009;Podet, Lee, Swann, & Dafny, 2010;Calipari et al, 2014;Jones & Dafny, 2014;Frolov et al, 2015).…”