Caudate neuronal recording in freely behaving animals following acute and chronic dose response methylphenidate exposure

Abstract

The misuse and abuse of the psychostimulant, methylphenidate (MPD) the drug of choice in the treatment of attention deficit hyperactivity disorder (ADHD) has seen a sharp uprising in recent years among both youth and adults for its cognitive enhancing effects and for recreational purposes. This uprise in illicit use has lead to many questions concerning the long term consequences of MPD exposure. The objective of this study was to record animal behavior concomitantly with the caudate nucleus (CN) neuronal activity following acute and repetitive (chronic) dose response exposure to methylphenidate (MPD). A saline control and three MPD dose (0.6, 2.5, and 10.0 mg/kg) groups were used. Behaviorally, the same MPD dose in some animals following chronic MPD exposure elicited behavioral sensitization and other animals elicited behavioral tolerance. Based on this finding, the CN neuronal population recorded from animals expressing behavioral sensitization were also evaluated separately from CN neurons recorded from animals expressing behavioral tolerance to chronic MPD exposure, respectively. Significant differences in CN neuronal population responses between the behaviorally sensitized and the behaviorally tolerant animals was observed for the 2.5 and 10.0 mg/kg MPD exposed groups. For 2.5 mg/kg MPD, behaviorally sensitized animals responded by decreasing their firing rates while behaviorally tolerant animals showed mainly an increase in their firing rates. The CN neuronal responses recorded from the behaviorally sensitized animals following 10.0 mg/kg MPD responded by increasing their firing rates whereas the CN neuronal recordings from the behaviorally tolerant animals showed that approximately half decreased their firing rates in response to 10.0 mg/kg MPD exposure. The comparison of percentage change in neuronal firing rates showed that the behaviorally tolerant animals trended to exhibit increases in their neuronal firing rates at ED1 following initial MPD exposure and oppositely at ED10 MPD rechallenge. While the behaviorally sensitized animals in general increased in their percentage change of firing rats were observed following acute 10.0 mg/kg MPD and the behaviorally sensitized 10.0 mg/kg MPD animals and a robust increase in neuronal firing rates at ED1 and ED10 rechallenge. These results suggest the need to first individually analyze animal behavioral activity, and than to evaluate the neuronal responses to the drug based on the animals behavioral response to chronic MPD exposure.

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.…”

“…A selected spike with peak amplitudes within the window was used to created templates using 1,000 waveform data points. These templates provided high dimensional reference points which allowed for single spike sorting (Chong et al, 2012;Claussen et al, 2014;Claussen & Dafny, 2015;Frolov et al, 2015), despite some false threshold crossing, movement artifacts noise, and waveform overlap ( Figure 1). All temporally displaced templates were compared with the incoming spike event to find the best fit to the selected template amplitude that yielded the least residue variance.…”

“…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).…”

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).…”

Pitx3Null Mutant (Striatal Dopamine-Deficient) Mice Have Exaggerated Spiny Projection Neuron Responses to l-DOPA and D1 Agonism and Lack Baseline Striatonigral Spiking

“…Ruskin et al, 1999) imply that further methods are required in order to distinguish D1-from D2-SPNs in vivo, let alone to distinguish the opposite responses that further parse each of those subpopulations since their pharmacological responses could be so similar (e.g. given our results or those of others like Inase et al, 1997, Claussen & Dafny, 2015. Ryan et al 1989 tried to disambiguate responses to amphetamine in healthy, mobile rats by antidromically activating putative D1-SPNs (as we have done here for the Pitx3 mutant mouse), but many of the identified cells responded unexpectedly; they showed general decreases in firing over tens of minutes and specific decreases using behavioral periods matched pre-and post-drug exposure (akin to a "behavioral clamp" experiment , e.g.…”