Dorsal raphe neuronal activities are modulated by methylphenidate

Tang, Bin; Dafny, Nachum

doi:10.1007/s00702-012-0917-5

Cited by 17 publications

(13 citation statements)

References 81 publications

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“…Previous experiments have shown that daily saline injections for three weeks do not alter behavioral locomotor activity, sensory evoked neuronal potentials, or electrophysiological neuronal firing rates (Yang et al, 2006a;b;c;d). Therefore, the activity after saline injection was used as control for the drug effect (Claussen and Dafny 2012; Frolov et al, 2015; Jones and Dafny, 2013; Salek et al, 2012; Tang and Dafny 2012; 2013; Yang et al, 2006b, 2007). To determine if MPD induced a significant change/response, multiple methods were employed as follow: the mean activity after treatment needs to be at least two standard errors (S.E.)…”

Section: Methodsmentioning

confidence: 99%

“…difference from the control firing rate. Because the firing rates did not hold up to normality assumptions used to determine parametric or non-parametric, significance was based also on the critical ratio test (

C . R . = 1 \frac{E - C}{\sqrt{E} + C} = \pm 1.96 = p < 0.05

) (C = control, E = drug activity) (Chong et al, 2012; Claussen and Dafny 2012; Dafny, 1975; 1982; Frolov et al, 2015; Jones and Dafny, 2013; Salek et al, 2012; Tang and Dafny 2012; 2013; Yang et al, 2006a;b;c). The following comparisons were made, from the three (0.6, 2.5, 10.0 mg/kg MPD) groups 1) neuronal activity recorded from all animals 2) neuronal activity recorded from animals expressing behavioral sensitization, and 3) neuronal activity recorded from animals expressing behavioral tolerance, to chronic MPD exposure.…”

Section: Methodsmentioning

confidence: 99%

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

Claussen

Dafny

2015

Pharmacology Biochemistry and Behavior

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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.

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Section: Methodsmentioning

confidence: 99%

C . R . = 1 \frac{E - C}{\sqrt{E} + C} = \pm 1.96 = p < 0.05

Section: Methodsmentioning

confidence: 99%

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

Claussen

Dafny

2015

Pharmacology Biochemistry and Behavior

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“…Studies have also reported that MPD induces an increase in DR neuronal activity directly and as measured by the expression of Fos-like immunoreactivity in DR neurons following treatment (Tang and Dafny 2013a; Tang and Dafny 2013b; Trinh et al, 2003). Adolescent mice have been shown to increase Fos expression in DR relative to other brain regions (Karanges et al, 2016).…”

Section: Discussionmentioning

confidence: 98%

Methylphenidate modulates dorsal raphe neuronal activity: Behavioral and neuronal recordings from adolescent rats

Kharas

Whitt

Reyes-Vasquez

et al. 2017

Brain Research Bulletin

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Methylphenidate (MPD) is a widely prescribed psychostimulants used for the treatment of attention deficit hyperactive disorder (ADHD). Unlike the psychostimulants cocaine and amphetamine, MPD does not exhibit direct actions on the serotonin transporter, however there is evidence suggesting that the therapeutic effects of MPD may be mediated in part by alterations in serotonin transmission. This study aimed to investigate the role of the dorsal raphe (DR) nucleus, one of the major sources of serotonergic innervation in the mammalian brain, in the response to MPD exposure. Freely behaving adolescent rats previously implanted bilaterally with permanent electrodes were used. An open field assay and a wireless neuronal recording system were used to concomitantly record behavioral and DR electrophysiological activity following acute and chronic MPD exposure. Four groups were used: one control (saline) and three experimental groups treated with 0.6, 2.5, and 10.0 mg/kg MPD respectively. Animals received daily MPD or saline injections on experimental days 1–6, followed by 3 washout days and MPD rechallenge dose on experimental day (ED)10. The same chronic dose of MPD resulted in either behavioral sensitization or tolerance, and we found that neuronal activity recorded from the DR neuronal units of rats expressing behavioral sensitization to chronic MPD exposure responded significantly differently to MPD rechallenge on ED10 compared to the DR unit activity recorded from animals that expressed behavioral tolerance. This correlation between behavioral response and DR neuronal activity following chronic MPD exposure provides evidence that the DR is involved in the acute effects as well as the chronic effects of MPD in adolescent rats.

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“…However, evidence from freely moving animals suggests that acute methylphenidate administration changes that activity of over half of the neurons in the DRN, in most cases increasing their firing rate [76]. Although the mechanism of action is unknown, again this means the drug is likely to produce an early increase in forebrain 5-HT levels without the need for a period of desensitisation.…”

Section: Serotonin Based Interventions For Adhd: Autoregulation Of Sementioning

confidence: 99%

Enhancing the efficacy of 5-HT uptake inhibitors in the treatment of attention deficit hyperactivity disorder

Riley

Overton

2019

Medical Hypotheses

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Attention Deficit Hyperactivity Disorder (ADHD) is one of the most common childhood behavioural disorders, the frontline treatments for which are drugs with abuse potential. As a consequence, there is an urgent need to develop non addictive drug treatments with equivalent efficacy. Preclinical evidence suggests that selective serotonin uptake inhibitors (SSRIs) are likely to be effective in ADHD, however clinical reports suggest that SSRIs are of limited therapeutic value for the treatment of ADHD. We propose that this disconnect can be explained by the pattern of drug administration in existing clinical trials (administration for short periods of time, or intermittently) leading to inadequate control of the autoregulatory processes which control 5-HT release, most notably at the level of inhibitory 5-HT1A somatodendritic autoreceptors. These autoreceptors reduce the firing rate of 5-HT neurons (limiting release) unless they are desensitised by a long term, frequent pattern of drug administration. As such, we argue that the participants in earlier trials were not administered SSRIs in a manner which realises any potential benefits of targeting 5-HT in the pharmacotherapy of ADHD. In light of this, we hypothesise that there may be under-researched potential to exploit 5-HT transmission therapeutically in ADHD, either through changing the administration regime, or by pharmacological means. Recent pharmacological research has successfully potentiated the effects of SSRIs in acute animal preparations by antagonising inhibitory 5-HT1A autoreceptors prior to the administration of the SSRI fluoxetine. We suggest that combination therapies linking SSRIs and 5-HT1A antagonists are a potential way forward in the development of efficacious nonaddictive pharmacotherapies for ADHD.

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Dorsal raphe neuronal activities are modulated by methylphenidate

Cited by 17 publications

References 81 publications

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

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

Methylphenidate modulates dorsal raphe neuronal activity: Behavioral and neuronal recordings from adolescent rats

Enhancing the efficacy of 5-HT uptake inhibitors in the treatment of attention deficit hyperactivity disorder

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