Descending glutamatergic pathways of PFC are involved in acute and chronic action of methylphenidate

Wanchoo, S.J.; Swann, Alan C.; Dafny, Nachum

doi:10.1016/j.brainres.2009.08.095

Cited by 30 publications

(26 citation statements)

References 65 publications

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“…Previous studies suggest that glutamatergic pathways are involved in the acute and chronic MPH regulation of locomotion in adult rats (61), and exposing rats to MPH during adolescence period results in increased stress reactivity (7). It awaits to be tested whether PFC network activity is altered after long-term exposure to different doses of MPH.…”

Section: Discussionmentioning

confidence: 99%

Methylphenidate Exerts Dose-Dependent Effects on Glutamate Receptors and Behaviors

Cheng

Xiong

Duffney

et al. 2014

Biological Psychiatry

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Background Methylphenidate (MPH), a psychostimulant drug for the treatment of attention-deficit hyperactivity disorder (ADHD), produces the effects of increasing alertness and improving attention, while its misuse has been associated with an increased risk of aggression and psychosis. In this study, we sought to determine the molecular mechanism underlying the complex actions of MPH. Methods Adolescent (4-week-old) rats were given one injection of MPH at different doses. The impact of MPH on glutamatergic signaling in pyramidal neurons of prefrontal cortex (PFC) was measured. MPH-induced behavioral changes were also examined in parallel. Results We found that administration of low-dose (0.5 mg/kg) MPH selectively potentiated NMDAR-mediated excitatory synaptic currents (EPSCs) via adrenergic receptor activation, while the high-dose (10 mg/kg) MPH suppressed both NMDAR- and AMPAR-EPSCs. The dual effects of MPH on EPSCs were associated with bi-directional changes in the surface level of glutamate receptor subunits. Behavioral tests also indicated that low-dose MPH facilitated the PFC-mediated temporal order recognition memory (TORM) and attention, while animals injected with high-dose MPH exhibited significantly elevated locomotive activity. Inhibiting the function of SNAP-25, a key SNARE proteins involved in NMDAR exocytosis, blocked the increase of NMDAR-EPSC by low-dose MPH. In animals exposed to repeated stress, administration of low-dose MPH effectively restored NMDAR function and TORM via a mechanism dependent on SNAP-25. Conclusions Our results have provided a potential mechanism underlying the cognitive enhancing effects of low-dose MPH, as well as the psychosis-inducing effects of high-dose MPH.

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Section: Discussionmentioning

confidence: 99%

Methylphenidate Exerts Dose-Dependent Effects on Glutamate Receptors and Behaviors

Cheng

Xiong

Duffney

et al. 2014

Biological Psychiatry

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“…The 6-OHDA was dissolved in 2 μl of 0.9% saline containing 0.2 mg/ml ascorbic acid (Jackson, 1983; Wanchoo et al, 2009). The cannula was left in place for additional three minutes after the completion of each injection to allow diffusion of the 6-OHDA to the surrounding tissue.…”

Section: Methodsmentioning

confidence: 99%

“…Bilateral ablation of the PFC and nucleus accumbens (NAc) by electrolytic lesion has been reported to prevent the expression of behavioral sensitization produced by repetitive psychostimulant administration (Lee, 2008; Podet et al, 2010; Tang, 2009). Similarly, bilateral injection of 6-hydroxydopamine (6-OHDA) into the PFC and NAc that specifically eliminated the dopaminergic system in these areas has shown to prevent the behavioral sensitization produced by chronic administration of MPD (Wanchoo et al, 2009). Another experiment investigating the effect of amphetamine induced taste aversion before and following 6-OHDA injection reported that 6-OHDA treated animals exhibit attenuation to the aversion preference assay (Roberts and Fibiger 1975).…”

Section: Introductionmentioning

confidence: 99%

Selective bilateral lesion to caudate nucleus modulates the acute and chronic methylphenidate effects

Claussen

Chong

Dafny

2012

Pharmacology Biochemistry and Behavior

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The psychostimulant methylphenidate (MPD) is currently the most prescribed drug therapy for attention deficit hyperactivity disorder (ADHD) and is used by students as a cognitive enhancer. The caudate nucleus (CN) is a structure within the motive circuit where MPD exerts its effects, it is known to contain high levels of dopaminergic cells and directly influence motor activity. The objective of this study was to understand the role of CN in response to acute and chronic administration of MPD using an open field assay. Specific and non-specific bilateral ablations were created in the CN using electrolytic lesion and injection of the neurotoxin 6-Hydoxydopamine (6-OHDA). Four groups of rats were used: intact control (n=4), sham operated (n=4), CN electrolytic lesion group (n=8) and CN 6-OHDA injected group (n=8). On experimental day one (ED1) all rats received a saline injection and baseline locomotive activity was recorded. On ED2 and ED3 CN sham, electrolytic lesion and/or 6-OHDA injected groups were made followed by four to five days recovery (ED3–7), followed by six daily 2.5 mg/kg MPD injections (ED9–14), three days of washout (ED15–17) and an MPD re-challenge of drug proceeding the washout days (ED18). Locomotor activity was obtained at ED1, 8, 9, 18 using an open field assay. The results show that the CN electrical lesion group responded to the acute and chronic MPD administration similar to the intact control and sham operated group, while the CN 6-OHDA injected lesion group that selectively depleted the CN dopaminergic neurophil prevented the acute and chronic effect of MPD administration. One possible interpretation why nonspecific electrical lesioning of the CN failed to prevent acute and chronic effects of MPD administration is due to destruction of both direct and the indirect CN pathways which act as an inhibitory/excitatory balance, making the net outcome no change for the electrical lesion group. The selective dopaminergic lesioning prevented the acute and the chronic effects of MPD administration suggesting dopaminergic pathways in CN play a significant role in the acute and chronic effect of MPD.

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“…The three treatment dosages 0.6 mg/kg, 2.5 mg/kg, and 10.0 mg/kg of MPD-D chosen in this study were based on our previous dose response studies. Chronic treatment with 2.5 mg/kg and, in a few cases, also the 0.6 mg/kg MPD dose elicited behavioral sensitization (Gaytan et al 1996a, 1997a, 2000a, 2000b; Lee et al 2008; Wanchoo et al 2009; Yang et al 2000a, 2001, 2000b, 2003, 2006a, 2006b, 2007). The doses in the present study correlate to low, medium, and high doses, respectively (Dafny and Yang 2006).…”

Section: 0 Methodsmentioning

confidence: 96%

Adult female rats' altered diurnal locomotor activity pattern following chronic methylphenidate treatment

Trinh

Kohllepel²,

Peng³

et al. 2013

J Neural Transm

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Methylphenidate (MPD) is one of the most prescribed pharmacological agents and also used as cognitive enhancement and for recreational purposes. The objective of this study was to investigate the repetitive dose-response effects of MPD on rhythm locomotor activity pattern of female WKY rats and compare to prior study done on male. The hypothesis is that change in the circadian activity pattern indicates a long-lasting effect of the drug. Four animal groups (saline control, 0.6, 2.5, and 10.0 mg/kg MPD dose groups) were housed in a sound-controlled room at 12:12 light/dark cycle. All received saline injections on experimental day 1 (ED 1). On EDs 2-7, the control group received saline injection; the other groups received 0.6, 2.5, or 10.0 mg/kg MPD, respectively. On ED 8-10, injections were withheld. On ED 11, each group received the same dose as EDs 2-7. Hourly histograms and cosine statistical analyses calculating the acrophase (ϕ), amplitude (A), and MESOR (M) were applied to assess the 24-hour circadian activity pattern. The 0.6 and 2.5 mg/kg MPD groups exhibited significant (p<0.05) change in their circadian activity pattern on ED 11. The 10.0 mg/kg MPD group exhibited tolerance on ED 11 and also a significant change in activity pattern on ED 8 compared to ED 1, consistent with withdrawal behavior (p<0.007). In conclusion, chronic MPD administration alters circadian locomotor activity of adult female WKY rats and confirms that chronic MPD use elicits long lasting effects

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Descending glutamatergic pathways of PFC are involved in acute and chronic action of methylphenidate

Cited by 30 publications

References 65 publications

Methylphenidate Exerts Dose-Dependent Effects on Glutamate Receptors and Behaviors

Methylphenidate Exerts Dose-Dependent Effects on Glutamate Receptors and Behaviors

Selective bilateral lesion to caudate nucleus modulates the acute and chronic methylphenidate effects

Adult female rats' altered diurnal locomotor activity pattern following chronic methylphenidate treatment

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