Glutaminergic signaling in the caudate nucleus is required for behavioral sensitization to methylphenidate

King, Nicholas; Floren, Samuel; Kharas, Natasha; Thomas, Ming; Dafny, Nachum

doi:10.1016/j.pbb.2019.172737

Cited by 10 publications

(18 citation statements)

References 120 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This attenuation of HA indicates that glutaminergic signaling in the NAc is critical in modulating behavior and influences signaling pathways differently. This fits with the current knowledge that glutaminergic inputs to the NAc come from other reward circuit nuclei [104,105], and with other work showing that glutaminergic signaling is responsible for modulating the core effect of MPD at other reward circuit nuclei [26,28,29,36,44,[46][47][48][49][50][51][52][53][54][55][56][57][58][59][60]. It also seems to indicate that different subcortical circuits govern different behavioral responses, as animals with glutaminergic lesions to the NAc, HA exhibited significantly less behavioral activity in response to both acute and chronic MPD exposure.…”

Section: Discussionsupporting

confidence: 90%

“…Glutaminergic signaling in the NAc has been unexplored till this present study, but has been shown to be critical in other reward circuit nuclei [26,28,29,36,44,[46][47][48][49][50][51][52][53][54][55][56][57][58][59][60]. This study found that following specific glutaminergic ablation of the NAc by ibotenic acid, animals showed the same general response to acute and chronic MPD exposure as the control and sham NAc lesion groups, with an acute increase in behavioral activity following MPD and then further augmentation with chronic exposure (Figure 2).…”

Section: Discussionmentioning

confidence: 99%

“…Non-specific and dopaminergic specific lesions to the NAc have shown it to be critical to regulating the response to MPD [44,45], however the role of the glutaminergic system remains uninvestigated. Glutaminergic signaling has been shown to modulate the long-term response between other reward/motive circuit nuclei [26,28,29,36,44,[46][47][48][49][50][51][52][53][54][55][56][57][58][59][60], and it known to participate in inputs to the NAc, however its role in the acute and chronic response to MPD is unknown.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

2021

Journal of Experimental Neurology

View full text Add to dashboard Cite

Methylphenidate (MPD) is a psychostimulant that is widely used to treat attention deficit hyperactivity disorder, and is being increasingly misused as a recreational drug and cognitive enhancer. MPD acts on the reward system of the CNS through specific signaling pathways to produce its effects on behavior, including tolerance, withdrawal, and sensitization. The nucleus accumbens (NAc) is one of the predominant components of this system, however the role of the NAc's glutaminergic system in the behavioral response to MPD has not been studied. The objective of this study was to assess the role of glutaminergic signaling and the response to acute and chronic MPD exposure as measured by three different locomotive behaviors following selective bilateral lesions. Three groups of n=8 rats were used: control, sham NAc lesions, and glutaminergic-specific (ibotenic acid toxin) NAc lesions. On experimental day (ED) 1, all groups received saline injections to establish a baseline. On ED 2, NAc surgeries took place, followed by a 5-day recovery period (ED 3-7). On ED 8 saline was given to obtain a post-surgical baseline. Groups then received six daily MPD 2.5 mg/kg injections (ED 9-14) to produce a chronic effect, behavioral sensitization in this study, then three days of washout with no injection (ED 15-17), followed by a re-challenge with the previous 2.5 mg/kg MPD dose on ED 18. Locomotive activity was recorded for 60 minutes after each injection by a computerized animal activity monitoring system. All groups showed an increase in behavioral activity following acute MPD exposure, and developed behavioral sensitization following chronic MPD exposure that was maintained after three days of MPD washout. Compared to controls and sham lesions, the horizontal activity response was significantly (P<0.05) attenuated both acutely and chronically following glutaminergic selective ibotenic acid lesions to the NAc however the other indices showed no change. This indicates that glutaminergic signaling in the NAc plays a role in modulating the response to acute and chronic MPD.

show abstract

Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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

2021

Journal of Experimental Neurology

View full text Add to dashboard Cite

show abstract

“…Our previous study also observed similar results [ 32 ]. Chronic MPH is known to induce long-term consequences in the prefrontal cortex and striatum, such as sensitization/tolerance [ 59 , 67 , 68 , 69 , 70 , 71 , 72 ]. In the prefrontal cortex, these effects appear to be age-dependent [ 73 ] and can last for more than 10 weeks [ 74 ], which may warrant long-term monitoring in patients withdrawing from MPH.…”

Section: Discussionmentioning

confidence: 99%

Consequences of Acute or Chronic Methylphenidate Exposure Using Ex Vivo Neurochemistry and In Vivo Electrophysiology in the Prefrontal Cortex and Striatum of Rats

Miceli

Derf²,

Gronier³

2022

IJMS

View full text Add to dashboard Cite

Methylphenidate (MPH) is among the main drugs prescribed to treat patients with attention-deficit and hyperactivity disease (ADHD). MPH blocks both the norepinephrine and dopamine reuptake transporters (NET and DAT, respectively). Our study was aimed at further understanding the mechanisms by which MPH could modulate neurotransmitter efflux, using ex vivo radiolabelled neurotransmitter assays isolated from rats. Here, we observed significant dopamine and norepinephrine efflux from the prefrontal cortex (PFC) after MPH (100 µM) exposure. Efflux was mediated by both dopamine and norepinephrine terminals. In the striatum, MPH (100 µM) triggered dopamine efflux through both sodium- and vesicular-dependent mechanisms. Chronic MPH exposure (4 mg/kg/day/animal, voluntary oral intake) for 15 days, followed by a 28-day washout period, increased the firing rate of PFC pyramidal neurons, assessed by in vivo extracellular single-cell electrophysiological recordings, without altering the responses to locally applied NMDA, via micro-iontophoresis. Furthermore, chronic MPH treatment resulted in decreased efficiency of extracellular dopamine to modulate NMDA-induced firing activities of medium spiny neurons in the striatum, together with lower MPH-induced (100 µM) dopamine outflow, suggesting desensitization to both dopamine and MPH in striatal regions. These results indicate that MPH can modulate neurotransmitter efflux in brain regions enriched with dopamine and/or norepinephrine terminals. Further, long-lasting alterations of striatal and prefrontal neurotransmission were observed, even after extensive washout periods. Further studies will be needed to understand the clinical implications of these findings.

show abstract

“…Evidence shows that an acute MOD administration decreases GABA release in the NAc, substantia nigra (SN), and globus pallidum (GP) but increases GLU release in the striatum [ 17 , 18 , 19 ] in adult rats. Interestingly, acute and chronic MPH fails to increase locomotor activity when glutamatergic synapses are disrupted [ 20 , 21 ]. Recently, our group demonstrated that chronic MOD administration in adolescent male rats decreases DA release in the NAc [ 22 ], suggesting an impairment of the mesocorticolimbic system.…”

Section: Introductionmentioning

confidence: 99%

Modafinil Administration to Preadolescent Rat Impairs Non-Selective Attention, Frontal Cortex D2 Expression and Mesolimbic GABA Levels

Cid-Jofré

Moreno

Sotomayor‐Zárate

et al. 2022

IJMS

View full text Add to dashboard Cite

The misuse of psychostimulants is an increasing behavior among young people, highlighting in some countries the abuse of modafinil (MOD) as a neuropotentiator. However, several clinical trials are investigating MOD as an alternative pharmacological treatment for attentional deficit and hyperactivity disorder (ADHD) in children and adolescents. On the other hand, the early use of psychostimulants and the misdiagnosis rates in ADHD make it crucial to investigate the brain effects of this type of drug in young healthy individuals. The aim of this work was to evaluate the effects of chronic MOD treatment on neurochemicals (γ-aminobutyric acid and glutamate), dopamine receptor 2 (D2) expression and behavior (non-selective attention “NSA”) in the mesocorticolimbic system of young healthy Sprague–Dawley rats. Preadolescent male rats were injected with MOD (75 mg/kg, i.p.) or a vehicle for 14 days (from postnatal day 22 to 35). At postnatal day 36, we measured the GLU and GABA contents and their extracellular levels in the nucleus accumbens (NAc). In addition, the GLU and GABA contents were measured in the ventral tegmental area (VTA) and D2 protein levels in the prefrontal cortex (PFC). Chronic use of MOD during adolescence induces behavioral and neurochemical changes associated with the mesocorticolimbic system, such as a reduction in PFC D2 expression, VTA GABA levels and NSA. These results contribute to the understanding of the neurological effects of chronic MOD use on a young healthy brain.

show abstract

Glutaminergic signaling in the caudate nucleus is required for behavioral sensitization to methylphenidate

Cited by 10 publications

References 120 publications

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

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

Consequences of Acute or Chronic Methylphenidate Exposure Using Ex Vivo Neurochemistry and In Vivo Electrophysiology in the Prefrontal Cortex and Striatum of Rats

Modafinil Administration to Preadolescent Rat Impairs Non-Selective Attention, Frontal Cortex D2 Expression and Mesolimbic GABA Levels

Contact Info

Product

Resources

About