GABA system changes in methylphenidate sensitized female rats

Freese, Luana; Muller, E.J.; Souza, Marilise Fraga de; Couto-Pereira, Natividade S.; Tosca, C.F.; Ferigolo, Maristela; Barros, Helena Maria Tannhauser

doi:10.1016/j.bbr.2012.03.017

Cited by 20 publications

(12 citation statements)

References 44 publications

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“…The current increase in estimated GABA+ levels found after an MPH challenge in EST subjects is in accordance with studies in healthy rats (Freese et al, 2012, Goitia et al, 2013). In these studies, a challenge with MPH increased the mRNA levels of glutamic acid decarboxylase (GAD) that encodes the protein converting glutamate into GABA (Freese et al, 2012).…”

Section: Discussionsupporting

confidence: 90%

“…In turn, as proposed recently, this could have increased GABA release from dopaminergic axons (e.g. (Freese et al, 2012, Tritsch et al, 2012)). Chronic MPH treatment may therefore have led to lasting increases in DA and GABA levels, and could eventually have resulted in a down-regulation of their respective receptors.…”

Section: Discussionmentioning

confidence: 58%

“…In these studies, a challenge with MPH increased the mRNA levels of glutamic acid decarboxylase (GAD) that encodes the protein converting glutamate into GABA (Freese et al, 2012). Also, a single administration of MPH increased GABAergic neurotransmission in healthy mice (Goitia et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…ADHD medication increases GABA in animal models (Freese et al, 2012, Goitia et al, 2013, Sotomayor-Zárate et al, 2010) and Bollmann et al (Bollmann et al, 2015) have demonstrated that age is a factor that needs to be considered as the GABAergic system continues to develop throughout childhood and adolescence (Andersen, 2003, Luján et al, 2005). Hence, an aberration from the normal development of the GABAergic system could result in a later imbalance between excitatory and inhibitory neurotransmission, that could play a role in the pathophysiology and persistence of ADHD (Ferreira et al, 2009, Luján et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Age-dependent, lasting effects of methylphenidate on the GABAergic system of ADHD patients

Solleveld

Schrantee

Puts³

et al. 2017

NeuroImage: Clinical

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Stimulants are the main pharmacological treatment for patients with attention-deficit/hyperactivity disorder (ADHD). Their current prescription rates are rising, both in children, adolescents and adults. Related to the impulse control phenotype, both preclinical and clinical studies have demonstrated lower γ-amino butyric acid (GABA) levels in prefrontal brain regions in ADHD. Whereas stimulant treatment increases GABA levels, preclinical studies have suggested that stimulant treatment effects may be age-dependent.As the long-term consequences of stimulant use in ADHD children and adolescents have so far been poorly studied, we used magnetic resonance spectroscopy to assess GABA+ and glutamate + glutamine (Glx) levels in the medial prefrontal cortex (mPFC) of adult ADHD patients, both before and after an oral methylphenidate (MPH) challenge. Three groups were studied: 1) ADHD patients who were first treated with stimulants before 16 years of age, i.e. during periods of ongoing brain development (early-stimulant-treated, EST); 2) patients first treated with stimulants in adulthood (i.e. > 23 years) (late-stimulant-treated, LST), and 3) stimulant-treatment-naive (STN) ADHD patients.Reduced basal GABA+ levels were found in EST compared to LST patients (p = 0.04), while after an MPH challenge, only the EST patients showed significant increases in GABA+ (p = 0.01). For Glx, no differences were found at baseline, nor after an MPH challenge.First stimulant exposure at a young age is thus associated with lower baseline levels of GABA+ and increased responsivity in adulthood. This effect could not be found in patients that started treatment at an adult age. Hence, while adult stimulant treatment seems to exert no major effects on GABA+ levels in the mPFC, MPH may induce long-lasting alterations in the adult mPFC GABAergic system when treatment was started at a young age.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Age-dependent, lasting effects of methylphenidate on the GABAergic system of ADHD patients

Solleveld

Schrantee

Puts³

et al. 2017

NeuroImage: Clinical

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“…It has been described in both laboratory animals and man (Tzschentke and Schmidt 1997;Steketee and Kalivas 2011). Behavioural sensitisation was, for example, re-ported for cocaine (Schroeder et al 2012;Ramos et al 2012), methylphenidate (Freese et al 2012), morphine (Hofford et al 2012), ethanol (Pastor et al 2012) and methamphetamine (Horio et al 2012;Landa et al 2011Landa et al , 2012.…”

mentioning

confidence: 99%

The effect of memantine on behavioural sensitisation to methamphetamine in mice

Landa¹,

Šlais²,

Šulcová³

2012

Vet. Med. - Czech

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After repeated administration the psychostimulant methamphetamine (Met) produces a substantial increase in behavioural responses, which is termed behavioural sensitisation. Many studies have reported that N-methyl-d-aspartate (NMDA) receptors play an important role in the development and expression of behavioural sensitisation. Memantine (Mem) is used particularly for the treatment of Alzheimer's disease and acts as a non-competitive NMDA glutamate receptor antagonist, possessing a variety of psychotropic effects. For example, there are studies indicating that memantine prevents the expression of withdrawal symptoms in mice and causes reversal of opioid dependence. Although not all pharmacological mechanisms of memantine have been clarified yet, it is known that memantine inhibits NMDA receptor inward currents. Thus, the present study was designed to assess whether memantine would influence behavioural sensitisation to the stimulatory effects of methamphetamine on mouse locomotion. Mice were randomly allocated into four groups. They were given vehicle on Day 1of the experiment and after five days without application they were administered seven drug daily doses (i.p.) from Day 7 to Day 13 of the study, as follows: (a) n 1, 2 : 2.5 mg/kg/day of Met; (b) n 3 : combination Met + Mem at the doses of 2.5 mg/kg/day and 5 mg/kg/day, respectively; (c) n 4 : Mem at the dose of 5 mg/kg/day. On Day 14 mice were given the first "challenge treatment" (a) n 1 : Met, (b) n 2 : Met + Mem, (c) n 3 : Met, (d) n 4 : Mem. The second "challenge treatment" was given after a six day wash-out period on Day 21: (a) n 1 : Met, (b) n 2 : Met + Mem, (c) n 3 : Met, (d) n 4 : Mem. Changes in locomotion were measured for a period of 3 min in the Open field on Days 1, 7, 14 and 21 to assess the sensitising phenomenon. Met pre-treatment significantly sensitised to the effects of the challenge doses (n 1 ). Mem given alone did not change the measured behavioural parameters after the acute dose but it significantly decreased locomotion after its repeated administration (n 4 ). Repeated pre-treatment with the Met + Mem combination (n 3 ) did not produce sensitisation after Met challenge doses and similarly, repeated pretreatment with Met did not induce sensitisation after the challenge dose of Met + Mem (n 2 ). Thus, our results suggest that the role of the NMDA receptor antagonist memantine in the development and expression of behavioural sensitisation to Met seems to be an inhibitory one.

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Topiramate via NMDA, AMPA/kainate, GABAA and Alpha2 receptors and by modulation of CREB/BDNF and Akt/GSK3 signaling pathway exerts neuroprotective effects against methylphenidate-induced neurotoxicity in rats

et al. 2017

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Chronic abuse of methylphenidate (MPH) often causes neuronal cell death. Topiramate (TPM) carries neuroprotective effects, but its exact mechanism of action remains unclear. In the present study, the role of various doses of TPM and its possible mechanisms, receptors and signaling pathways involved against MPH-induced hippocampal neurodegeneration were evaluated in vivo. Thus, domoic acid (DOM) was used as AMPA/kainate receptor agonist, bicuculline (BIC) as GABA receptor antagonist, ketamine (KET) as NMDA receptor antagonist, yohimbine (YOH) as α adrenergic receptor antagonist and haloperidol (HAL) was used as dopamine D receptor antagonist. Open field test (OFT) was used to investigate the disturbances in motor activity. Hippocampal neurodegenerative parameters were evaluated. Protein expressions of CREB/BDNF and Akt/GSK3 signaling pathways were also evaluated. Cresyl violet staining was performed to show and confirm the changes in the shape of the cells. TPM (70 and 100 mg/kg) reduced MPH-induced rise in lipid peroxidation, oxidized form of glutathione (GSSG), IL-1β and TNF-α levels, Bax expression and motor activity disturbances. In addition, TPM treatment increased Bcl-2 expression, the level of reduced form of glutathione (GSH) and the levels and activities of superoxide dismutase, glutathione peroxidase and glutathione reductase enzymes. TPM also inhibited MPH-induced hippocampal degeneration. Pretreatment of animals with DOM, BIC, KET and YOH inhibited TPM-induced neuroprotection and increased oxidative stress, neuroinflammation, neuroapoptosis and neurodegeneration while reducing CREB, BDNF and Akt protein expressions. Also pretreatment with DOM, BIC, KET and YOH inhibited TPM-induced decreases in GSK3. It can be concluded that the mentioned receptors by modulation of CREB/BDNF and Akt/GSK3 pathways, are involved in neuroprotection of TPM against MPH-induced neurodegeneration.

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GABA system changes in methylphenidate sensitized female rats

Cited by 20 publications

References 44 publications

Age-dependent, lasting effects of methylphenidate on the GABAergic system of ADHD patients

Age-dependent, lasting effects of methylphenidate on the GABAergic system of ADHD patients

The effect of memantine on behavioural sensitisation to methamphetamine in mice

Topiramate via NMDA, AMPA/kainate, GABAA and Alpha2 receptors and by modulation of CREB/BDNF and Akt/GSK3 signaling pathway exerts neuroprotective effects against methylphenidate-induced neurotoxicity in rats

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