Methylphenidate enhances extinction of contextual fear

Abraham, Antony D.; Cunningham, Christopher L.; Lattal, K. Matthew

doi:10.1101/lm.024752.111

Cited by 55 publications

(48 citation statements)

References 38 publications

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“…These findings also raise questions about the potential mechanism(s) underlying the symptom improvement observed in this study. Preclinical data indicate that MPH can enhance fear extinction, (Abraham et al, 2012) suggesting one such possible mechanism. If this is, indeed, the mechanism of action of MPH on reducing PTSD symptoms, then one might consider designing a future trial where MPH (vs placebo) is administered in conjunction with exposure therapy.…”

Section: Discussion Overviewmentioning

confidence: 99%

Randomized Placebo-Controlled Trial of Methylphenidate or Galantamine for Persistent Emotional and Cognitive Symptoms Associated with PTSD and/or Traumatic Brain Injury

McAllister

Zafonte

Jain

et al. 2015

Neuropsychopharmacol

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We report findings from a 12-week randomized double-blinded placebo-controlled trial of methylphenidate or galantamine to treat emotional and cognitive complaints in individuals (n = 32) with a history of PTSD, TBI, or both conditions. In this small pilot study, methylphenidate treatment was associated with clinically meaningful and statistically significant improvement compared with placebo on the primary outcome, a measure of cognitive complaints (Ruff Neurobehavioral Inventory-Postmorbid Cognitive Scale), as well as on the secondary outcomes reflecting post-concussive (Rivermead Post Concussive Symptom Questionnaire) and post-traumatic stress symptoms (Posttraumatic Stress Disorder Checklist). Treatment was well tolerated. These results suggest the need for a larger RCT to replicate and confirm these findings. Design considerations for such a trial should include the need for multiple sites to facilitate adequate recruitment and extension of the treatment and follow-up periods.

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Section: Discussion Overviewmentioning

confidence: 99%

Randomized Placebo-Controlled Trial of Methylphenidate or Galantamine for Persistent Emotional and Cognitive Symptoms Associated with PTSD and/or Traumatic Brain Injury

McAllister

Zafonte

Jain

et al. 2015

Neuropsychopharmacol

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“…Most animal studies have used doses 2 -40 times higher than the clinically relevant dose in an effort to model addiction (Gainetdinov et al 1999;Kuczenski and Segal 2002;Abraham et al 2012). We have advocated using a one-to-one dosing scheme unless specific evidence warrants using a different dose in mice (Wood et al 2007;Shuman et al 2009;Wood and Anagnostaras 2009).…”

Section: Discussionmentioning

confidence: 99%

Animal model of methylphenidate's long-term memory-enhancing effects

et al. 2014

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Methylphenidate (MPH), introduced more than 60 years ago, accounts for two-thirds of current prescriptions for attention deficit hyperactivity disorder (ADHD). Although many studies have modeled MPH's effect on executive function, almost none have directly modeled its effect on long-term memory (LTM), even though improvement in LTM is a critical target of therapeutic intervention in ADHD. We examined the effects of a wide range of doses of MPH (0.01 -10 mg/kg, i.p.) on Pavlovian fear learning, a leading model of memory. MPH's effects were then compared to those of atomoxetine (0.1 -10 mg/kg, i.p.), bupropion (0.5 -20 mg/kg, i.p.), and citalopram (0.01 -10 mg/kg, i.p.). At low, clinically relevant doses, MPH enhanced fear memory; at high doses it impaired memory. MPH's memory-enhancing effects were not confounded by its effects on locomotion or anxiety. Further, MPH-induced memory enhancement seemed to require both dopamine and norepinephrine transporter inhibition. Finally, the addictive potential of MPH (1 mg/kg and 10 mg/kg) was compared to those of two other psychostimulants, amphetamine (0.005 mg/kg and 1.5 mg/kg) and cocaine (0.15 mg/kg and 15 mg/ kg), using a conditioned place preference and behavioral sensitization paradigm. We found that memory-enhancing effects of psychostimulants observed at low doses are readily dissociable from their reinforcing and locomotor activating effects at high doses. Together, our data suggest that fear conditioning will be an especially fruitful platform for modeling the effects of psychostimulants on LTM in drug development.

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“…Several studies have investigated ways to enhance fear extinction (Abraham et al, 2012;Berlau and McGaugh, 2006;McGaugh et al, 1990;Mueller et al, 2008). Treatment with D-cycloserine, a partial agonist of NMDA receptors at the glycine modulatory site, enhanced extinction memory (Bouton et al, 2008;Mao et al, 2008;Walker et al, 2002).…”

Section: Role Of Hippocampal Ne In the Persistence Of Extinction Ltmmentioning

confidence: 99%

Delayed Noradrenergic Activation in the Dorsal Hippocampus Promotes the Long-Term Persistence of Extinguished Fear

Chai

Liu

Xue

et al. 2014

Neuropsychopharmacol

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Fear extinction has been extensively studied, but little is known about the molecular processes that underlie the persistence of extinction long-term memory (LTM). We found that microinfusion of norepinephrine (NE) into the CA1 area of the dorsal hippocampus during the early phase (0 h) after extinction enhanced extinction LTM at 2 and 14 days after extinction. Intra-CA1 infusion of NE during the late phase (12 h) after extinction selectively promoted extinction LTM at 14 days after extinction that was blocked by the b-receptor antagonist propranolol, protein kinase A (PKA) inhibitor Rp-cAMPS, and protein synthesis inhibitors anisomycin and emetine. The phosphorylation levels of PKA, cyclic adenosine monophosphate response element-binding protein (CREB), GluR1, and the membrane GluR1 level were increased by NE during the late phase after extinction that was also blocked by propranolol and Rp-cAMPS. These results suggest that the enhancement of extinction LTM persistence induced by NE requires the activation of the b-receptor/PKA/CREB signaling pathway and membrane GluR1 trafficking. Moreover, extinction increased the phosphorylation levels of Erk1/2, CREB, and GluR1, and the membrane GluR1 level during the late phase, and anisomycin/emetine alone disrupted the persistence of extinction LTM, indicating that the persistence of extinction LTM requires late-phase protein synthesis in the CA1. Propranolol and Rp-cAMPS did not completely disrupt the persistence of extinction LTM, suggesting that another b-receptor/PKA-independent mechanism underlies the persistence of extinction LTM. Altogether, our results showed that enhancing hippocampal noradrenergic activity during the late phase after extinction selectively promotes the persistence of extinction LTM.

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Methylphenidate enhances extinction of contextual fear

Cited by 55 publications

References 38 publications

Randomized Placebo-Controlled Trial of Methylphenidate or Galantamine for Persistent Emotional and Cognitive Symptoms Associated with PTSD and/or Traumatic Brain Injury

Randomized Placebo-Controlled Trial of Methylphenidate or Galantamine for Persistent Emotional and Cognitive Symptoms Associated with PTSD and/or Traumatic Brain Injury

Animal model of methylphenidate's long-term memory-enhancing effects

Delayed Noradrenergic Activation in the Dorsal Hippocampus Promotes the Long-Term Persistence of Extinguished Fear

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