title: Animal model of methylphenidate's long-term memory-enhancing effects.
abstract: 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.
authors.affiliation: Molecular Cognition Laboratory, Department of Psychology, University of California, San Diego, California 92093-0109, USA.
authors.forename: Stephanie A
authors.initials: SA
authors.lastname: Carmack
authors.forename: Kristin K
authors.initials: KK
authors.lastname: Howell
authors.forename: Kleou
authors.initials: K
authors.lastname: Rasaei
authors.forename: Emilie T
authors.initials: ET
authors.lastname: Reas
authors.forename: Stephan G
authors.initials: SG
authors.lastname: Anagnostaras
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D000069445:Atomoxetine Hydrochloride; D016642:Bupropion / Q000494:pharmacology; D000697:Central Nervous System Stimulants / Q000494:pharmacology; D015283:Citalopram / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology; D003214:Conditioning, Classical / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D005239:Fear / Q000187:drug effects*; D005260:Female; D008124:Locomotion / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D057567:Memory, Long-Term / Q000187:drug effects*; D008774:Methylphenidate / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018697:Nootropic Agents / Q000494:pharmacology*; D011437:Propylamines / Q000494:pharmacology; D012054:Reinforcement, Psychology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D013028:Space Perception / Q000187:drug effects
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000661:Amphetamine; D000069445:Atomoxetine Hydrochloride; D016642:Bupropion; D000697:Central Nervous System Stimulants; D015283:Citalopram; D003042:Cocaine; D008774:Methylphenidate; D018697:Nootropic Agents; D011437:Propylamines; D017367:Selective Serotonin Reuptake Inhibitors