title: 1H MRS-detectable metabolic brain changes and reduced impulsive behavior in adult rats exposed to methylphenidate during adolescence.
abstract: Administration of methylphenidate (MPH, Ritalin) to children affected by attention deficit hyperactivity disorder (ADHD) is an elective therapy, which however raises concerns for public health, due to possible persistent neuro-behavioral alterations. We investigated potential long-term consequences at adulthood of MPH exposure during adolescence, by means of behavioral and brain MRS assessment in drug-free state. Wistar adolescent rats (30- to 44-day-old) were treated with MPH (0 or 2 mg/kg once/day for 14 days) and then left undisturbed until adulthood. Levels of impulsive behavior were assessed in the intolerance-to-delay task: Food-restricted rats were tested in operant chambers with two nose-poking holes, delivering one food pellet immediately, or five pellets after a delay whose length was increased over days. MPH-exposed animals showed a less marked shifting profile from the large/late to the small/soon reward, suggesting reduced basal levels of impulsivity, compared to controls. In vivo MRI-guided 1H MRS examinations at 4.7 T in anaesthetised animals revealed long-term biochemical changes in the dorsal striatum (STR), nucleus accumbens (NAcc), and prefrontal cortex (PFC) of MPH-exposed rats. Notably, total creatine and taurine, metabolites respectively involved in bioenergetics and synaptic efficiency, were up-regulated in the STR and conversely down-regulated in the NAcc of MPH-exposed rats. A strong correlation was evident between non-phosphorylated creatine in the STR and behavioral impulsivity. Moreover, unaltered total creatine and increased phospho-creatine/creatine ratio were detected in the PFC, suggesting improved cortical energetic performance. Because of this enduring rearrangement in the forebrain function, MPH-exposed animals may be more efficient when faced with delay of reinforcement. In summary, MPH exposure during adolescence produced enduring MRS-detectable biochemical modifications in brain reward-related circuits, which may account for increased self-control capacity of adult rats.
authors.affiliation: Section of Behavioural Neurosciences, Department of Cell Biology and Neurosciences, Istituto Superiore di Sanità, Roma, Italy.
authors.forename: W
authors.initials: W
authors.lastname: Adriani
authors.forename: R
authors.initials: R
authors.lastname: Canese
authors.forename: F
authors.initials: F
authors.lastname: Podo
authors.forename: G
authors.initials: G
authors.lastname: Laviola
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism*; D000697:Central Nervous System Stimulants / Q000008:administration & dosage*; D005260:Female; D007175:Impulsive Behavior / Q000188:drug therapy*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D008774:Methylphenidate / Q000008:administration & dosage*; D011247:Pregnancy; D051381:Rats; D017208:Rats, Wistar; D013223:Statistics as Topic
chemical_list: D000697:Central Nervous System Stimulants; D008774:Methylphenidate