Brief and extended abstinence from chronic oral methylphenidate treatment produces reversible behavioral and physiological effects.

Methylphenidate (MP) is a commonly prescribed psychostimulant to individuals with Attention Deficit Hyperactivity Disorder, and is often used illicitly among healthy individuals with intermittent breaks to coincide with breaks from school. This study examined how intermittent abstinence periods impact the physiological and behavioral effects of chronic oral MP self-administration in rats, and whether these effects persist following prolonged abstinence from the drug. Rats were treated orally with water, low-dose (LD), or high-dose (HD) MP, beginning at PND 28. This daily access continued for three consecutive weeks followed by a 1-week abstinence; after three repeats of this cycle, there was a 5-week abstinence period. Throughout the study, we examined body weight, food intake, locomotor activity, and anxiety- and depressive-like behaviors. During the treatment phase, HD MP decreased body weight, food intake, and depressive- and anxiety-like behaviors, while it increased locomotor activity. During intermittent abstinence, the effects of MP on locomotor activity were eliminated. During prolonged abstinence, most of the effects of HD MP were ameliorated to control levels, with the exception of weight loss and anxiolytic effects. These findings suggest that intermittent exposure to chronic MP causes physiological and behavioral effects that are mostly reversible following prolonged abstinence.

Combined methylphenidate and fluoxetine treatment in adolescent rats significantly impairs weight gain with minimal effects on skeletal development.

Methylphenidate (MP) is frequently prescribed to treat Attention-Deficit/Hyperactivity Disorder (ADHD); however, many patients with ADHD experience depression and anxiety. As such, concomitant administration of selective serotonin reuptake inhibitors such as fluoxetine (FLX) is common. Our laboratory and others have shown that MP impairs skeletal development in preclinical and clinical settings, and FLX has also been linked to skeletal deficits. Unfortunately, little is known about the effects of combined MP and FLX treatment on skeletal development. The objective of this study was to investigate the effects of MP and FLX on bone morphology and biomechanical properties in adolescent rats. Four-week-old male Sprague-Dawley rats were randomly divided into the following 4 groups: Water, MP, FLX, and MP + FLX. As body weights in the MP, FLX, and MP + FLX groups were all lower than Water, the data were compared directly and after adjusting to body weight via linear regression. The direct comparison revealed that MP + FLX rats had significantly shorter (~12 %) and narrower femora and tibiae (~10 %) compared to most other groups, along with shorter (26-35 %), disorganized tibial growth plates. MicroCT analyses of the trabecular compartment of the proximal tibia identified reductions of 47 % for TV, 86 % for BV, 74 % for BV/TV, 68 % for Tb.N, 25 % in Tb.Th, and 74 % in vBMD concomitant with increases of 44 % for Tb.Sp for MP + FLX compared to Water. Similar analyses of femoral midshaft cortical bone identified reductions of 29 % for Ct.V, 30 % for Ps.V, 30 % for Ec. V, and 51 % for pMOI, as well as increases of 17 % for Ct.Th and 2 % for TMD for MP + FLX compared to Water. Biomechanically, MP + FLX femora were weaker, as indicated by a reduction in ultimate force (14 %) in MP + FLX compared to Water. The microstructural and biomechanical effects of MP + FLX were eliminated after adjustment for body weight, though the detrimental effects on growth plate morphology remained. We conclude that while the adverse microstructural and biomechanical effects of MP + FLX seen via direct comparison are predominantly attributable to reductions in body weight rather than direct effects on bone, MP and FLX, particularly in combination show detrimental effects on growth plate structure and chondrocyte morphology. These findings warrant further research into the effect of these drugs on weight gain, skeletal development and growth plate morphology, as well as consideration by physicians treating children and adolescents with ADHD.

Combined Chronic Oral Methylphenidate and Fluoxetine Treatment During Adolescence: Effects on Behavior.

BACKGROUND: Attention Deficit Hyperactivity Disorder (ADHD) can be comorbid with depression, often leading to the prescription of both methylphenidate (MP) and selective serotonin reuptake inhibitor (SSRI) antidepressants, such as fluoxetine (FLX). Moreover, these drugs are often misused as cognitive enhancers. This study examined the effects of chronic oral co-administration of MP and FLX on depressive- and anxiety-like behaviors. METHODS: Adolescent rats received daily either water (control), MP, FLX, or the combination of MP plus FLX in their drinking water over the course of 4 weeks. RESULTS: Data analysis shows a decrease in food consumption and body weight for rats exposed to FLX or the combination of MP and FLX. Sucrose consumption was significantly greater in FLX or MP+FLX groups compared to controls. FLX-treated rats showed no effect in the elevated plus maze (EPM; open arm time) and forced swim test (FST; latency to immobility). However, rats treated with the combination (MP+FLX) showed significant anxiolytic-like and anti-depressive-like behaviors (as measured by EPM and FST), as well as significant increases in overall activity (distance traveled in open field test). Finally, the combined MP+FLX treatment induced a decrease in anxiety and depressive- like behaviors significantly greater than the response from either of these drugs alone. CONCLUSION: These behavioral results characterize the long-term effects of these drugs (orally administered) that are widely co-administered and co-misused and provide important insight into the potential neurobiological and neurochemical effects. Future research will determine the potential risks of the long-term use of MP and FLX together.

Abstinence from Chronic Methylphenidate Exposure Modifies Cannabinoid Receptor 1 Levels in the Brain in a Dose-dependent Manner.

INTRODUCTION: Methylphenidate (MP) is a widely used psychostimulant prescribed for Attention Deficit Hyperactivity Disorder and is also used illicitly by healthy individuals. Chronic exposure to MP has been shown to affect physiology, behavior measures, and neurochemistry. METHODS: The present study examined its effect on the endocannabinoid system. Adolescent rats had daily oral access to either water (control), low dose MP (4/10 mg/kg), or high dose MP (30/60 mg/kg). After 13 weeks of exposure, half of the rats in each group were euthanized, with the remaining rats underwent a four-week- long abstinence period. Cannabinoid receptor 1 binding (CB1) was measured with in vitro autoradiography using [3H] SR141716A. RESULTS: Rats who underwent a 4-week abstinence period after exposure to chronic HD MP showed increased CB1 binding in several cortical and basal ganglia regions of the brain compared to rats with no abstinence period. In contrast to this, rats who underwent a 4-week abstinence period after exposure to chronic LD MP showed lower CB1 binding mainly in the basal ganglia regions and the hindlimb region of the somatosensory cortex compared to rats with no abstinence period. Following 4 weeks of drug abstinence, rats who were previously given HD MP showed higher [3H] SR141716A binding in many of the cortical and basal ganglia regions examined than rats given LD MP. These results highlight the biphasic effects of MP treatment on cannabinoid receptor levels. Abstinence from HD MP seemed to increase CB1 receptor levels, while abstinence from LD MP seemed to decrease CB1 levels. CONCLUSION: Given the prolific expression of cannabinoid receptors throughout the brain, many types of behaviors may be affected as a result of MP abstinence. Further research will be needed to help identify these behavioral changes.