Methylphenidate potentiates morphine-induced antinociception, hyperthermia, and locomotor activity in young adult rats

Halladay, Lindsay R.; Iñiguez, Sergio D.; Furqan, Faiza; Previte, Matt C.; Chisum, Ashley M.; Crawford, Cynthia A.

doi:10.1016/j.pbb.2008.11.011

Cited by 26 publications

(14 citation statements)

References 62 publications

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“…As adults, MPH- and MPH+FLX-pretreated rats showed enhanced susceptibility to swimming stress, whereas FLX-pretreated rats showed decreased vulnerability. Together, these data support evidence that juvenile exposure to MPH induces enduring vulnerability to stress (Lagace et al, 2006; Halladay et al, 2009; Wiley et al, 2009), while FLX exposure results in an anxiogenic and stress-resistant behavioral phenotype in adulthood (Karpova et al, 2009; Iñiguez et al, 2010a). We now extend these findings to combined juvenile MPH+FLX exposure.…”

Section: Discussionsupporting

confidence: 76%

Juvenile Administration of Concomitant Methylphenidate and Fluoxetine Alters Behavioral Reactivity to Reward- and Mood-Related Stimuli and Disrupts Ventral Tegmental Area Gene Expression in Adulthood

Warren¹,

Iñiguez²,

Alcantara³

et al. 2011

Journal of Neuroscience

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There is a rise in the concurrent use of methylphenidate (MPH) and fluoxetine (FLX) in pediatric populations. However, the long-term neurobiological consequences of combined MPH and FLX treatment (MPH+FLX) during juvenile periods are unknown. We administered saline (VEH), MPH, FLX, or MPH+FLX to juvenile Sprague-Dawley male rats from postnatal day 20–35, and assessed their reactivity to reward- and mood-related stimuli 24-h or 2-months after drug exposure. We also assessed mRNA and protein levels within the ventral tegmental area (VTA) to determine the effect of MPH, FLX, or MPH+FLX on the extracellular signal-regulated protein kinase-1/2 (ERK) pathway – a signaling cascade implicated in motivation and mood regulation. MPH+FLX enhanced sensitivity to drug (i.e., cocaine) and sucrose rewards, as well as anxiety- (i.e., elevated plus-maze) and stress- (i.e., forced swimming) eliciting situations when compared to VEH-treated rats. MPH+FLX exposure also increased mRNA of ERK2 and its downstream targets cAMP response element-binding protein (CREB), brain-derived neurotrophic factor (BDNF), cFos, early growth response protein-1 (zif268), and mammalian target of rapamycin (mTOR), and also increased protein phosphorylation of ERK2, CREB, and mTOR 2-months after drug exposure when compared to VEH-treated rats. Using herpes simplex virus-mediated gene transfer to block ERK2 activity within the VTA, we rescued the MPH+FLX-induced behavioral deficits seen in the forced swimming task 2-months after drug treatment. These results indicate that concurrent MPH+FLX exposure during preadolescence increases sensitivity to reward-related stimuli while simultaneously enhancing susceptibility to stressful situations, at least in part, due to long-lasting disruptions in ERK signaling within the VTA.

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Section: Discussionsupporting

confidence: 76%

Juvenile Administration of Concomitant Methylphenidate and Fluoxetine Alters Behavioral Reactivity to Reward- and Mood-Related Stimuli and Disrupts Ventral Tegmental Area Gene Expression in Adulthood

Warren¹,

Iñiguez²,

Alcantara³

et al. 2011

Journal of Neuroscience

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“…Although interactions between MPH and the brain opioid system have been reported previously (Crawford et al, 2007; Halladay et al, 2009; Wiley et al, 2009), our findings break new ground because they reveal MOPR as a pharmacological target for mitigating abuse potential of MPH. Previous studies in normal human volunteers tested the benefits of amphetamine + naltrexone combination on minimizing the subjective, positive effects (feelings of liking or euphoria) of amphetamine (Jayaram-Lindstrom et al, 2008; Jayaram-Lindstrom et al, 2007; Jayaram-Lindstrom et al, 2004).…”

Section: Discussionsupporting

confidence: 51%

“…Although the principal molecular targets of MPH in the CNS are dopamine and noradrenaline, at sufficiently high doses MPH can also activate the μ opioid receptor (MOPR) in the brain (Crawford et al, 2007; Halladay et al, 2009; Wiley et al, 2009). Since reinforcing effects of highly addictive substances such as cocaine and heroin involve MOPR activation (Soderman and Unterwald, 2008; Zubieta et al, 1996), the reinforcing effects of high doses of MPH also may be mediated via MOPR activation.…”

Section: Introductionmentioning

confidence: 99%

Methylphenidate and μ opioid receptor interactions: A pharmacological target for prevention of stimulant abuse

Zhu¹,

Spencer²,

Liu‐Chen³

et al. 2011

Neuropharmacology

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Methylphenidate (MPH) is one of the most commonly used and highly effective treatments for attention deficit hyperactivity disorder (ADHD) in children and adults. As the therapeutic use of MPH has increased, so has its abuse and illicit street-use. Yet, the mechanisms associated with development of MPH-associated abuse and dependence are not well understood making it difficult to develop methods to help its mitigation. As a result, many ADHD patients especially children and youth, that could benefit from MPH treatment do not receive it and risk life-long disabilities associated with untreated ADHD. Therefore, understanding the mechanisms associated with development of MPH addiction and designing methods to prevent it assume high public health significance. Using a mouse model we show that supra-therapeutic doses of MPH produce rewarding effects (surrogate measure for addiction in humans) in a conditioned place preference paradigm and upregulate μ opioid receptor (MOPR) activity in the striatum and nucleus accumbens, brain regions associated with reward circuitry. Co-administration of naltrexone, a non-selective opioid receptor antagonist, prevents MPH-induced MOPR activation and the rewarding effects. The MPH-induced MOPR activation and rewarding effect require activation of the dopamine D1 but not the D2 receptor. These findings identify the MOPR as a potential target for attenuating rewarding effects of MPH and suggest that a formulation that combines naltrexone with MPH could be a useful pharmaceutical approach to alleviate abuse potential of MPH and other stimulants.

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“…As adults, MPH- and MPH+FLX-pretreated rats showed enhanced susceptibility to swimming stress, whereas FLX-pretreated rats showed decreased vulnerability. These data support evidence that juvenile exposure to MPH induces enduring vulnerability to stress (Lagace et al, 2006; Halladay et al, 2009; Wiley et al, 2009), while FLX exposure results in a stress-resistant behavioral phenotype in adulthood (Karpova et al, 2009; Iñiguez et al, 2010b). Long-term, MPH+FLX pretreated rats did not show substantial change in total immobility, but did show a “depression-like” behavioral profile in latency to immobility.…”

Section: Discussionsupporting

confidence: 83%

Life-long consequences of juvenile exposure to psychotropic drugs on brain and behavior

Steiner

Warren

Waes

et al. 2014

Progress in Brain Research

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Psychostimulants such as methylphenidate (MPH) and antidepressants such as fluoxetine (FLX) are widely used in the treatment of various mental disorders or as cognitive enhancers. These medications are often combined, for example, to treat co-morbid disorders. There is a considerable body of evidence from animal models indicating that individually these psychotropic medications can have detrimental effects on brain and behavior, especially when given during sensitive periods of brain development. However, almost no studies investigate possible interactions between these drugs. This is surprising given that their combined neurochemical effects (enhanced dopamine and serotonin neurotransmission) mimic some effects of illicit drugs such as cocaine and amphetamine. Here we summarize recent studies in juvenile rats on the molecular effects in the mid- and forebrain and associated behavioral changes, after such combination treatments. Our findings indicate that these combined MPH+FLX treatments can produce similar molecular changes as seen after cocaine exposure, while inducing behavioral changes indicative of dysregulated mood and motivation, effects that often endure into adulthood.

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Methylphenidate potentiates morphine-induced antinociception, hyperthermia, and locomotor activity in young adult rats

Cited by 26 publications

References 62 publications

Juvenile Administration of Concomitant Methylphenidate and Fluoxetine Alters Behavioral Reactivity to Reward- and Mood-Related Stimuli and Disrupts Ventral Tegmental Area Gene Expression in Adulthood

Juvenile Administration of Concomitant Methylphenidate and Fluoxetine Alters Behavioral Reactivity to Reward- and Mood-Related Stimuli and Disrupts Ventral Tegmental Area Gene Expression in Adulthood

Methylphenidate and μ opioid receptor interactions: A pharmacological target for prevention of stimulant abuse

Life-long consequences of juvenile exposure to psychotropic drugs on brain and behavior

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