Chronic methylphenidate alters locomotor activity and dopamine transporters differently from cocaine

Izenwasser, Sari; Coy, Abigail E; Ladenheim, Bruce; Loeloff, Richard; Cadet, Jean Lud; French, Dawn

doi:10.1016/s0014-2999(99)00274-5

Cited by 61 publications

(42 citation statements)

References 19 publications

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“…A number of signaling molecules/ mechanisms involved in gene regulation are affected by methylphenidate treatment. These include, for example, the dopamine transporter (Izenwasser et al, 1999;Moll et al, 2001) and the vesicular monoamine transporter (Sandoval et al, 2002); levels of GluR2 glutamate receptors (Andersen et al, 2002) and D1 dopamine receptors (Papa et al, 2002); protein kinase A and dopamine-stimulated adenylyl cyclase activities (Crawford et al, 1998); as well as the transcription factor CREB (Andersen et al, 2002). Several of these play a role in the regulation of dopamine-mediated c-fos and zif 268 expression in the striatum, and such changes could thus underlie altered gene induction after repeated methylphenidate treatment.…”

Section: Methylphenidate-induced Gene Regulation M Yano and H Steinermentioning

confidence: 99%

Topography of Methylphenidate (Ritalin)-Induced Gene Regulation in the Striatum: Differential Effects on c-Fos, Substance P and Opioid Peptides

Yano

Steiner

2004

Neuropsychopharmacol

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Dopamine action alters gene regulation in striatal neurons. Methylphenidate increases extracellular levels of dopamine. We investigated the effects of acute methylphenidate treatment on gene expression in the striatum of adult rats. Molecular changes were mapped in 23 striatal sectors mostly defined by their predominant cortical inputs in order to determine the functional domains affected. Acute administration of 5 and 10 mg/kg (i.p.) of methylphenidate produced robust increases in the expression of the transcription factor c-fos and the neuropeptide substance P. Borderline effects were found with 2 mg/kg, but not with 0.5 mg/kg. For 5 mg/kg, c-fos mRNA levels peaked at 40 min and returned to baseline by 3 h after injection, while substance P mRNA levels peaked at 40-60 min and were back near control levels by 24 h. These molecular changes occurred in most sectors of the caudate-putamen, but were maximal in dorsal sectors that receive sensorimotor and medial agranular cortical inputs, on middle to caudal levels. In rostral and ventral striatal sectors, changes in c-fos and substance P expression were weaker or absent. No effects were seen in the nucleus accumbens, with the exception of c-fos induction in the lateral part of the shell. In contrast to c-fos and substance P, acute methylphenidate treatment had minimal effects on the opioid peptides dynorphin and enkephalin. These results demonstrate that acute methylphenidate alters the expression of c-fos and substance P preferentially in the sensorimotor striatum. These molecular changes are similar, but not identical, to those produced by other psychostimulants.

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Section: Methylphenidate-induced Gene Regulation M Yano and H Steinermentioning

confidence: 99%

Topography of Methylphenidate (Ritalin)-Induced Gene Regulation in the Striatum: Differential Effects on c-Fos, Substance P and Opioid Peptides

Yano

Steiner

2004

Neuropsychopharmacol

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“…Accordingly, critical questions about treatment of ADHD with psychostimulants are: do children and adolescents sensitize during repeated drug exposure and, if so, does sensitization persist? Unfortunately, animal studies have provided conflicting answers (Laviola et al 1995;Ujike et al 1995;Snyder et al 1998;Wood et al 1998;Izenwasser et al 1999;McDougall et al 1999;Zavala et al 2000). Sensitization to MP in rodent models has been well documented (Shuster et al 1982;Gaytan et al 1997;Crawford et al 1998; but see McNamara et al 1993), but the use of relatively high doses in most studies, and the apparent inability of MP to induce long-term locomotor sensitization in young animals (McDougall et al 1999), has raised questions regarding the clinical relevance of such findings (National Institute of Mental Health 1999).…”

Section: Treatment Of Attention Deficit Hyperactivity Disorder With Tmentioning

confidence: 99%

Enhanced Reactivity and Vulnerability to Cocaine Following Methylphenidate Treatment in Adolescent Rats

Brandon

Marinelli²,

Baker

et al. 2001

Neuropsychopharmacology

226

147

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Treatment of attention deficit hyperactivity disorder with the psychostimulant drug methylphenidate (MP) has increased dramatically among schoolchildren. We tested whether repeated exposure to moderate doses of MP (5 and 10 mg/kg IP for 5 or 7 days) in adolescent rats increased reactivity to cocaine measured by motor responses (ambulations and rearing) to a cocaine challenge in adulthood. We later tested whether repeated exposure to a low dose of MP (2 mg/kg IP for 7 days) enhanced the psychomotor effects of cocaine, measured by different challenge doses (0-30 mg/kg) as well as to the reinforcing effects of cocaine, measured by self-administration of lowdose infusion (75 g/kg, IV). We found that exposure to moderate doses of MP enhanced psychomotor responses to cocaine but exposure to a low dose only increased cocaine self-administration. These results suggest that adolescent exposure to low doses of MP in rats mayMethylphenidate (Ritalin ® ) is used widely in the treatment of attention deficit hyperactivity disorder (ADHD), the most commonly diagnosed disorder of childhood (Swanson et al. 1998). During the 1990s, diagnosis and treatment of this disorder grew dramatically in the United States. Estimates show that up to 15% of school age children may be affected in certain geographical locations (Scahill and Schwab-Stone 2000) and that prevalence is estimated to be 5-10% in the general population (Swanson et al. 1998). In addition, preschoolers (Zito et al. 2000) and children who do not meet the diagnostic criteria for ADHD (Marshall 2000) have recently been identified as two new groups increasingly exposed to this drug. The duration of treatment is several years in childhood, more often extending into adolescence and adulthood (Garland 1998;Robin 1999;Silver 2000;Spencer et al. 2000).Animal studies have shown that MP is a psychostimulant, which, as with cocaine, blocks the dopamine transporter (DAT) (Kuczenski and Segal 1997); thereby increasing extracellular dopamine (DA) levels in the striatum and nucleus accumbens (Kuczenski 1983), brain regions involved in the locomotor and reinforcing effects of psychostimulants and other drugs of abuse (Koob and Bloom 1988 NO . 5 et al. 1999). Oral therapeutic doses of MP effectively block more than 50% of DATs (Volkow et al. 1998); thereby increasing extracellular DA levels (Volkow et al. 2001). These actions are highly associated with the reinforcing properties of drugs (Ritz et al. 1987). Taken together, the well-documented abuse potential of psychostimulants (for reviews see White and Wolf 1991;Robinson and Berridge 1993;Self and Nestler 1995), studies linking ADHD with subsequent substance abuse (Wilens et al. 1997;Clure et al. 1999;Schubiner et al. 2000), and the dearth of controlled studies on the effects of long-term stimulant exposure on the brain, all make MP exposure an important public health issue.Animal models of drug addiction clearly indicate that repeated exposure to psychostimulants results in augmented behaviors (sensitization) that can be detected lo...

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“…While many drugs are specific to a particular transporter, others are non-selective and affect uptake in multiple monoaminergic systems. It is the interaction of pharmacological agents at each of these transporters that results in unique behavioral profiles (Ginsburg et al, 2005;Izenwasser et al, 1999). It has been suggested that stimulant dependence, withdrawal, and pharmacotherapeutic strategies targeted for treating addiction involve both the dopaminergic and serotonergic systems (Baumann et al, 1995;Hitzig, 1993;Parsons et al, 1995;Rocha et al, 1998;Rothman et al, 1998;Rothman and Baumann, 2003;Sora et al, 2001;Walsh and Cunningham, 1997).…”

Section: Introductionmentioning

confidence: 99%

Voltammetric characterization of the effect of monoamine uptake inhibitors and releasers on dopamine and serotonin uptake in mouse caudate-putamen and substantia nigra slices

2007

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SummaryFast scan cyclic voltammetry is an electrochemical technique used to measure dynamics of transporter-mediated monoamine uptake in real time and provides a tool to evaluate the detailed effects of monoamine uptake inhibitors and releasers on dopamine and serotonin transporter function. We measured the effects of cocaine, methylphenidate, 2β-propanoyl-3β-(4tolyl) tropane (PTT), fluoxetine, amphetamine, methamphetamine, 3,4-methylenedioxymethamphetamine (MDMA), phentermine and fenfluramine on dopamine and serotonin uptake following electrically stimulated release in mouse caudate-putamen and substantia nigra pars reticulata slices. We determined rank orders of uptake inhibition effects based on two variables; increases in apparent K m for dopamine and serotonin uptake and inhibition constant (K i ) values. For example, the rank order of uptake inhibition based on apparent K m values at the dopamine transporter was amphetamine ≥ PTT ≥ methylphenidate ≫ methamphetamine = phentermine = MDMA > cocaine ≫ fluoxetine = fenfluramine, and at the serotonin transporter was fluoxetine = methamphetamine = fenfluramine = MDMA > amphetamine = cocaine = PTT ≥ methylphenidate > phentermine. Additionally, changes in electrically stimulated release were documented. This is the first study using voltammetry to measure the effects of a wide range of monoamine uptake inhibitors and releasers on dopamine and serotonin uptake in mouse brain slices. These studies also highlight methodological considerations for comparison of effects between heterogeneous brain regions.

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Chronic methylphenidate alters locomotor activity and dopamine transporters differently from cocaine

Cited by 61 publications

References 19 publications

Topography of Methylphenidate (Ritalin)-Induced Gene Regulation in the Striatum: Differential Effects on c-Fos, Substance P and Opioid Peptides

Topography of Methylphenidate (Ritalin)-Induced Gene Regulation in the Striatum: Differential Effects on c-Fos, Substance P and Opioid Peptides

Enhanced Reactivity and Vulnerability to Cocaine Following Methylphenidate Treatment in Adolescent Rats

Voltammetric characterization of the effect of monoamine uptake inhibitors and releasers on dopamine and serotonin uptake in mouse caudate-putamen and substantia nigra slices

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