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Alan J Fischman - One of the best experts on this subject based on the ideXlab platform.
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understanding the central pharmacokinetics of spheroidal oral drug absorption system sodas dexmethylphenidate a positron emission tomography study of Dopamine Transporter receptor occupancy measured with c 11 altropane
The Journal of Clinical Psychiatry, 2012Co-Authors: Thomas J Spencer, Tara Mirto, Allison Clarke, Ali A Bonab, Jessica Martin, Alan J Fischman, Darin D DoughertyAbstract:OBJECTIVE: Pediatric studies of the long-acting formulation (spheroidal oral drug absorption system [SODAS]) of the isomer dexmethylphenidate have shown a dose-dependent efficacy through 12 hours. However, there are no studies of central nervous system (CNS) Dopamine Transporter occupancies. METHOD: Eighteen healthy volunteers underwent positron emission tomography (PET) imaging with C-11 altropane before and after administration of oral doses of SODAS dexmethylphenidate. Each group of 6 subjects received 1 of 3 doses (20 mg, 30 mg, 40 mg) before PET imaging at 1, 8, 10, 12 (20 mg and 30 mg), or 1, 8, 10, and 14 (40 mg) hours after dosing. Transporter occupancy was calculated by standard methods. The study was conducted from January 2007 through December 2007. RESULTS: For all doses, plasma dexmethylphenidate levels and CNS Dopamine Transporter occupancies were greatest at 8 hours and decreased over time at 10, 12, and 14 hours. Plasma dexmethylphenidate levels were correlated to dose (P < .003). Mean plasma levels were ≥ 6 ng/mL to at least 8 hours with 20 mg (5.7 ng/mL), 10 hours with 30 mg, and 12 hours (extrapolated) with 40 mg. Dopamine Transporter occupancies in the right caudate were 47% at 8 hours with 20 mg, 42% at hour 10 with 30 mg, and 46% (extrapolated) at hour 12 with 40 mg. Dopamine Transporter occupancy was significantly correlated with plasma concentration of dexmethylphenidate (P < .001). CONCLUSIONS: These results confirm the study hypothesis that central Dopamine Transporter occupancy parallels peripheral pharmacokinetic findings in orally administered long-acting dexmethylphenidate in later hours after administration. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00593138.
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further evidence of Dopamine Transporter dysregulation in adhd a controlled pet imaging study using altropane
Biological Psychiatry, 2007Co-Authors: Thomas J Spencer, Ali A Bonab, Jessica Martin, Peter C Meltzer, Darin D Dougherty, Bertha K. Madras, Scott L Rauch, Joseph Biederman, E Livni, Alan J FischmanAbstract:Background The Dopamine Transporter (DAT) is known to be a key regulator of Dopamine, and recent studies of genetics, treatment, and imaging have highlighted the role of DAT in attention-deficit/hyperactivity disorder (ADHD). The findings of in vivo neuroimaging of DAT in ADHD have been somewhat discrepant, however. Method Dopamine Transporter binding was measured using a highly selective ligand (C-11 altropane) and positron emission tomography (PET). The sample consisted of 47 well-characterized, treatment-naive, nonsmoking, non-comorbid adults with and without ADHD. Additionally, control subjects had few symptoms of ADHD. Results Results showed significantly increased DAT binding in the right caudate in adults with ADHD compared with matched control subjects without this disorder. Conclusions These results confirm abnormal DAT binding in the striatum of adults with ADHD and provide further support that dysregulation of DAT may be an important component of the pathophysiology of ADHD.
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pet study examining pharmacokinetics detection and likeability and Dopamine Transporter receptor occupancy of short and long acting oral methylphenidate
American Journal of Psychiatry, 2006Co-Authors: Thomas J Spencer, Ali A Bonab, Darin D Dougherty, Bertha K. Madras, Joseph Biederman, E Livni, Patrick E Ciccone, Dolly A Parasrampuria, Alan J FischmanAbstract:Objective: The abuse potential of methylphenidate has been related to the drug’s capacity to produce a rapid onset of blockade of the presynaptic Dopamine Transporter in the brain. An oral once-aday osmotic controlled-release formulation of methylphenidate produces a more gradual rise in plasma methylphenidate concentration, compared with immediate-release methylphenidate. The authors hypothesized that osmotic-release methylphenidate would also produce a slower onset of blockade of the presynaptic Dopamine Transporter and would be associated with a lower risk for detection and likeability, compared to immediaterelease methylphenidate. Method: Twelve healthy adults were randomly assigned to receive single doses of immediate-release methylphenidate or osmotic-release methylphenidate. Doses predicted to produce equivalent maximum concentration (Cmax) values were selected (40 mg of immediate-release methylphenidate and 90 mg of osmoticrelease methylphenidate). Plasma dmethylphenidate levels and responses to detection/likeability questionnaire items were obtained hourly for 10 hours after administration of methylphenidate on two separate occasions for each subject. Dopamine Transporter receptor occupancies were measured at hours 1, 3, 5, and 7 by using a carbon-11-labeled imaging agent (Altropane) and positron emission tomography. Results: Despite similar Cmax values for both formulations, osmotic-release methylphenidate was associated with a longer time to maximum concentration, longer time to maximum CNS Dopamine Transporter occupancy, and no detection/likeability, compared with immediate-release methylphenidate. Conclusions: The findings suggest that the abuse potential of oral methylphenidate is strongly influenced by the rate of delivery and not solely by the magnitude of plasma concentration or brain Transporter occupancy. These results advance understanding of the underlying central effects of methylphenidate in humans and identify a potentially less abusable methylphenidate formulation.
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the Dopamine Transporter and attention deficit hyperactivity disorder
Biological Psychiatry, 2005Co-Authors: Bertha K. Madras, Gregory M. Miller, Alan J FischmanAbstract:The high incidence of attention-deficit/hyperactivity disorder (ADHD) and escalating use of ADHD medications present a compelling case for clarifying the pathophysiology of, and developing laboratory or radiologic tests for, ADHD. Currently, the majority of specific genes implicated in ADHD encode components of catecholamine signaling systems. Of these, the Dopamine Transporter (DAT) is a principal target of the most widely used antihyperactivity medications (amphetamine and methylphenidate); the DAT gene is associated with ADHD, and some studies have detected abnormal levels of the DAT in brain striatum of ADHD subjects. Medications for ADHD interfere with Dopamine transport by brain-region- and drug-specific mechanisms, indirectly activating Dopamine- and possibly norepinephrine-receptor subtypes that are implicated in enhancing attention and experiential salience. The most commonly used DAT-selective ADHD medications raise extracellular Dopamine levels in DAT-rich brain regions. In brain regions expressing both the DAT and the norepinephrine Transporter (NET), the relative contributions of Dopamine and norepinephrine to ADHD pathophysiology and therapeutic response are obfuscated by the capacity of the NET to clear Dopamine as well as norepinephrine. Thus, ADHD medications targeting DAT or NET might disperse Dopamine widely and consign Dopamine storage and release to regulation by noradrenergic, as well as Dopaminergic neurons.
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Dopamine Transporter density in patients with attention deficit hyperactivity disorder
The Lancet, 1999Co-Authors: Darin D Dougherty, Ali A Bonab, Thomas J Spencer, Bertha K. Madras, Scott L Rauch, Alan J FischmanAbstract:Dopamine Transporter density was measured in vivo in six adult patients with attention deficit hyperactivity disorder. We have shown a 70% increase in age-corrected Dopamine Transporter density in patients with attention hyperactivity disorder compared with healthy controls.
Bertha K. Madras - One of the best experts on this subject based on the ideXlab platform.
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further evidence of Dopamine Transporter dysregulation in adhd a controlled pet imaging study using altropane
Biological Psychiatry, 2007Co-Authors: Thomas J Spencer, Ali A Bonab, Jessica Martin, Peter C Meltzer, Darin D Dougherty, Bertha K. Madras, Scott L Rauch, Joseph Biederman, E Livni, Alan J FischmanAbstract:Background The Dopamine Transporter (DAT) is known to be a key regulator of Dopamine, and recent studies of genetics, treatment, and imaging have highlighted the role of DAT in attention-deficit/hyperactivity disorder (ADHD). The findings of in vivo neuroimaging of DAT in ADHD have been somewhat discrepant, however. Method Dopamine Transporter binding was measured using a highly selective ligand (C-11 altropane) and positron emission tomography (PET). The sample consisted of 47 well-characterized, treatment-naive, nonsmoking, non-comorbid adults with and without ADHD. Additionally, control subjects had few symptoms of ADHD. Results Results showed significantly increased DAT binding in the right caudate in adults with ADHD compared with matched control subjects without this disorder. Conclusions These results confirm abnormal DAT binding in the striatum of adults with ADHD and provide further support that dysregulation of DAT may be an important component of the pathophysiology of ADHD.
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pet study examining pharmacokinetics detection and likeability and Dopamine Transporter receptor occupancy of short and long acting oral methylphenidate
American Journal of Psychiatry, 2006Co-Authors: Thomas J Spencer, Ali A Bonab, Darin D Dougherty, Bertha K. Madras, Joseph Biederman, E Livni, Patrick E Ciccone, Dolly A Parasrampuria, Alan J FischmanAbstract:Objective: The abuse potential of methylphenidate has been related to the drug’s capacity to produce a rapid onset of blockade of the presynaptic Dopamine Transporter in the brain. An oral once-aday osmotic controlled-release formulation of methylphenidate produces a more gradual rise in plasma methylphenidate concentration, compared with immediate-release methylphenidate. The authors hypothesized that osmotic-release methylphenidate would also produce a slower onset of blockade of the presynaptic Dopamine Transporter and would be associated with a lower risk for detection and likeability, compared to immediaterelease methylphenidate. Method: Twelve healthy adults were randomly assigned to receive single doses of immediate-release methylphenidate or osmotic-release methylphenidate. Doses predicted to produce equivalent maximum concentration (Cmax) values were selected (40 mg of immediate-release methylphenidate and 90 mg of osmoticrelease methylphenidate). Plasma dmethylphenidate levels and responses to detection/likeability questionnaire items were obtained hourly for 10 hours after administration of methylphenidate on two separate occasions for each subject. Dopamine Transporter receptor occupancies were measured at hours 1, 3, 5, and 7 by using a carbon-11-labeled imaging agent (Altropane) and positron emission tomography. Results: Despite similar Cmax values for both formulations, osmotic-release methylphenidate was associated with a longer time to maximum concentration, longer time to maximum CNS Dopamine Transporter occupancy, and no detection/likeability, compared with immediate-release methylphenidate. Conclusions: The findings suggest that the abuse potential of oral methylphenidate is strongly influenced by the rate of delivery and not solely by the magnitude of plasma concentration or brain Transporter occupancy. These results advance understanding of the underlying central effects of methylphenidate in humans and identify a potentially less abusable methylphenidate formulation.
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primate trace amine receptor 1 modulation by the Dopamine Transporter
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Gregory M. Miller, Christopher D Verrico, Amy K Jassen, Martha Konar, Hong Yang, Helen N Panas, Mary E Bahn, Ryan T Johnson, Bertha K. MadrasAbstract:Recently identified trace amine receptors are potential direct targets for drugs of abuse, including amphetamine and 3,4-methylenedioxymethamphetamine (MDMA). We cloned full-length rhesus monkey trace amine receptor 1 (rhTA1) that was 96% homologous to human TA1. The trace amines tyramine and β-phenylethylamine (PEA) and the monoamine Transporter substrates (±)-amphetamine and (±)-MDMA stimulated cAMP accumulation in rhTA1-expressing cell lines, as measured by a cAMP response element-luciferase assay. Cocaine did not stimulate cAMP accumulation in rhTA1 cells, but it blocked [3H]PEA transport mediated by the Dopamine Transporter. Cotransfection with the human Dopamine Transporter enhanced PEA-, amphetamine-, and MDMA-mediated rhTA1 receptor activation, but it diminished tyramine activation of rhTA1. Because TA1 (EGFP-rhTA1 chimera) was largely intracellular, conceivably the Dopamine Transporter can facilitate access of specific agonists to intracellular TA1. rhTA1 mRNA expression was detected in rhesus monkey substantia nigra, implying that TA1 may be colocalized with the Dopamine Transporter in Dopamine neurons. In summary, primate TA1 receptors are direct targets of trace amines, amphetamine, and MDMA. These receptors could also be indirect targets of amphetamine, MDMA, and cocaine through modification of monoamine Transporter function. Conceivably, rhTA1 receptors may be located on pre- or postsynaptic membranes. Interference with the carrier function of monoamine Transporters with a consequent rise of extracellular levels of trace amines could activate these receptors. The cloning of a highly homologous TA1 from rhesus monkey and demonstration that rhTA1 receptors are activated by drugs of abuse, indicate that nonhuman primates may serve to model physiological and pharmacological TA1-mediated responses in humans.
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primate trace amine receptor 1 modulation by the Dopamine Transporter
Journal of Pharmacology and Experimental Therapeutics, 2005Co-Authors: Gregory M. Miller, Christopher D Verrico, Amy K Jassen, Martha Konar, Hong Yang, Helen N Panas, Mary E Bahn, Ryan S Johnson, Bertha K. MadrasAbstract:Recently identified trace amine receptors are potential direct targets for drugs of abuse, including amphetamine and 3,4-methylenedioxymethamphetamine (MDMA). We cloned full-length rhesus monkey trace amine receptor 1 (rhTA(1)) that was 96% homologous to human TA(1). The trace amines tyramine and beta-phenylethylamine (PEA) and the monoamine Transporter substrates (+/-)-amphetamine and (+/-)-MDMA stimulated cAMP accumulation in rhTA(1)-expressing cell lines, as measured by a cAMP response element-luciferase assay. Cocaine did not stimulate cAMP accumulation in rhTA(1) cells, but it blocked [(3)H]PEA transport mediated by the Dopamine Transporter. Cotransfection with the human Dopamine Transporter enhanced PEA-, amphetamine-, and MDMA-mediated rhTA(1) receptor activation, but it diminished tyramine activation of rhTA(1). Because TA(1) (EGFP-rhTA(1) chimera) was largely intracellular, conceivably the Dopamine Transporter can facilitate access of specific agonists to intracellular TA(1). rhTA(1) mRNA expression was detected in rhesus monkey substantia nigra, implying that TA(1) may be colocalized with the Dopamine Transporter in Dopamine neurons. In summary, primate TA(1) receptors are direct targets of trace amines, amphetamine, and MDMA. These receptors could also be indirect targets of amphetamine, MDMA, and cocaine through modification of monoamine Transporter function. Conceivably, rhTA(1) receptors may be located on pre- or postsynaptic membranes. Interference with the carrier function of monoamine Transporters with a consequent rise of extracellular levels of trace amines could activate these receptors. The cloning of a highly homologous TA(1) from rhesus monkey and demonstration that rhTA(1) receptors are activated by drugs of abuse, indicate that nonhuman primates may serve to model physiological and pharmacological TA(1)-mediated responses in humans.
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the Dopamine Transporter and attention deficit hyperactivity disorder
Biological Psychiatry, 2005Co-Authors: Bertha K. Madras, Gregory M. Miller, Alan J FischmanAbstract:The high incidence of attention-deficit/hyperactivity disorder (ADHD) and escalating use of ADHD medications present a compelling case for clarifying the pathophysiology of, and developing laboratory or radiologic tests for, ADHD. Currently, the majority of specific genes implicated in ADHD encode components of catecholamine signaling systems. Of these, the Dopamine Transporter (DAT) is a principal target of the most widely used antihyperactivity medications (amphetamine and methylphenidate); the DAT gene is associated with ADHD, and some studies have detected abnormal levels of the DAT in brain striatum of ADHD subjects. Medications for ADHD interfere with Dopamine transport by brain-region- and drug-specific mechanisms, indirectly activating Dopamine- and possibly norepinephrine-receptor subtypes that are implicated in enhancing attention and experiential salience. The most commonly used DAT-selective ADHD medications raise extracellular Dopamine levels in DAT-rich brain regions. In brain regions expressing both the DAT and the norepinephrine Transporter (NET), the relative contributions of Dopamine and norepinephrine to ADHD pathophysiology and therapeutic response are obfuscated by the capacity of the NET to clear Dopamine as well as norepinephrine. Thus, ADHD medications targeting DAT or NET might disperse Dopamine widely and consign Dopamine storage and release to regulation by noradrenergic, as well as Dopaminergic neurons.
Jacob Eriksen - One of the best experts on this subject based on the ideXlab platform.
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a c terminal pdz domain binding sequence is required for striatal distribution of the Dopamine Transporter
Nature Communications, 2013Co-Authors: Mattias Rickhag, Ina Ammendrupjohnsen, Freja Herborg Hansen, Kristine Norgaard Strandfelt, Bjorn Andresen, Kamil Gotfryd, Ib Vestergaardklewe, Kenneth L Madsen, Gunnar Sorensen, Jacob EriksenAbstract:The mechanisms controlling Dopamine Transporter (DAT) levels in the striatum are poorly understood. Rickhag and colleagues generate DAT knock-in mice with disrupted PDZ-binding motifs and find that PDZ-domain interactions are necessary for distribution of DAT to striatal nerve terminals.
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a c terminal pdz domain binding sequence is required for striatal distribution of the Dopamine Transporter
Nature Communications, 2013Co-Authors: Mattias Rickhag, Ina Ammendrupjohnsen, Freja Herborg Hansen, Kristine Norgaard Strandfelt, Bjorn Andresen, Kamil Gotfryd, Ib Vestergaardklewe, Kenneth L Madsen, Gunnar Sorensen, Jacob EriksenAbstract:The Dopamine Transporter mediates reuptake of Dopamine from the synaptic cleft. The cellular mechanisms controlling Dopamine Transporter levels in striatal nerve terminals remain poorly understood. The Dopamine Transporters contain a C-terminal PDZ (PSD-95/Discs-large/ZO-1) domain-binding sequence believed to bind synaptic scaffolding proteins, but its functional significance is uncertain. Here we demonstrate that two different Dopamine Transporter knock-in mice with disrupted PDZ-binding motifs (Dopamine Transporter-AAA and Dopamine Transporter+Ala) are characterized by dramatic loss of Dopamine Transporter expression in the striatum, causing hyperlocomotion and attenuated response to amphetamine. In cultured Dopaminergic neurons and striatal slices from Dopamine Transporter-AAA mice, we find markedly reduced Dopamine Transporter surface levels and evidence for enhanced constitutive internalization. In Dopamine Transporter-AAA neurons, but not in wild-type neurons, surface levels are rescued in part by expression of a dominant-negative dynamin mutation (K44A). Our findings suggest that PDZ-domain interactions are critical for synaptic distribution of Dopamine Transporter in vivo and thereby for proper maintenance of Dopamine homoeostasis.
Mattias Rickhag - One of the best experts on this subject based on the ideXlab platform.
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a c terminal pdz domain binding sequence is required for striatal distribution of the Dopamine Transporter
Nature Communications, 2013Co-Authors: Mattias Rickhag, Ina Ammendrupjohnsen, Freja Herborg Hansen, Kristine Norgaard Strandfelt, Bjorn Andresen, Kamil Gotfryd, Ib Vestergaardklewe, Kenneth L Madsen, Gunnar Sorensen, Jacob EriksenAbstract:The mechanisms controlling Dopamine Transporter (DAT) levels in the striatum are poorly understood. Rickhag and colleagues generate DAT knock-in mice with disrupted PDZ-binding motifs and find that PDZ-domain interactions are necessary for distribution of DAT to striatal nerve terminals.
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a c terminal pdz domain binding sequence is required for striatal distribution of the Dopamine Transporter
Nature Communications, 2013Co-Authors: Mattias Rickhag, Ina Ammendrupjohnsen, Freja Herborg Hansen, Kristine Norgaard Strandfelt, Bjorn Andresen, Kamil Gotfryd, Ib Vestergaardklewe, Kenneth L Madsen, Gunnar Sorensen, Jacob EriksenAbstract:The Dopamine Transporter mediates reuptake of Dopamine from the synaptic cleft. The cellular mechanisms controlling Dopamine Transporter levels in striatal nerve terminals remain poorly understood. The Dopamine Transporters contain a C-terminal PDZ (PSD-95/Discs-large/ZO-1) domain-binding sequence believed to bind synaptic scaffolding proteins, but its functional significance is uncertain. Here we demonstrate that two different Dopamine Transporter knock-in mice with disrupted PDZ-binding motifs (Dopamine Transporter-AAA and Dopamine Transporter+Ala) are characterized by dramatic loss of Dopamine Transporter expression in the striatum, causing hyperlocomotion and attenuated response to amphetamine. In cultured Dopaminergic neurons and striatal slices from Dopamine Transporter-AAA mice, we find markedly reduced Dopamine Transporter surface levels and evidence for enhanced constitutive internalization. In Dopamine Transporter-AAA neurons, but not in wild-type neurons, surface levels are rescued in part by expression of a dominant-negative dynamin mutation (K44A). Our findings suggest that PDZ-domain interactions are critical for synaptic distribution of Dopamine Transporter in vivo and thereby for proper maintenance of Dopamine homoeostasis.
Nora D Volkow - One of the best experts on this subject based on the ideXlab platform.
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the Dopamine Transporter gene slc6a3 multidisease risks
Molecular Psychiatry, 2021Co-Authors: Maarten E. A. Reith, Nora D Volkow, Manju A Kurian, Sandhya Kortagere, Corinde E Wiers, Hui Sun, Aurelio Galli, Zhicheng LinAbstract:The human Dopamine Transporter gene SLC6A3 has been consistently implicated in several neuropsychiatric diseases but the disease mechanism remains elusive. In this risk synthesis, we have concluded that SLC6A3 represents an increasingly recognized risk with a growing number of familial mutants associated with neuropsychiatric and neurological disorders. At least five loci were related to common and severe diseases including alcohol use disorder (high activity variant), attention-deficit/hyperactivity disorder (low activity variant), autism (familial proteins with mutated networking) and movement disorders (both regulatory variants and familial mutations). Association signals depended on genetic markers used as well as ethnicity examined. Strong haplotype selection and gene-wide epistases support multimarker assessment of functional variations and phenotype associations. Inclusion of its promoter region’s functional markers such as DNPi (rs67175440) and 5’VNTR (rs70957367) may help delineate condensate-based risk action, testing a locus-pathway-phenotype hypothesis for one gene-multidisease etiology.
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long term stimulant treatment affects brain Dopamine Transporter level in patients with attention deficit hyperactive disorder
PLOS ONE, 2013Co-Authors: Nora D Volkow, Genejack Wang, Timothy Wigal, Scott H Kollins, Jeffrey H Newcorn, Frank Telang, Jean LoganAbstract:Objective: Brain Dopamine dysfunction in attention deficit/hyperactivity disorder (ADHD) could explain why stimulant medications, which increase Dopamine signaling, are therapeutically beneficial. However while the acute increases in Dopamine induced by stimulant medications have been associated with symptom improvement in ADHD the chronic effects have not been investigated. Method: We used positron emission tomography and [ 11 C]cocaine (Dopamine Transporter radioligand) to measure Dopamine Transporter availability in the brains of 18 never-medicated adult ADHD subjects prior to and after 12 months of treatment with methylphenidate and in 11 controls who were also scanned twice at 12 months interval but without stimulant medication. Dopamine Transporter availability was quantified as non-displaceable binding potential using a kinetic model for reversible ligands. Results: Twelve months of methylphenidate treatment increased striatal Dopamine Transporter availability in ADHD (caudate, putamen and ventral striatum: +24%, p,0.01); whereas there were no changes in control subjects retested at 12month interval. Comparisons between controls and ADHD participants revealed no significant difference in Dopamine Transporter availability prior to treatment but showed higher Dopamine Transporter availability in ADHD participants than control after long-term treatment (caudate: p,0.007; putamen: p,0.005). Conclusion: Upregulation of Dopamine Transporter availability during long-term treatment with methylphenidate may decrease treatment efficacy and exacerbate symptoms while not under the effects of the medication. Our findings also suggest that the discrepancies in the literature regarding Dopamine Transporter availability in ADHD participants (some studies reporting increases, other no changes and other decreases) may reflect, in part, differences in treatment histories. Citation: Wang G-J, Volkow ND, Wigal T, Kollins SH, Newcorn JH, et al. (2013) Long-Term Stimulant Treatment Affects Brain Dopamine Transporter Level in
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association of Dopamine Transporter reduction with psychomotor impairment in methamphetamine abusers
American Journal of Psychiatry, 2001Co-Authors: Nora D Volkow, Linda Chang, Genejack Wang, Joanna S Fowler, Maria Leonidoyee, Dinko Franceschi, Mark J Sedler, John S Gatley, Robert Hitzemann, Yushin DingAbstract:OBJECTIVE: Methamphetamine is a popular and highly addictive drug of abuse that has raised concerns because it has been shown in laboratory animals to be neurotoxic to Dopamine terminals. The authors evaluated if similar changes occur in humans and assessed if they were functionally significant. METHOD: Positron emission tomography scans following administration of [11C]d-threo-methylphenidate (a Dopamine Transporter ligand) measured Dopamine Transporter levels (a marker of Dopamine cell terminals) in the brains of 15 detoxified methamphetamine abusers and 18 comparison subjects. Neuropsychological tests were also performed to assess motor and cognitive function. RESULTS: Methamphetamine abusers showed significant Dopamine Transporter reduction in the striatum (mean differences of 27.8% in the caudate and 21.1% in the putamen) relative to the comparison subjects; this reduction was evident even in abusers who had been detoxified for at least 11 months. Dopamine Transporter reduction was associated with mo...
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Dopamine Transporter occupancies in the human brain induced by therapeutic doses of oral methylphenidate
American Journal of Psychiatry, 1998Co-Authors: Nora D Volkow, Genejack Wang, Joanna S Fowler, Robert Hitzemann, Yushin Ding, Jean Logan, S J Gatley, Naomi PappasAbstract:Objective: The therapeutic effects of methylphenidate in the treatment of attention deficit disorder have been attributed to its ability to increase the synaptic concentration of Dopamine by blocking the Dopamine Transporters. However, the levels of Dopamine Transporter blockade achieved by therapeutic doses of methylphenidate are not known. This study measured, for the first time, Dopamine Transporter occupancy by orally administered methylphenidate in the human brain and its rate of uptake in the brain. Method: Positron emission tomography (PET) and [ 11 C]cocaine were used to estimate Dopamine Transporter occupancies after different doses of oral methylphenidate in seven normal subjects (mean age=24 years, SD=7). In addition, the pharmacokinetics of oral methylphenidate were measured in the baboon brain through use of PET and [ 11 C]methylphenidate administered through an orogastric tube. Results: At 120 minutes after administration, oral methylphenidate produced a dose-dependent blockade of Dopamine Transporter; means=12% (SD= 4%) for 5 mg, 40% (SD=12%) for 10 mg, 54% (SD=5%) for 20 mg, 72% (SD=3%) for 40 mg, and 74% (SD=2%) for 60 mg. The estimated dose of oral methylphenidate required to block 50% of the Dopamine Transporter corresponded to 0.25 mg/kg. Oral methylphenidate did not reach peak concentration in brain until 60 minutes after its administration. Conclusions: Oral methylphenidate is very effective in blocking Dopamine Transporters, and at the weight-adjusted doses used therapeutically (0.3 to 0.6 mg/kg), it is likely to occupy more than 50% of the Dopamine Transporters. The time to reach peak brain uptake for oral methylphenidate in brain corresponds well with the reported time course to reach peak behavioral effects.