Agathobaculum butyriciproducens Shows Neuroprotective Effects in a 6-OHDA-Induced Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is the second-most prevalent neurodegenerative disease and is characterized by dopaminergic neuronal death in the midbrain. Recently, the association between alterations in PD pathology and the gut microbiota has been explored. Microbiota-targeted interventions have been suggested as a novel therapeutic approach for PD. Agathobaculum butyriciproducens SR79T (SR79) is an anaerobic bacterium. Previously, we showed that SR79 treatment induced cognitive improvement and reduced Alzheimer's disease pathologies in a mouse model. In this study, we hypothesized that SR79 treatment may have beneficial effects on PD pathology. To investigate the therapeutic effects of SR79 on PD, 6-hydroxydopamine (6-OHDA)-induced mouse models were used. D-Amphetamine sulfate (d-AMPH)-induced behavioral rotations and dopaminergic cell death were analyzed in unilateral 6-OHDA-lesioned mice. Treatment with SR79 significantly decreased ipsilateral rotations induced by d-AMPH. Moreover, SR79 treatment markedly activated the AKT/GSK3ß signaling pathway in the striatum. In addition, SR79 treatment affected the Nrf2/ARE signaling pathway and its downstream target genes in the striatum of 6-OHDA-lesioned mice. Our findings suggest a protective role of SR79 in 6-OHDA-induced toxicity by regulating the AKT/Nrf2/ARE signaling pathway and astrocyte activation. Thus, SR79 may be a potential microbe-based intervention and therapeutic strategy for PD.

Effects of monoamine depletion on the ketamine-induced locomotor activity of preweanling, adolescent, and adult rats: Sex and age differences.

Ketamine significantly increases the locomotor activity of rodents, however this effect varies according to the sex and age of the animal being tested. To determine the role monoamine systems play in ketamine's locomotor activating effects: (a) male and female preweanling, adolescent, and adult rats were pretreated with vehicle or the monoamine depleting agent reserpine (1 or 5 mg/kg), and (b) the behavioral actions of ketamine (20 or 40 mg/kg) were then compared to d-amphetamine (2 mg/kg) and cocaine (10 or 15 mg/kg). The ability of reserpine to deplete dorsal striatal dopamine (DA) and serotonin (5-HT) in male and female rats was determined using HPLC. Ketamine caused substantial increases in the locomotion of preweanling rats and older female rats (adolescents and adults), but had only small stimulatory effects on adolescent and adult male rats. When compared to cocaine and d-amphetamine, ketamine was especially sensitive to the locomotor-inhibiting effects of monoamine depletion. Ketamine-induced locomotion is at least partially mediated by monoamine systems, since depleting DA and 5-HT levels by 87-96% significantly attenuated the locomotor activating effects of ketamine in male and female rats from all three age groups. When administered to reserpine-pretreated rats, ketamine produced a different pattern of behavioral effects than either psychostimulant, suggesting that ketamine does not stimulate locomotor activity via actions at the presynaptic terminal. Instead, our results are consistent with the hypothesis that ketamine increases locomotor activity through a down-stream mechanism, possibly involving ascending DA and/or 5-HT projection neurons.

Targeting of dopamine transporter to filopodia requires an outward-facing conformation of the transporter.

Dopamine transporter (DAT) has been shown to accumulate in filopodia in neurons and non-neuronal cells. To examine the mechanisms of DAT filopodial targeting, we used quantitative live-cell fluorescence microscopy, and compared the effects of the DAT inhibitor cocaine and its fluorescent analog JHC1-64 on the plasma membrane distribution of wild-type DAT and two non-functional DAT mutants, R60A and W63A, that do not accumulate in filopodia. W63A did not bind JHC1-64, whereas R60A did, although less efficiently compared to the wild-type DAT. Molecular dynamics simulations predicted that R60A preferentially assumes an outward-facing (OF) conformation through compensatory intracellular salt bridge formation, which in turn favors binding of cocaine. Imaging analysis showed that JHC1-64-bound R60A mutant predominantly localized in filopodia, whereas free R60A molecules were evenly distributed within the plasma membrane. Cocaine binding significantly increased the density of R60A, but not that of W63A, in filopodia. Further, zinc binding, known to stabilize the OF state, also increased R60A concentration in filopodia. Finally, amphetamine, that is thought to disrupt DAT OF conformation, reduced the concentration of wild-type DAT in filopodia. Altogether, these data indicate that OF conformation is required for the efficient targeting of DAT to, and accumulation in, filopodia.

Effects of D1 and D2 receptor antagonists on the discriminative stimulus effects of methylendioxypyrovalerone and mephedrone in male Sprague-Dawley rats trained to discriminate D-amphetamine.

Psychopharmacology research has amassed substantial evidence for similarities between synthetic cathinones and other commonly abused psychostimulants. Few studies have utilized drug discrimination methods to investigate synthetic cathinones, and the precise neurochemical substrates underlying their interoceptive effects have not been examined. The present study assessed the involvement of D1 and D2 dopaminergic receptors in the stimulus effects of 3,4-methylenedioxypyrovalerone (MDPV) and mephedrone (MEPH) in rats trained to discriminate D-amphetamine. Eight male Sprague-Dawley rats were trained to discriminate 0.5 mg/kg D-amphetamine (AMPH) from saline. Dose-response curves were then generated with AMPH (0.0-1.0 mg/kg), MDPV (0.0-1.0 mg/kg), and MEPH (0.0-2.0 mg/kg). Subsequently, Sch 39166 (0.3 mg/kg) and haloperidol (0.5 mg/kg) were administered in combination with select doses of MDPV and MEPH. Both MDPV and MEPH produced full substitution for AMPH. Sch 39166 produced a downward shift in the MDPV and MEPH dose-response curves and haloperidol produced similar results with MDPV. These preliminary findings indicate that MDPV and MEPH produce interoceptive stimuli that are similar to those produced by AMPH and that D1 and D2 dopamine receptors contribute to these effects. Additional studies are warranted to investigate the contribution of other receptor mechanisms involved in the interoceptive stimuli produced by synthetic cathinones.

Neurotransmitter and psychostimulant recognition by the dopamine transporter.

Na(+)/Cl(-)-coupled biogenic amine transporters are the primary targets of therapeutic and abused drugs, ranging from antidepressants to the psychostimulants cocaine and amphetamines, and to their cognate substrates. Here we determine X-ray crystal structures of the Drosophila melanogaster dopamine transporter (dDAT) bound to its substrate dopamine, a substrate analogue 3,4-dichlorophenethylamine, the psychostimulants d-amphetamine and methamphetamine, or to cocaine and cocaine analogues. All ligands bind to the central binding site, located approximately halfway across the membrane bilayer, in close proximity to bound sodium and chloride ions. The central binding site recognizes three chemically distinct classes of ligands via conformational changes that accommodate varying sizes and shapes, thus illustrating molecular principles that distinguish substrates from inhibitors in biogenic amine transporters.

An update on lisdexamfetamine dimesylate for the treatment of attention deficit hyperactivity disorder.

INTRODUCTION: The efficacy and safety of stimulants for the pharmacologic management of attention deficit hyperactivity disorder (ADHD) is well documented. The US Food and Drug Administration approval of additional classes of medication even within stimulant treatments expands the prescribing options for practitioners. The focus of this paper is the prodrug amphetamine stimulant, lisdexamfetamine (LDX) , which is an example of such an agent with a novel delivery system. AREAS COVERED: This review covers the proof-of-concept and later studies of LDX to describe its use to treat ADHD in pediatric and adult populations. A literature search and review of LDX were carried out using the PubMed database up to August 2012. EXPERT OPINION: Clinical studies of LDX in children and adults with ADHD demonstrate its tolerability and its efficacy in reducing ADHD symptoms. Future research should be less restrictive in order to address some of the unmet needs in ADHD treatment. The inclusion of patients with ADHD and co-occurring mental health disorders and/or medical conditions is typically not studied in clinical trials nor is the prior ADHD treatment exposure of study participants. The preschool age population also is understudied in recently approved ADHD treatments such as LDX. Finally, how to approach the treatment of participants or first-degree relatives with a medical history or presence of substance use disorder presents an ongoing clinical challenge.

Transient enhanced expression of Cdk5 activator p25 after acute and chronic d-amphetamine administration.

The cellular and molecular mechanisms of sensitization in the addictive process are still unclear. Recently, chronic treatment with cocaine has been shown to upregulate the expression of cyclin-dependent kinase 5 (cdk5) and its specific activator, p35, in the striatum, as a downstream target gene of DeltaFosB, and has been implicated in compensatory adaptive changes associated with psychostimulants. Cdk5 is a serine/threonine kinase and its activation is achieved through association with a regulatory subunit, either p35 or p39. P35 is cleaved by the protease calpain, which results in the generation of a truncated product termed p25, which contains all elements necessary for cdk5 activation. The cdk5/p35 complex plays an essential role in neuronal development and survival. It has also been involved in neuronal trafficking and transport and in dopaminergic transmission, indicating its role either in presynaptic and postsynaptic signaling. In this study we report that the cdk5/p35 complex participates in acute and chronic d-amphetamine (AMPH)-evoked behavioral events, and we show a surprisingly transient enhanced expression of p25 and a lasting increased expression of p35 in dorsal striatal synaptosomes after acute and chronic AMPH administration. Pak1, a substrate for cdk5, is also enriched in the synaptosomal fraction of acute AMPH-treated rats. Our data suggest that the transient upregulation of p25 may regulate the activity of cdk5 in phosphorylating particular substrates, such as Pak1, implicated in the compensatory adaptive morphophysiologic changes associated with the process of behavioral sensitization to psychostimulants.

Relative bioavailability of lisdexamfetamine 70-mg capsules in fasted and fed healthy adult volunteers and in solution: a single-dose, crossover pharmacokinetic study.

The relative bioavailability of oral lisdexamfetamine dimesylate, a prodrug of d-amphetamine, and active d-amphetamine was assessed in an open-label, single-dose, 3-treatment, 3-period, randomized, crossover study in 18 healthy adult volunteers. Following a fast of at least 10 hours, subjects were administered an intact capsule of 70 mg lisdexamfetamine, a solution containing the capsule contents, or an intact capsule with a high-fat meal. Standard meals started 4 hours following lisdexamfetamine administration. Blood samples were taken predose (0 hours) and 0.5 to 72 hours postdose, and the concentrations of d-amphetamine and lisdexamfetamine were measured. AUC and C(max) for d-amphetamine were similar when lisdexamfetamine 70 mg was administered to healthy adults in the fed or fasted state. The AUC of intact lisdexamfetamine was similar when the latter was taken without food or in solution, but C(max) was lower when lisdexamfetamine was administered with food. The t(max) of d-amphetamine and intact lisdexamfetamine was similar when taken in solution or in the fasted state but was about 1 hour longer when taken with food. Adverse events were typical for amphetamine products. These findings indicate that food does not have a significant effect on d-amphetamine or lisdexamfetamine bioavailability in healthy adults and that lisdexamfetamine was well tolerated.

An evaluation of the cytochrome p450 inhibition potential of lisdexamfetamine in human liver microsomes.

The human cytochrome P450 (P450) system is implicated in many drug interactions. Lisdexamfetamine dimesylate (NRP104), the proposed generic name for a new agent under investigation for treatment of attention deficit hyperactivity disorder, was recently analyzed for inhibitory drug-drug interactions with seven major P450 isoforms using pooled human liver microsomes. Probe substrates were used near the K(m) concentration values reported in the literature for CYP1A2 (phenacetin), CYP2A6 (coumarin), CYP2B6 (bupropion), CYP2C9 (tolbutamide), CYP2C19 ([S]-mephenytoin), CYP2D6 (dextromethorphan), and CYP3A4 (midazolam and testosterone), and lisdexamfetamine was evaluated at concentrations ranging from 0.01 to 100 muM for its ability to inhibit the activity of these seven P450 isoforms. NADPH was added to one set of samples to initiate metabolic reactions, which were then terminated by adding organic solvent, vortexing the samples, and placing them on ice. The relevant substrates were then introduced to both sets of samples so that the percentage of remaining activity could be measured and compared. In addition, these samples were compared with other samples with the same concentrations of lisdexamfetamine but without preincubation. None of the seven P450 isoforms showed any concentration-dependent inhibition. Comparison of results from microsomes preincubated with and without NADPH showed no mechanism-based inhibition. Neither concentration-dependent nor mechanism-based inhibition caused by time-dependent inactivation of human P450 isoforms was shown for lisdexamfetamine during in vitro testing. The evidence suggests that lisdexamfetamine has a low potential for drug-drug interactions or initiation of drug-drug interactions.

The science of stimulant abuse.

Stimulant medications, although classified by the US Drug Enforcement Agency as controlled with a Schedule IIa rating, are ubiquitous in our society because of their popularity as an effective treatment for childhood ADHD. The number of stimulant products available for practitioners has tripled in the last decade. Although stimulants' action on central dopamine systems can be reinforcing, especially when delivered via intraperitoneal or intravenous routes in laboratory animals, they are far less addicting when taken orally by children in the context of a medical treatment. Fortunately, the therapeutic stimulants, available orally, have different pharmacodynamic and pharmacokinetic properties than the illicit stimulants, methamphetamine and cocaine. The lack of intravenous forms of the therapeutic stimulants acts as a natural barrier and tends to prevent addiction. Furthermore, MPH produces dysphoria in school age children, further limiting its reinforcing properties. These pharmacokinetics and pharmacodynamics of methylphenidate and amphetamine treatments for ADHD thus are less addicting because of their delivery systems. Future products, employing novel methods that only allow the drug molecule to be available if ingested, should further increase the safety of these important therapeutic agents.

The partial D2-like dopamine receptor agonist terguride acts as a functional antagonist in states of high and low dopaminergic tone: evidence from preweanling rats.

RATIONALE: In adult rats, the partial D(2)-like agonist terguride acts as an antagonist at normosensitive D(2)-like post-synaptic receptors, while it acts as an agonist at the same receptors during states of low dopaminergic tone. OBJECTIVE: The purpose of the present study was to determine whether partial D(2)-like agonists exhibit both antagonistic and agonistic actions during the preweanling period. METHODS: In experiments 1 and 2 (examining the agonistic actions of terguride), preweanling rats were either given an escalating regimen of amphetamine to induce a state of amphetamine withdrawal or pretreated with the tyrosine hydroxylase inhibitor AMPT. Distance traveled was measured after rats were injected with saline, terguride (0.4-1.6 mg/kg), or the full D(2)-like receptor agonist NPA (0.01 mg/kg). In experiment 3 (examining the antagonistic actions of terguride), preweanling rats were pretreated with terguride 30 min before they were tested with saline, NPA (0.05 mg/kg), or amphetamine (1.5 mg/kg). RESULTS: NPA had an exaggerated locomotor activating effect when tested under conditions of amphetamine withdrawal, while the partial D(2)-like agonist did not enhance distance traveled under any circumstance. Similarly, NPA increased and terguride did not affect the distance-traveled scores of AMPT-pretreated rats. In experiment 3, terguride pretreatment significantly reduced the distance traveled of amphetamine-treated and NPA-treated rats. CONCLUSIONS: The behavioral evidence indicates that, during the preweanling period, terguride antagonizes D(2)-like post-synaptic receptors in a state of high dopaminergic tone; however, there is no evidence that terguride is capable of stimulating D(2)-like post-synaptic receptors during states of low dopaminergic tone.

Oral D-amphetamine causes prolonged displacement of [11C]raclopride as measured by PET.

Parenterally administered D-amphetamine has been used as a challenge drug to release dopamine, which in turns inhibits [11C]raclopride binding to dopaminergic D2 receptors as measured using positron emission tomography (PET) techniques. The primary objective of this study was to determine whether orally administered D-amphetamine would inhibit [11C]raclopride binding in a manner similar to that produced by intravenously administered D-amphetamine. The secondary objective was to assess the timeline of these effects. Twelve healthy human volunteers participated in this study. Subjects were scanned at baseline and 2 h after D-amphetamine administration (n = 5); at baseline, 2 and 6 h postdrug (n = 4); or at baseline, 2 and 24 h postdrug (n = 3). Orally administered D-amphetamine caused a significant decrease in [11C]raclopride binding at 2 h (13% +/- 5%). Receptor availability was still decreased at 6 h (18% +/- 6%), even though physiological effects had completely returned to baseline. [11C]Raclopride binding returned to baseline at 24 h. The percentage of [11C]raclopride displacement was not correlated with plasma D-amphetamine concentrations. In conclusion, orally administered D-amphetamine caused a reliable and prolonged [11C]raclopride displacement, the magnitude of which is similar to that observed after intravenous administration. Possible mechanisms for the observed prolonged displacement may include persistence of intrasynaptic dopamine and/or receptor internalization.

Differential sensitivity to NaCl for inhibitors and substrates that recognize mutually exclusive binding sites on the neuronal transporter of dopamine in rat striatal membranes.

Addition of NaCl (90--290 mM) to a 10 mM Na(+) medium did not significantly modify B(max) and K(d) values for [3H]mazindol binding to the dopamine neuronal transporter (DAT) studied on rat striatal membranes at 20 degrees C. Addition of NaCl differentially affected the ability of other uptake inhibitors and substrates to block the [3H]mazindol binding. Ratios of 50% inhibiting concentrations calculated for 290 and 90 mM NaCl allowed to distinguish three groups of agents: substrates which were more potent in the presence of 290 mM NaCl (group 1; ratio < 1) and two groups of uptake inhibitors displaying ratio values either ranging around two (group 2: WIN 35,428, cocaine, methylphenidate, pyrovalerone) or close to unity (group 3: BTCP, mazindol, benztropine, nomifensine). However, agents from these three groups recognize mutually exclusive binding sites since in interaction studies the presence of WIN 35,428 (group 2) or mazindol (group 3) increased the 50% inhibiting concentrations of D-amphetamine (group 1) and WIN 35,428 on the [3H]mazindol binding to theoretical values expected for a competition of all of these compounds for the same binding domain on the DAT.

Involvement of CYP2D6 in the in vitro metabolism of amphetamine, two N-alkylamphetamines and their 4-methoxylated derivatives.

1. Amphetamine (AM) and five amphetamine derivatives, N-ethylamphetamine (NEA), N-butylamphetamine (NBA), 4-methoxyamphetamine (M-AM), 4-methoxy-N-ethylamphetamine (M-NEA) and 4-methoxy-N-butylamphetamine (M-NBA) were incubated with microsomal preparations from cells expressing human CYP2D6 to determine whether the enzyme was capable of catalyzing the direct ring oxidation of all substrates; the N-dealkylation of NEA, NBA, M-NEA and M-NBA; and the O-demethylation of M-AM, M-NEA and M-NBA. 2. None of the six compounds examined was N-dealkylated to any extent. 3. The only metabolites produced from AM, NEA and NBA were the corresponding ring 4-hydroxylated compounds, and the rates of formation were low. 4. All ring 4-methoxylated substrates were efficiently O-demethylated by CYP2D6 to their corresponding phenols. The size of the N-alkyl group influenced the rates of formation of these phenolamines. In contrast to reported findings with 2- and 3-methoxyamphetamines, none of the 4-methoxyamphetamines was ring-oxidized in the CYP2D6 enzyme system to 2- or 3-hydroxy-4-methoxyamphetamines or to dihydroxyamphetamines.

Phosphorylation and sequestration of serotonin transporters differentially modulated by psychostimulants.

Many psychotropic drugs interfere with the reuptake of dopamine, norepinephrine, and serotonin. Transport capacity is regulated by kinase-linked pathways, particularly those involving protein kinase C (PKC), resulting in transporter phosphorylation and sequestration. Phosphorylation and sequestration of the serotonin transporter (SERT) were substantially impacted by ligand occupancy. Ligands that can permeate the transporter, such as serotonin or the amphetamines, prevented PKC-dependent SERT phosphorylation. Nontransported SERT antagonists such as cocaine and antidepressants were permissive for SERT phosphorylation but blocked serotonin effects. PKC-dependent SERT sequestration was also blocked by serotonin. These findings reveal activity-dependent modulation of neurotransmitter reuptake and identify previously unknown consequences of amphetamine, cocaine, and antidepressant action.

Effect of d-amphetamine repeated administration on rat antioxidant defences.

The purpose of this study was to evaluate rat tissue antioxidant status after repeated administration of d-amphetamine. Three groups of four rats each were used: control, d-amphetamine sulphate dosed (s.c., 20 mg/kg per day), and pair-fed. After 14 days of d-amphetamine daily administration, superoxide dismutase (CuZnSOD and MnSOD), catalase, glutathione peroxidase (GPx), glutathione reductase (GRed), glutathione-S-transferase (GST), glutathione (GSH), cysteine and thiobarbituric acid reactive substances (TBARS) were measured in liver, kidney, and heart. Various serum and urine parameters were also analysed. d-Amphetamine treatment induced an increase of liver GSH, as well as a decrease of cysteine and MnSOD levels in this organ. A small increase in serum transaminases was also observed in comparison to the pair-fed group. Hepatic levels of TBARS, GPx, GRed and CuZnSOD were found to be similar among the three groups of rats. d-Amphetamine treatment induced an increase of kidney GST, GRed and catalase levels, and an elevation of N-acetyl-beta-D-glucosaminidase efflux to the urine, accompanied by a decrease in urinary creatinine, compared to the pair-fed group. In d-amphetamine treated animals, heart cysteine levels were significantly depleted when compared to the pair-fed group, but all three groups of rats were found to have similar heart antioxidant enzyme levels. These results indicate that repeated administration of d-amphetamine caused a certain degree of stress in liver and kidney, which was followed by adaptations of antioxidant defences. The mechanisms involved in d-amphetamine-induced toxicity may explain the different adaptations observed for the studied organs.

Distinct binding patterns of [3H]raclopride and [3H]spiperone at dopamine D2 receptors in vivo in rat brain. Implications for pet studies.

Positron emission tomography studies (PET) on dopamine (DA) D2 receptors of schizophrenics provided conflicting data, perhaps because the ligands generally used, raclopride (RAC) and spiperone (SPI), did not label the same sites. In this study, we found that the in vivo binding characteristics of [3H]RAC labeled twice as many sites in striatum and olfactory tubercle and [3H]SPI twice as many sites in pituitary. 2) The kinetic was much shorter with [3H]RAC than [3H]SPI in striatum. 3) RAC, unlike SPI, did not exhibit limbic selectivity. 4) The modulation of [3H]RAC and [3H]SPI binding by endogenous DA were diametrically opposite: D-amphetamine decreased, and reserpine + alpha-methyl-p-tyrosine increased [3H]RAC binding in striatum whereas the opposite occurred with [3H]SPI. This distinct binding pattern of [3H]RAC and [3H]SPI suggests that these two radioligands do not label the same receptor sites.

Cyclosporine-A increases locomotor activity in rats with 6-hydroxydopamine-induced hemiparkinsonism: relevance to neural transplantation.

BACKGROUND: The immunosuppressant cyclosporine-A (CsA) is the primary drug for neural transplantation in Parkinson's disease. However, little is known of its direct effects on movement disorders. Our previous observation of increased locomotor activity in normal rats injected with CsA prompted us to investigate further the effects of CsA on hemiparkinsonian rats. METHODS: We examined the effects of CsA with 6-hydroxydopamine-induced hemiparkinsonism. The animals were randomly assigned to either intraperitoneal injections of CsA (15 mg/kg) or olive oil (the vehicle used for CsA) for 32 days. All animals were tested using the elevated body swing test, and the spontaneous and the amphetamine-induced rotational tests prior to and following the 32-day drug regimen. RESULTS: As revealed by the elevated body swing test, CsA-treated rats had significantly higher mean percent contralateral (to the lesion) swings compared to their pretreatment level (p < 0.01) or to vehicle-treated rats at posttreatment (p < 0.005). In the spontaneous rotational test, CsA-treated rats displayed ipsilateral (to the lesion) rotations which were significantly higher than their pretreatment rotational behavior (p < 0.005) or the posttreatment rotational behavior of olive oil-treated rats (p < 0.0001). Similarly, CsA-treated rats displayed significantly more amphetamine-induced ipsilateral rotations compared to their or the olive oil-treated rats pretreatment level (p < 0.05). CONCLUSION: Our present observations extend our previous findings on motor alterations produced by CsA on normal rats to hemiparkinsonian rats. These results taken together would suggest that CsA may interact with the locomotor effects observed following neural transplantation with adjunctive CsA immunosuppression.

Aromatic ring oxidation of N-n-butylamphetamine is enhanced in the rat by prior treatment with quinidine.

Prior administration of quinidine is known to reduce aromatic oxidation of amphetamine and its analog methoxyphenamine by inhibiting the cytochrome P450IID6 results in isozyme. In contrast, it is now shown that prior administration of quinidine results in a significant increase in the aromatic oxidation of N-n-butylamphetamine in rat, suggesting that the P450IID6 isozyme is not involved in this metabolic reaction.

Stimulant drug treatment of hyperactivity: biochemical correlates.

To compare the effects of the stimulant drugs dextroamphetamine and methylphenidate on urinary and plasma monoamines and metabolites within the same clinical sample, thirty-one children with attention-deficit disorder with hyperactivity were treated with dextroamphetamine (up to 1.5 mg/kg/day), methylphenidate (up to 3.0 mg/kg/day), and placebo in an 11-week double-blind crossover trial. As expected, both drugs showed striking clinical efficacy, and within a subsample of the group, earlier findings were confirmed, that dextroamphetamine but not methylphenidate lowered urinary and plasma 3-methoxy-4-hydroxyphenylglycol and whole body norepinephrine turnover, and that urinary and plasma concentration of homovanillic acid was unaltered by either drug. Methylphenidate but not dextroamphetamine increased plasma norepinephrine. Urinary epinephrine and metanephrine were increased with both drugs, but this increase did not correlate significantly with clinical improvement.