Synaptic Dopamine Concentration Research Articles

Copper Overload Increased Rat Striatal Levels of Both Dopamine and Its Main Metabolite Homovanillic Acid in Extracellular Fluid.

Copper is a trace element whose electronic configuration provides it with essential structural and catalytic functions. However, in excess, both its high protein affinity and redox-catalyzing properties can lead to hazardous consequences. In addition to promoting oxidative stress, copper is gaining interest for its effects on neurotransmission through modulation of GABAergic and glutamatergic receptors and interaction with the dopamine reuptake transporter. The aim of the present study was to investigate the effects of copper overexposure on the levels of dopamine, noradrenaline, and serotonin, or their main metabolites in rat's striatum extracellular fluid. Copper was injected intraperitoneally using our previously developed model, which ensured striatal overconcentration (2 mg CuCl2/kg for 30 days). Subsequently, extracellular fluid was collected by microdialysis on days 0, 15, and 30. Dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and noradrenaline (NA) levels were then determined by HPLC coupled with electrochemical detection. We observed a significant increase in the basal levels of DA and HVA after 15 days of treatment (310% and 351%), which was maintained after 30 days (358% and 402%), with no significant changes in the concentrations of 5-HIAA, DOPAC, and NA. Copper overload led to a marked increase in synaptic DA concentration, which could contribute to the psychoneurological alterations and the increased oxidative toxicity observed in Wilson's disease and other copper dysregulation states.

Role of COMT V158M Polymorphism in the Development of Dystonia after Administration of Antipsychotic Drugs.

Antipsychotics (APDs) represent the main pharmacological strategy in the treatment of schizophrenia; however, their administration often may result in severe adverse effects, such as extrapyramidal symptoms. Typically, dystonic movements are considered the result of impaired function and/or abnormalities of dopaminergic neurotransmission/signaling in the basal ganglia. The catechol O-methyltransferase (COMT) gene is located within the 22q11.2 region, and its product is an enzyme involved in transferring a methyl group from S-adenosylmethionine to catecholamines, including dopamine. Studies showed that COMT Val158Met polymorphism modifies enzymatic activity and, consequently, synaptic dopamine concentration in specific brain areas. We identified a patient with 22q11.2 deletion syndrome presenting with cervical and trunk dystonia after paliperidone administration, which persisted even after drug discontinuation. Given the patient’s genetic condition, we hypothesized that the dopaminergic dysfunction had been aggravated by COMT involvement, thus causing dystonia. In line with this hypothesis, we carried out a study on psychiatric patients in chronic treatment with APD to evaluate the distribution of the COMT Val158Met polymorphism and its role in the onset of adverse extrapyramidal symptoms. The study included four patients with dystonia after administration of APDs compared to 17 patients who never presented adverse drug reactions. Our data suggest that the Val/Val and Met/Met polymorphisms of the COMT gene are associated with a protective effect for the development of collateral extrapyramidal symptoms in patients treated with APDs, while the Val/Met genotype could be considered a risk factor for the development of dystonia after APDs administration.

Differential associations of dopamine synthesis capacity with the dopamine transporter and D2 receptor availability as assessed by PET in the living human brain

BackgroundThe dopamine (DA) neurotransmission has been implicated in fundamental brain functions, exemplified by movement controls, reward-seeking, motivation, and cognition. Although dysregulation of DA neurotransmission in the striatum is known to be involved in diverse neuropsychiatric disorders, it is yet to be clarified whether components of the DA transmission, such as synthesis, receptors, and reuptake are coupled with each other to homeostatically maintain the DA neurotransmission. The purpose of this study was to investigate associations of the DA synthesis capacity with the availabilities of DA transporters and D2 receptors in the striatum of healthy subjects. MethodsFirst, we examined correlations between the DA synthesis capacity and DA transporter availability in the caudate and putamen using PET data with L-[β-11C]DOPA and [18F]FE-PE2I, respectively, acquired from our past dual-tracer studies. Next, we investigated relationships between the DA synthesis capacity and D2 receptor availability employing PET data with L-[β-11C]DOPA and [11C]raclopride, respectively, obtained from other previous dual-tracer assays. ResultsWe found a significant positive correlation between the DA synthesis capacity and DA transporter availability in the putamen, while no significant correlations between the DA synthesis capacity and D2 receptor availability in the striatum. ConclusionThe intimate association of the DA synthesis rate with the presynaptic reuptake of DA indicates homeostatic maintenance of the baseline synaptic DA concentration. In contrast, the total abundance of D2 receptors, which consist of presynaptic autoreceptors and postsynaptic modulatory receptors, may not have an immediate relationship to this regulatory mechanism.

Dopamine transporter is downregulated and its association with chaperone protein Hsc70 is enhanced by activation of dopamine D3 receptor

Synaptic dopamine (DA) concentrations are largely determined by the activities of presynaptic D2 and D3 autoreceptors (D2R and D3R) and DA transporter (DAT). Furthermore, the activity of DAT is regulated by phosphorylation events and protein interactions that affect its surface expression. Because DA autoreceptors and DAT coordinately maintain synaptic DA homeostasis, we hypothesized that D3R might crosstalk with DAT to fine-tune synaptic DA concentrations. To test this hypothesis, we established [3H]DA uptake and DAT surface expression assays in hD3/rDAT-double-transfected HEK-293 cells or limbic forebrain synaptosomal preparations. Ropinirole, a preferential D3R agonist, reduced [3H]DA uptake in HEK-hD3/rDAT cells in a dose-dependent manner, an effect which could be blocked by the D2R/D3R antagonist, raclopride. Furthermore, ropinirole also reduced DAT surface expression in limbic forebrain synaptosomes, and this effect could be blocked by raclopride or the internalization inhibitor, concanavalin A. To identify potential mediators of this apparent D3R-DAT crosstalk, DAT-associated proteins were co-immunoprecipitated from limbic forebrain synaptosomes after D3R activation and identified by MALDI-TOF. From this analysis, the Hsc70 chaperone was identified as a DAT-associated protein. Interestingly, ropinirole induced the association of Hsc70/Hsp70 with DAT, and the Hsc70/Hsp70 inhibitor, apoptozole, prevented the ropinirole-induced reduction of DAT surface expression. Together, these results suggest that D3R negatively regulates DAT activity by promoting the association of DAT and Hsc70/Hsp70.

Methylphenidate Does Not Hypersensitize the Rat Heart to Ischemic Injury

BackgroundMethylphenidate is commonly used for the treatment of attention deficit hyperactivity disorder. The cardiovascular safety of methylphenidate has been a subject of debate with some studies indicating that methylphenidate increases the likelihood of experiencing a myocardial infarction. However, it is unknown whether methylphenidate alters the extent of myocardial injury during an ischemic insult. Previous work demonstrated that a history of methamphetamine exposure increases infarct size and postischemic recovery of contractile function in the ischemic heart in a sex‐dependent manner. Methylphenidate and methamphetamine both increase synaptic concentrations of dopamine and norepinephrine, resulting in enhanced adrenergic and dopaminergic signaling. However, it is unknown whether methylphenidate also hypersensitizes the heart to ischemia. The purpose of this study was to determine whether methylphenidate increases the extent of myocardial injury during an ischemic insult.MethodsMale and female rats were treated with methylphenidate (5 mg/kg/day) or saline for 10 days. Hearts were subjected to a 20 min ischemic insult and 2 hours of reperfusion on a Langendorff isolated heart apparatus on day 11. Cardiac contractile function was monitored via an intraventricular balloon, and myocardial injury was assessed by triphenyltetrazolium chloride staining.ResultsMethylphenidate significantly increased locomotor activity in male and female rats. Male hearts had significantly larger infarcts than female hearts, but methylphenidate had no impact on infarct size or postischemic recovery of contractile function in hearts of either sex.ConclusionThese data indicate that methylphenidate does not increase myocardial sensitivity to ischemic injury.Support or Funding InformationThis work was supported by 1R15HL145546 to BRR.

Management of methylphenidate in adults with ADHD: Benefits and risks

The prevalence of adult ADHD is estimated to 5.3% and is often comorbid with substance use disorder (SUD) . The odds Ratio ranges from 1.5 to 7.9, depending on the substance and the dependence level. Conversely, the prevalence of ADHD among patients with SUD is 10.8%, versus 3.8% for patients without SUD. Methylphenidate (MPH) alleviates ADHD symptoms and is currently considered as a first choice medication. MPH competitively binds and blocks the dopamine (DAT) and norepinephrine (NET) transporters with no or low affinity for the serotonin transporter . This mechanism of action is similar to a cocaine intake, which results in a rapid increase of the synaptic dopamine concentration preferentially in the nucleus accumbens . However, the subjective effects are highly dependent on the rate of input. Oral or IV MPH leads to different effects even when the increase of dopamine concentration is comparable. It is more the change per unit time of the dopamine increase (rapid elevation) that is associated to the perception of euphoria than the increase of dopamine itself . A formulation with a slow rate of delivery will lead to a lower risk of reinforcing effect (euphoria) and abuse than an immediate release formulation. The benefits of MPH in adult ADHD have been demonstrated in open-label prospective studies and in randomized clinical trials. Meanwhile prescribing MPH to patients with comorbid SUD has always been challenging for clinicians. In this presentation, we will address the benefits and pitfalls of using MPH in adults with ADHD comorbid SUD, depending on the type of SUD: amphetamine, cocaine, nicotine, alcohol, cannabis and opiates. Overall, due to the prevalence of ADHD in SUD and to the benefits of MPH observed in this population, and considering the mild or low side effects observed, the response to MPH treatment deserve to be evaluated individually.

Dopamine-sensitive signaling mediators modulate psychostimulant-induced ultrasonic vocalization behavior in rats

The mesolimbic dopamine system plays a major role in psychostimulant-induced ultrasonic vocalization (USV) behavior in rodents. Within this system, psychostimulants elevate synaptic concentrations of dopamine thereby leading to exaggerated activation of postsynaptic dopamine receptors within the D1-like and D2-like subfamilies. Dopamine receptor stimulation activate several transmembrane signaling systems and cognate intracellular mediators; downstream activation of transcription factors then conveys the information from receptor activation to appropriate modulation of cellular and physiologic functions. We previously showed that cocaine-induced USV behavior was associated with enhanced expression of the neurotrophin BDNF. Like cocaine, amphetamine also increases synaptic dopamine levels, albeit primarily through facilitating dopamine release. Therefore, in the present study we investigated whether amphetamine and cocaine similarly activate dopamine-linked signaling cascades to regulate intracellular mediators leading to induction of USV behavior. The results show that amphetamine increased the emission of 50kHz USVs and this effect was blocked by SCH23390, a D1 receptor antagonist. Similar to cocaine, amphetamine increased BDNF protein expression in discrete brain regions, while pretreatment with K252a, a trkB neurotrophin receptor inhibitor, significantly reduced amphetamine-induced USV behavior. Inhibition of cyclic-AMP/PKA signaling with H89 or inhibition of PLC signaling with U73122 significantly blocked both the acute and subchronic amphetamine-induced USV behavior. In contrast, pharmacologic inhibition of either pathway enhanced cocaine-induced USV behavior. Although cocaine and amphetamine similarly modulate neurotrophin expression and USV, the molecular mechanisms by which these psychostimulants differentially activate dopamine receptor subtypes or other monoaminergic systems may be responsible for the distinct aspects of behavioral responses.

Insights into the Modulation of Dopamine Transporter Function by Amphetamine, Orphenadrine, and Cocaine Binding.

Human dopamine (DA) transporter (hDAT) regulates dopaminergic signaling in the central nervous system by maintaining the synaptic concentration of DA at physiological levels, upon reuptake of DA into presynaptic terminals. DA translocation involves the co-transport of two sodium ions and the channeling of a chloride ion, and it is achieved via alternating access between outward-facing (OF) and inward-facing states of DAT. hDAT is a target for addictive drugs, such as cocaine, amphetamine (AMPH), and therapeutic antidepressants. Our recent quantitative systems pharmacology study suggested that orphenadrine (ORPH), an anticholinergic agent and anti-Parkinson drug, might be repurposable as a DAT drug. Previous studies have shown that DAT-substrates like AMPH or -blockers like cocaine modulate the function of DAT in different ways. However, the molecular mechanisms of modulation remained elusive due to the lack of structural data on DAT. The newly resolved DAT structure from Drosophila melanogaster opens the way to a deeper understanding of the mechanism and time evolution of DAT–drug/ligand interactions. Using a combination of homology modeling, docking analysis, molecular dynamics simulations, and molecular biology experiments, we performed a comparative study of the binding properties of DA, AMPH, ORPH, and cocaine and their modulation of hDAT function. Simulations demonstrate that binding DA or AMPH drives a structural transition toward a functional form predisposed to translocate the ligand. In contrast, ORPH appears to inhibit DAT function by arresting it in the OF open conformation. The analysis shows that cocaine and ORPH competitively bind DAT, with the binding pose and affinity dependent on the conformational state of DAT. Further assays show that the effect of ORPH on DAT uptake and endocytosis is comparable to that of cocaine.

Striatal tyrosine hydroxylase-positive neurons are associated with l-DOPA-induced dyskinesia in hemiparkinsonian mice

L-3,4-Dihydroxyphenylalanine (L-DOPA) is the therapeutic gold standard in Parkinson’s disease. However, long-term treatment is complicated by the induction of debilitating abnormal involuntary movements termed L-DOPA-induced dyskinesias (LIDs). Until today the underlying mechanisms of LID pathogenesis are not fully understood. The aim of this study was to reveal new factors, which may be involved in the induction of LID. We have focused on the expression of striatal tyrosine hydroxylase-positive (TH+) neurons, which are capable of producing either L-DOPA or dopamine (DA) in target areas of ventral midbrain DAergic neurons.To address this issue, a daily L-DOPA dose was administered over the course of 15days to mice with unilateral 6-hydroxydopamine-induced lesions of the medial forebrain bundle and LIDs were evaluated. Remarkably, the number of striatal TH+ neurons strongly correlated with both induction and severity of LID as well as ΔFosB expression as an established molecular marker for LID. Furthermore, dyskinetic mice showed a marked augmentation of serotonergic fiber innervation in the striatum, enabling the decarboxylation of L-DOPA to DA. Axial, limb and orolingual dyskinesias were predominantly associated with TH+ neurons in the lateral striatum, whereas medially located TH+ neurons triggered locomotive rotations. In contrast, identified accumbal and cortical TH+ cells did not contribute to the generation of LID.Thus, striatal TH+ cells and serotonergic terminals may cooperatively synthesize DA and subsequently contribute to supraphysiological synaptic DA concentrations, an accepted cause in LID pathogenesis.

A microdialysis and behavioural investigation of modafinil in freely moving rats

Modafinil (Provigil®) is an unusual stimulant that is widely used to treat narcolepsy in USA and Europe. It has an enigmatic mechanism of action (see reviews by Minzenberg & Carter, 2008; Heal et al, 2012). Modafinil has stimulant-like effects in humans and animals, but its pharmacology is different from the catecholaminergic stimulants d-amfetamine and methylphenidate. Although modafinil has low micromolar affinity for DAT (Zolkowska et al., 2009; Madras et al., 2006) and no affinity for NET or SERT (Madras et al, 2006; Minzenberg & Carter, 2008), positron emission tomography (PET) experiments have paradoxically revealed that therapeutic doses of modafinil occupy a substantial proportion of striatal DAT sites in the brains of humans (Volkow et al, 2009). Modafinil also decreased [11C]raclopride binding (Volkow et al, 2009), indicating occupancy of DAT sites resulted in increased synaptic concentrations of dopamine.

Serotonergic mechanisms responsible for levodopa-induced dyskinesias in Parkinson’s disease patients

Levodopa-induced dyskinesias (LIDs) are the most common and disabling adverse motor effect of therapy in Parkinson's disease (PD) patients. In this study, we investigated serotonergic mechanisms in LIDs development in PD patients using 11C-DASB PET to evaluate serotonin terminal function and 11C-raclopride PET to evaluate dopamine release. PD patients with LIDs showed relative preservation of serotonergic terminals throughout their disease. Identical levodopa doses induced markedly higher striatal synaptic dopamine concentrations in PD patients with LIDs compared with PD patients with stable responses to levodopa. Oral administration of the serotonin receptor type 1A agonist buspirone prior to levodopa reduced levodopa-evoked striatal synaptic dopamine increases and attenuated LIDs. PD patients with LIDs that exhibited greater decreases in synaptic dopamine after buspirone pretreatment had higher levels of serotonergic terminal functional integrity. Buspirone-associated modulation of dopamine levels was greater in PD patients with mild LIDs compared with those with more severe LIDs. These findings indicate that striatal serotonergic terminals contribute to LIDs pathophysiology via aberrant processing of exogenous levodopa and release of dopamine as false neurotransmitter in the denervated striatum of PD patients with LIDs. Our results also support the development of selective serotonin receptor type 1A agonists for use as antidyskinetic agents in PD.

Pre-pulse inhibition and striatal dopamine in subjects at an ultra-high risk for psychosis

Reduced prepulse inhibition (PPI) of the acoustic startle response is thought to represent a robust biomarker in schizophrenia. Reduced PPI has been demonstrated in subjects at ultra high risk (UHR) for developing psychosis. Imaging studies report disruption of striatal dopaminergic neurotransmission in patients with schizophrenia. First, we compared the PPI of the acoustic startle response in UHR subjects versus healthy controls, to see if we could replicate previous findings of reduced PPI; secondly, we investigated our hypothesis that PPI would be negatively correlated with striatal synaptic dopamine (DA) concentration. We measured the startle reactivity and PPI of the acoustic startle response in 14 UHR subjects, and 14 age- and gender-matched healthy controls. Imaging of 11 UHR subjects and 11 healthy controls was completed by an [(123)I]-IBZM (radiotracer for dopamine D2/3 receptors) SPECT, at baseline and again after DA depletion with alpha-methyl-para-tyrosine (AMPT). The percentage change in striatal [(123)I]-IBZM radiotracer binding potential is a proxy of striatal synaptic DA concentration. UHR subjects showed reduced PPI, compared to control subjects. In both UHR and control subjects, there were no significant correlations between striatal synaptic DA concentration and PPI. We provide further evidence for the hypothesis that these two biomarkers are measuring different aspects of pathophysiology.

Chapter Five - Adenosine Receptors and Dyskinesia in Pathophysiology

First, the recent progress in the pathogenesis of levodopa-induced dyskinesia was described. Serotonin neurons play an important role in conversion from levodopa to dopamine and in the release of converted dopamine into the striatum in the Parkinsonian state. Since serotonin neurons lack buffering effects on synaptic dopamine concentration, the synaptic dopamine markedly fluctuates depending on the fluctuating levodopa concentration in the serum after taking levodopa. The resultant pulsatile stimulation makes the striatal direct-pathway neurons get potential that releases excessive GABA into the output nuclei of the basal ganglia. When levodopa is administered, the stored GABA is released, the output nuclei become hypoactive, and then dyskinesias emerge. Second, effects of adenosine A2A receptor antagonists on dyskinesia were described. It has been demonstrated that the expression of adenosine A2A receptors is increased in Parkinson's disease (PD) patients with dyskinesias, suggesting that blockade of A2A receptors is beneficial for dyskinesias. Preclinical studies have shown that A2A receptor antagonists reduce liability of dyskinesias in PD models. Clinical trials have demonstrated that A2A antagonists increase functional ON-time (ON without troublesome dyskinesia) in PD patients suffering from wearing-off phenomenon, although they may increase dyskinesia in patients with advanced PD.

Striatal dopamine D2/3 receptor binding following dopamine depletion in subjects at Ultra High Risk for psychosis

Altered striatal dopaminergic neurotransmission is thought to be fundamental to schizophrenia. Increased presynaptic dopaminergic activity ([18F]–DOPA PET) may predate the onset of psychotic symptoms and correlates to clinical symptoms in subjects at Ultra High Risk (UHR) for developing psychosis. Postsynaptic dopaminergic neurotransmission has not been investigated yet in UHR patients. We hypothesized that synaptic dopamine concentration would be increased in UHR patients, and that synaptic dopamine concentration would be related to symptom severity. 14 UHR patients and 15 age and IQ matched controls completed an [123I]–IBZM SPECT scan at baseline and again after dopamine depletion with alpha-methyl-para-tyrosine (AMPT). We measured changes in radiotracer binding potential, compared these between UHR patients and controls, and correlated these to symptom severity. The UHR group as a whole did not differ significantly from controls. AMPT significantly reduced symptom severity in the UHR group (p=0.014). Higher synaptic dopamine concentration predicted larger reduction of positive symptoms following depletion in the UHR group (p=0.01). In UHR patients, positive symptoms responded to dopamine depletion, comparable to observations in schizophrenia, suggesting a similar mechanism. Higher synaptic dopamine concentration was associated with more severe positive symptoms and a greater reduction of these symptoms following depletion.

Bupropion Binds in the Middle (M2-9) of the Torpedo Nicotinic Acetylcholine Receptor Ion Channel

Bupropion is clinically prescribed for the treatment of depression (Wellbutrin) and for smoking cessation (Zyban). While there is consensus that the primary mechanism of action involves increased synaptic concentrations of dopamine and norepinephrine via inhibition of the respective reuptake transporters, DAT and NET, there is growing evidence that some of the therapeutic benefits of bupropion may result from non-competitive antagonism of neuronal nicotinic acetylcholine receptors (nAChRs), in particular α4β2 and α3β4 subtypes. To aid in elucidating the mechanism of bupropion action and the development of new therapeutic agents for smoking cessation and depression, our goal is to determine the specific molecular interactions between bupropion and several nAChR subtypes (Torpedo, α4β2, α3β4). We first established that bupropion dose-dependently and reversibly inhibits ACh-induced currents in Xenopus laevis oocytes injected with affinity-purified and lipid-reconstituted Torpedo nAChRs (IC50 0.34 μM). Using a photoreactive analog of bupropion ([125I]-SADU-3-72), we next established that bupropion inhibits the binding of [125I]-SADU-3-72 to the Torpedo nAChR (IC50 closed state, 3.6 μM; desensitized state, 1.2 μM) and that binding to the closed nAChR is fully inhibited by tetracaine (IC50 0.42 μM) consistent with a bupropion/[125I]-SADU-3-72 binding site within the nAChR channel. [125I]-SADU-3-72 photolabeled Torpedo nAChR subunits in an agonist-sensitive and bupropion-inhibitable (specific) manner. Finally for the closed nAChR, we identified sites of specific [125I]-SADU-3-72 labeling within δM2 (δLeu265/δM2-9) and βM2 (βLeu257/βM2-9). In the desensitized state, TCP-inhibitable (specific) labeling was identified within δM2 (δLeu265, δM2-9 with minor labeling of δSer258, δM2-2). Our results establish that bupropion binds in the middle (M2-9) of the Torpedo nAChR channel, with a slightly broader binding locus in the desensitized channel. Currently, studies are underway to identify the site(s) of [125I]-SADU-3-72 labeling in affinity-purified α4β2 and α3β4 nAChRs.

Editorial comments: treatment of motor fluctuations in Parkinson’s disease

This timely debate tries to address a common clinical problem faced by movement disorders specialists. Following the initial impressive improvement gained by dopaminergic medications, many patients develop dyskinesias and fluctuations which are clearly drug related. The pathogenesis of these problems is still unclear, but the most reasonable explanation is that with the ongoing degeneration of dopaminergic pathways in the striatum, the ability of these terminals to regulate or stabilize the synaptic concentration of dopamine is lost. Thus a direct relationship between blood levels and motor effect is reached, leading to insufficient or excessive stimulation of postsynaptic dopamine receptors (Korczyn 1972). Attempts to control the dopaminergic tone by frequent smaller doses are of minor help at best. These pharmacokinetic considerations have led to the development of two methods which allow continuous stable serum levels of dopamine agonists, the apomorphine pump which delivers apomorphine subcutaneously, and the intraduodenal delivery of levodopa (with carbidopa) through a percutaneous enteric gastrostomy (PEG). Both systems have now been used for a number of years and provide significant benefit. Intracranial surgical attempts to control parkinsonian symptoms are much older than these approaches. Ablative surgery at various sites can control tremor, while newer approaches have been developed which can also affect other motor symptoms. The newest target is the subthalamic nucleus, and rather than destructive lesions the modern approach is to stimulate this area. Presumably the electrical stimulation is inhibitory, although the exact neural circuitry which is affected and the mechanism of activity are still far from being fully understood. Early studies in University Hospital, Grenoble, France, have succeeded to overcome the initial reluctance of neurologists to submit their patients to surgery. Over the past two decades, several centers over the world have been able to confirm these results. As both papers mention, there are no head-to-head studies which compare these methods, and it is perhaps not surprising that each center maintains the method in which it gained experience. The specialist facing a patient with motor fluctuations must, therefore, assume that these methods are comparable in their outcome, and thus the decision must be made individually in each case. The indications are similar, but there are differences in contraindications. As both papers stress, the final decision as to the choice of method must rest with the patient. However, the critical recommendation of the specialist must depend on the experience of the teams in the geographical area.In that respect, DBS is significantly more demanding. It requires a dedicated team of neurologists, neurosurgeons, radiologists, psychologists and neurophysiologists to evaluate the patient and perform the surgery. Moreover, the post-operative care may demand adjustment of the current parameter which is usually done by the neurologist. Thus it is clear that only centers with a dedicated team should be allowed to perform the surgical intervention. The Grenoble team depends on electrophysiological identification of the stimulation target. This time and effort consuming procedure is not performed in several other centers, who claim to have equally good results. A. D. Korczyn (&) Tel Aviv, Israel e-mail: amoskor@post.tau.ac.il

Contingent negative variation as a dopaminergic biomarker: evidence from dose-related effects of methylphenidate

RationaleThe basal ganglia play an important role in motor control, which is dependent on dopaminergic input. Preparation of a motor response has been associated with dopamine release in the basal ganglia, and response readiness may therefore serve as a pharmacodynamic marker of dopamine activity.MethodsWe measured response readiness using the amplitude of the contingent negative variation (CNV), a slow negative shift in the electroencephalogram. The CNV is evoked in a paradigm in which a warning stimulus (S1) signals the occurrence of the imperative stimulus (S2) 4 s later, to which the participant has to respond. CNV was assessed in healthy volunteers after administration of placebo or 10, 20 or 40 mg of methylphenidate, a catecholamine re-uptake blocker which primarily enhances the synaptic concentration of dopamine and to a lesser extent also noradrenaline. In addition, participants filled out two visual analogue scales measuring subjective ratings of mood and alertness: Profile of Mood States and Bond and Lader.ResultsMethylphenidate dose dependently increased CNV amplitude and decreased reaction times. Furthermore, participants reported improved mood, feeling more alert, vigorous and content and less angry and tired after methylphenidate.ConclusionsThese results indicate that dopamine availability increases response readiness as measured by the CNV paradigm. The CNV appears to be a good candidate biomarker for assessing changes in dopaminergic function by treatments that either directly or indirectly target the dopaminergic system.

Postsynaptic nigrostriatal dopamine receptors and their role in movement regulation

The article presents the hypothesis that nigrostriatal dopamine may regulate movement by modulation of tone and contraction in skeletal muscles through a concentration-dependent influence on the postsynaptic D1 and D2 receptors on the follow manner: nigrostriatal axons innervate both receptor types within the striatal locus somatotopically responsible for motor control in agonist/antagonist muscle pair around a given joint. D1 receptors interact with lower and D2 receptors with higher dopamine concentrations. Synaptic dopamine concentration increases immediately before movement starts. We hypothesize that increasing dopamine concentrations stimulate first the D1 receptors and reduce muscle tone in the antagonist muscle and than stimulate D2 receptors and induce contraction in the agonist muscle. The preceded muscle tone reduction in the antagonist muscle eases the efficient contraction of the agonist. Our hypothesis is applicable for an explanation of physiological movement regulation, different forms of movement pathology and therapeutic drug effects. Further, this hypothesis provides a theoretical basis for experimental investigation of dopaminergic motor control and development of new strategies for treatment of movement disorders.

A Possible Biological Mechanism for the B Vitamins Altering Behaviour in Attention-Deficit/Hyperactivity Disorder

There is a growing body of recent evidence showing that micronutrients (combinations of minerals, vitamins and amino acids) improve the symptoms of attention-deficit/hyperactivity disorder (ADHD). Dopamine agonists, such as methylphenidate, have long been identified as effective in treating ADHD symptoms, by inhibiting dopamine transporter (DAT) function. This article explores the role that B vitamins might have in the treatment of ADHD symptoms by investigating the structural similarities between B vitamins and methylphenidate. We suggest that the presence of B vitamins and their postulated structure activity relationships (SARs) with dopamine may be responsible for the observed pharmacological effect. This pharmacological activity is likely to be via their competitive binding to the DAT dopamine binding site with a concomitant increase in synaptic dopamine concentration, which in turn might activate the postsynaptic dopamine D2 receptor and thus ameliorate the symptoms ofADHD.Further research is required to assess the validity of the intriguing possibility that B vitamins and methylphenidate share a common neurochemical mechanism of action.

Cocaine, metamfetamine, and MDMA abuse: the role and clinical importance of neuroadaptation

Introduction. This article reviews the role and clinical importance of specific neuroadaptations that may occur following use of cocaine, metamfetamine, and 3,4,methylenedioxymetamfetamine (MDMA). Methods. A literature search was performed using OVID MEDLINE and PubMed for all years to the present date, which identified 250 papers of which 154 were considered relevant. Mechanisms of action of cocaine and metamfetamine. Cocaine and metamfetamine increase central nervous system synaptic dopamine primarily by increasing the release of dopamine into the synapse and binding to the dopamine reuptake transporter, which prevents the reuptake of dopamine from the synapse back into the nerve cell. Synaptic dopamine then stimulates post synaptic receptors. The continued release of dopamine and prevention of reuptake results in a supraphysiological concentration of dopamine, which causes euphoria or a “high.” The greater the concentration of dopamine, the greater the high. Continued supraphysiological concentrations of dopamine and postsynaptic receptor stimulation may cause physiological and anatomical changes (neuroadaptations) in the central nervous system (CNS) synapse that attempt to maintain homeostasis. An example of a dopaminergic neuroadaptation is the decrease in number of post synaptic D2 receptors that occurs when synaptic dopamine concentrations remain supraphysiological. This neuroadaptation attempts to maintain homeostasis, that is, the decreased number of D2 receptors provides fewer receptors to be constantly stimulated by increased synaptic dopamine. Although metamfetamine also increases synaptic dopamine similarly to cocaine, metamfetamine also increases cytoplasmic dopamine, which causes CNS oxidative stress and neurotoxicity. The clinical impact of the oxidative stress is unknown. Mechanisms of action of MDMA. MDMA increases concentrations of synaptic serotonin by increasing the release of serotonin and binding to the serotonin reuptake transporter, preventing the reuptake of serotonin from the synapse back into the nerve cell. An example of a serotonergic neuroadaptation is a decrease in the number of serotonin presynaptic autoreceptors (one of the regulators of synaptic serotonin concentration) to maintain homeostasis. MDMA also causes a decrease in serotonergic biochemical markers and neuronal axotomy in rats and nonhuman primates. Abstinence may allow reinnervation, but the axonal regrowth pattern is abnormal. Whether axotomy and reinnervation also occur in humans is unknown. Pharmacogenomics may play a role in the varied response of the individual to MDMA. Conclusions. Neuroadaptations may be transient or permanent. The duration of drug use or drug concentration needed to cause neuroadaptations is unknown, but some neuroadaptations begin shortly after initiation of drug use and are dependent on variables such as genetics and age at the initiation of use. Understanding the concept of neuroadaptation and some specific neuroadaptations that occur will allow clinicians to better understand the interindividual variability in response to drugs of abuse.