Mechanism of action of methylphenidate: insights from PET imaging studies

Methylphenidate (MPH) is the most commonly prescribed drug for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD). We have used Positron Emission Tomography (PET) to investigate the mechanism of action of MPH in the human brain. We have shown (a) that oral MPH reaches peak concentration in the brain 60-90 minutes after its administration, (b) that therapeutic doses of MPH block more than 50% of the dopamine transporters (DAT), and (c) that of the two enantiomers that compose MPH, it is d-threo-methylphenidate (d-MPH) and not l-threo-methylphenidate (l-MPH) that binds to the DAT. We have also shown that therapeutic doses of MPH significantly enhance extracellular dopamine (DA) in the basal ganglia, which is an effect that appears to be modulated by the rate of DA release and that is affected by age (older subjects show less effect). Thus, we postulate (a) that MPH's therapeutic effects are in part due to amplification of DA signals, (b) that variability in responses is in part due to differences in DA tone between subjects, and (c) that MPH's effects are context dependent. Because DA enhances task specific neuronal signaling and decreases noise, we also postulate that MPH-induced increases in DA could improve attention and decrease distractibility; and that since DA modulates motivation, the increases in DA would also enhance the saliency of the task facilitating the 'interest it elicits' and thus improving performance.     

Adrenal medulla graft induced recovery of function in an animal model of Parkinson's disease: possible mechanisms of action

Following unilateral dopamine (DA) denervation of the striatum in animals, there is an asymmetry in the striatal DA system. Animals with such denervations will rotate vigorously when given dopaminergic drugs. Adrenal medulla grafts placed in the lateral ventricle adjacent to a DA-denervated striatum decrease rotational behaviour induced by DA receptor agonists or DA-releasing agents. This discussion reviews research on the use of adrenal medulla grafts to reverse behavioural deficits following DA-denervation of the striatum. Results from basic animal research and from the application of the procedure to patients with Parkinson's disease suggests that at least three different fundamental processes may mediate the functional effects of adrenal medulla grafts: (a) Adrenal medulla grafts may induce changes in the blood-brain barrier; (b) adrenal medulla grafts may induce an increase in serum DA; and (c) adrenal medulla grafts may have a trophic effect on the host brain. Hypotheses are proposed to explain the behavioural effects of adrenal medulla grafts in light of the processes that are thought to mediate their effects.     

Brain catecholamines and memory modulation: effects of footshock, amygdala implantation, and stimulation

The results of previous studies indicate that the extent of a transient decline in brain norepinephrine (NE) levels shortly after training and administration of any of several memory modulating treatments is correlated with later retention performance. The present experiment assessed such changes after one-trial inhibitory (passive) avoidance training and, in addition, measured concentration changes in 3-methoxy-4-hydroxyphenylglycol (MHPG), the major metabolite of brain NE, as well as dopamine (DA) and epinephrine (EPI) levels. The results indicate that the decreases in brain NE after footshock are accompanied by an increase in MHPG, thus providing additional evidence that brain NE is released after training. DA levels were unchanged after training; brainstem EPI levels increased after the training footshock, but forebrain EPI levels were unchanged. A second experiment examined brain catecholamine levels in animals which received post-training electrical stimulation of the amygdala. The findings of this experiment indicate that the amygdala damage which accompanies electrode implantation apparently results in a chronic change in whole brain NE levels and metabolism. After amygdala, NE concentrations in both brainstem and forebrain samples were reduced by 20% and MHPG was increased by 22-34%. Furthermore, NE levels were not responsive to training in implanted animals. Thus, brain NE levels after training were not predictive of retention performance in amygdala-implanted or -stimulated animals. However, the significance of such findings for understanding the possible role of central NE in memory storage is complicated by the severe modification of the dynamics of brain aminergic systems in animals bearing amygdala electrodes.     

The control of responsiveness in ADHD by catecholamines: evidence for dopaminergic, noradrenergic and interactive roles

We explore the neurobiological bases of attention deficit hyperactivity disorder (ADHD) from the viewpoint of the neurochemistry and psychopharmacology of the catecholamine-based behavioural systems. The contributions of dopamine (DA) and noradrenaline (NA) neurotransmission to the motor and cognitive symptoms of ADHD (e.g. hyperactivity, variable and impulsive responses) are studied in rodent and primate models. These models represent elements of the behavioural units observed in subjects with ADHD clinically, or in laboratory settings (e.g. locomotion, changed sensitivity/responsivity to novelty/reinforcement and measures of executive processing). In particular, the models selected emphasize traits that are strongly influenced by mesocorticolimbic DA in the spontaneously hypertensive (SHR) and the Naples high excitability (NHE) rat lines. In this context, the mode of action of methylphenidate treatment is discussed. We also describe current views on the altered control by mesolimbic catecholamines of appropriate and inappropriate goal-directed behaviour, and the tolerance or intolerance of delayed reinforcement in ADHD children and animal models. Recent insights into the previously underestimated role of the NA system in the control of mesocortical DA function, and the frontal role in processing information are elaborated.     

The role of nucleus accumbens dopamine in outcome encoding in instrumental and Pavlovian conditioning

Considerable evidence suggests that dopamine in the core subregion of the nucleus accumbens is not only involved in Pavlovian conditioning but also supports instrumental performance. However, it is largely unknown whether NAc dopamine is required for outcome encoding which plays an important role both in Pavlovian stimulus-outcome learning and instrumental action-outcome learning. Therefore, we tested rats with 6-hydroxydopamine (6-OHDA) induced dopamine depletion of the NAc core for their sensitivity to outcome devaluation in a Pavlovian and an instrumental task. Results indicate that 6-OHDA-lesioned animals were sensitive to outcome devaluation in an instrumental task. This finding provides support to the notion that NAc core dopamine may not be crucial in encoding action-outcome associations. However, during instrumental conditioning lever pressing rates in 6-OHDA-lesioned animals were markedly lower which could reflect an impaired behavioral activation. By contrast, after outcome-specific devaluation in a Pavlovian task, performance in 6-OHDA-lesioned animals was impaired, i.e. their magazine-directed responding was non-selectively reduced. One possibility to explain non-selective responding is that NAc core DA depletion impaired the ability of conditioned stimuli to activate the memory of the current value of the reinforcer.     

Requirement of dopamine signaling in the amygdala and striatum for learning and maintenance of a conditioned avoidance response

Two-way active avoidance (2WAA) involves learning Pavlovian (association of a sound cue with a foot shock) and instrumental (shock avoidance) contingencies. To identify regions where dopamine (DA) is involved in mediating 2WAA, we restored DA signaling in specific brain areas of dopamine-deficient (DD) mice by local reactivation of conditionally inactivated Th genes using viral gene therapy. Among all targeted areas--prefrontal cortex (PFC), amygdala, ventral striatum, dorsal striatum, and whole striatum--only restoration of DA signaling to both the whole striatum together with the amygdala enabled DD mice to acquire 2WAA. However, after prolonged overtraining during which DD mice had DA synthesis systemically reconstituted pharmacologically with L-3,4-dihydroxyphenylalanine (L-Dopa), DA signaling in the striatum alone was sufficient to maintain 2WAA, whereas DA signaling in the PFC together with the amygdala was insufficient to maintain 2WAA. Our results indicate that learning 2WAA requires DA signaling in both the amygdala and the entire striatum; however, after sufficient training, DA signaling in the striatum alone can maintain the learned avoidance behavior.     

Dopamine and cognitive functioning: brain imaging findings in Huntington's disease and normal aging

Recent brain imaging studies in Huntington's disease (HD) and normal aging suggest a relationship between central dopaminergic neurotransmission and cognitive performance. Results demonstrate substantial losses in dopamine (DA) function in both HD and aging. Moreover, HD patients and older adults show deficits across multiple cognitive domains, including episodic memory, speed of processing, and executive functioning. Although few studies are available at present, there is converging evidence that multiple measures of pre- and postsynaptic DA biochemistry are (a) highly interrelated, and (b) strongly associated with the cognitive deficits that accompany HD and aging. There is also emerging evidence that DA neurotransmission influences cognitive performance independent of HD or age. In general, the research reviewed in this article indicates that the nigrostriatal DA system is an important component of a frontostriatal circuitry that is critically involved in cognitive functioning.     

The putative role of free radicals in the loss of neuronal functioning in senescence.

One of the hallmarks of the aging process is a loss of sensitivity in central neuronal receptors to agonist stimulation. This appears to be especially true in central (hippocampal, striatal) muscarinic cholinergic systems and in the striatal dopamine systems. For these two systems, any decline in their sensitivity can be of extreme importance in determining the behavioral capabilities of the organism. Decrements in the striatal dopamine system may be reflected as motor behavioral deficits, while the central cholinergic systems play a major role in the processing of memory through the activation of muscarinic receptors (mAChR). Declines in the function of these receptors appear to be at least partially responsible for the marked deterioration of cognitive function in normal aging and, more notably, in Alzheimer's disease (AD). Previous work has indicated only minimal success in improving performance in tasks that assess memory in senescent animals or humans with pharmacological agents which enhance cholinergic functioning. The present review describes research that indicates that two of the factors involved in this decline in receptor sensitivity include: (a) decreased receptor concentrations and (b) age-related decrements in signal transduction pathways. Studies are reviewed that indicate that the oxidative neural damage that occurs via kainic acid or ionizing radiation parallel those seen in aging. It is suggested that the common mechanism that may exist among all of the age-, disease-, excitatory amino acid- or radiation-induced deficits in neuronal transmission may involve free-radical-mediated alterations in membrane integrity through lipid peroxidation.     

The putative role of free radicals in the loss of neuronal functioning in senescence

One of the hallmarks of the aging process is a loss of sensitivity in central neuronal receptors to agonist stimulation. This appears to be especially true in central (hippocampal, striatal) muscarinic cholinergic systems and in the striatal dopamine systems. For these two systems, any decline in their sensitivity can be of extreme importance in determining the behavioral capabilities of the organism. Decrements in the striatal dopamine system may be reflected as motor behavioral deficits, while the central cholinergic systems play a major role in the processing of memory through the activation of muscarinic receptors (mAChR). Declines in the function of these receptors appear to be at least partially responsible for the marked deterioration of cognitive function in normal aging and, more notably, in Alzheimer’s disease (AD). Previous work has indicated only minimal success in improving performance in tasks that assess memory in senescent animals or humans with pharmacological agents which enhance cholinergic functioning. The present review describes research that indicates that two of the factors involved in this decline in receptor sensitivity include: (a) decreased receptor concentrations and (b) age-related decrements in signal transduction pathways. Studies are reviewed that indicate that the oxidative neural damage that occurs via kainic acid or ionizing radiation parallel those seen in aging. It is suggested that the common mechanism that may exist among all of the age-, disease-, excitatory amino acid- or radiation-induced deficits in neuronal transmission may involve free-radical-mediated alterations in membrane integrity through lipid peroxidation.     

Olfactory adaptation and recovery in man as measured by two psychophysical techniques

Olfactory adaptation and recovery was investigated in man, using two psychophysical procedures: modified category scaling and threshold detection. Both procedures yielded similar qualitative information regarding loss and recovery of olfactory sensitivity as a function of time and concentration of adapting stimuli. However, quantitative differences were observed that could be partially attributed to artifacts inherent in each procedure. Often more than 50% adaptation (and recovery) occurred within the first 2 min with either test procedure. In all experiments the rate of adaptation and recovery was greater at the higher of two adapting concentrations (10 × and 20 × the detection threshold I_t). Recovery occurred more rapidly than adaptation. The usefulness of both techniques is discussed in terms of the overall problem of characterizing the olfactory adaptation and recovery process in man.     

Catecholamine modulation of prefrontal cortical cognitive function

The prefrontal cortex (PFC) utilizes working memory to guide behavior and to release the organism from dependence on environmental cues and is commonly disrupted in neuropsychiatric disorders, normal aging, or exposure to uncontrollable stress. This review posits that the PFC is very sensitive to changes in the neuromodulatory inputs it receives from norepinephrine (NE) and dopamine (DA) systems and that this sensitivity can lead to marked changes in the working-memory functions of the PFC. While NE and DA have important beneficial influences on processing in this area, very high levels of catecholamine release, for example, during exposure to uncontrollable stress, disrupt the cognitive functions of the PFC. This fresh understanding of the neurochemical influences on PFC function has led to new treatments for cognitive disorders such as Attention Deficit Hyperactivity Disorder (ADHD), and may help to elucidate the prevalence of PFC dysfunction in other mental disorders.     

Treadmill gait analysis does not detect motor deficits in animal models of Parkinson's disease or amyotrophic lateral sclerosis

Computerized treadmill gait analysis in models of toxicant exposure and neurodegenerative disorders holds much potential for detection and therapeutic intervention in these models, and researchers must validate the technology that assists in that data collection and analysis. The present authors used a commercially available computerized gait analysis system that used (a) a motorized treadmill on retired breeder male C57BL/6J mice, (b) the toxicant-induced (1-methyl-1-, 2-, 3-, 6-tetrahydropyridine) MPTP mouse model of Parkinson's disease (PD), and (c) the superoxide dismutase 1 (SOD1) G93A transgenic mouse model of amyotrophic lateral sclerosis (ALS). The authors compared the detection of deficits by computerized treadmill gait analysis in MPTP-treated mice with inked-paw stride length and correlated these measures to dopamine (DA) loss. The authors found that the computerized treadmill gait analysis system did not distinguish MPTP-treated mice from vehicle controls, despite a nearly 90% deficit of striatal DA. In contrast, decreases in inked-paw stride length correlated strongly with DA losses in these same animals. Computerized treadmill gait analysis could neither reliably distinguish SOD1 G93A mutant mice from controls from 6 to 12 weeks of age nor detect any consistent early motor deficits in these mice. On the basis of the authors' findings, they inferred that computerized gait analysis on a motorized treadmill is not suited to measuring motor deficits in either the MPTP mouse model of PD or the SOD1 G93A mouse model of ALS.     

Treadmill Gait Analysis Does Not Detect Motor Deficits in Animal Models of Parkinson's Disease or Amyotrophic Lateral Sclerosis

Computerized treadmill gait analysis in models of toxicant exposure and neurodegenerative disorders holds much potential for detection and therapeutic intervention in these models, and researchers must validate the technology that assists in that data collection and analysis. The present authors used a commercially available computerized gait analysis system that used (a) a motorized treadmill on retired breeder male C57BL/6J mice, (b) the toxicant-induced (1-methyl-1-, 2-, 3-, 6-tetrahydropyridine) MPTP mouse model of Parkinson's disease (PD), and (c) the superoxide dismutase 1 (SOD1) G93A transgenic mouse model of amyotrophic lateral sclerosis (ALS). The authors compared the detection of deficits by computerized treadmill gait analysis in MPTP-treated mice with inked-paw stride length and correlated these measures to dopamine (DA) loss. The authors found that the computerized treadmill gait analysis system did not distinguish MPTP-treated mice from vehicle controls, despite a nearly 90% deficit of striatal DA. In contrast, decreases in inked-paw stride length correlated strongly with DA losses in these same animals. Computerized treadmill gait analysis could neither reliably distinguish SOD1 G93A mutant mice from controls from 6 to 12 weeks of age nor detect any consistent early motor deficits in these mice. On the basis of the authors' findings, they inferred that computerized gait analysis on a motorized treadmill is not suited to measuring motor deficits in either the MPTP mouse model of PD or the SOD1 G93A mouse model of ALS.     

Role of dopamine,the frontal cortex and memory circuits in drug addiction: insight from imaging studies

Drug addiction is characterized by a set of recurring processes (intoxication, withdrawal, craving) that lead to the relapsing nature of the disorder. We have used positron emission tomography to investigate in humans the role of dopamine (DA) and the brain circuits it regulates in these processes. We have shown that increases in DA are associated with the subjective reports of drug reinforcement corroborating the relevance of drug-induced DA increases in the rewarding effects of drugs in humans. During withdrawal we have shown in drug abusers significant reductions in DA D2 receptors and in DA release. We postulate that this hypodopaminergic state would result in a decreased sensitivity to natural reinforcers perpetuating the use of the drug as a means to compensate for this deficit and contributing to the anhedonia and dysphoria seen during withdrawal. Because the D2 reductions are associated with decreased activity in the anterior cingulate gyrus and in the orbitofrontal cortex we postulate that this is one of the mechanisms by which DA disruption leads to compulsive drug administration and the lack of control over drug intake in the drug-addicted individual. This is supported by studies showing that during craving these frontal regions become hyperactive in proportion to the intensity of the craving. Craving is also associated with activation of memory circuits including the amygdala (implicated in conditioned learning), hippocampus (implicated in declarative learning), and dorsal striatum (implicated in habit learning) all of which receive DA innervation. We therefore postulate that dopamine contributes to addiction by disrupting the frontal cortical circuits that regulate motivation, drive, and self-control and by memory circuits that increase the motivational salience of the drug and drug-associated stimuli.     

Potential noradrenergic targets for cognitive enhancement in schizophrenia

Substantial evidence suggests that alterations in noradrenergic function contribute to the cognitive impairments of schizophrenia. Activation of post-junctional alpha 2a-adrenergic receptors in the prefrontal cortex by the alpha 2a-selective agonist guanfacine has demonstrated some preliminary benefit in subjects with schizophrenia treated with atypical antipsychotics. alpha 1-adrenergic receptor activity may be less important in mediating the cognitive impairments of schizophrenia. beta-adrenergic receptors may serve as another potential target for cognitive remediation in schizophrenia. However, the potential increase in memory consolidation in schizophrenia patients produced by beta-adrenergic agonists may be outweighed by the impairment in cognitive flexibility and executive functioning produced by beta-adrenergic agonists. Finally, norepinephrine reuptake inhibitors, such as atomoxetine, hold promise as potential cognitive enhancers in schizophrenia because of their ability to indirectly but selectively increase extracellular dopamine concentrations in the prefrontal cortex.     

The association of environmental,individual factors,and dopamine pathway gene variation with smoking cessation

This study aimed to examine whether dopamine (DA) pathway gene variation were associated with smoking cessation, and compare the relative importance of infulence factors on smoking cessation. Participants were recruited from 17 villages of Shandong Province, China. Twenty-five single nucleotide polymorphisms in 8 DA pathway genes were genotyped. Weighted gene score of each gene was used to analyze the whole gene effect. Logistic regression was used to calculate odds ratios (OR) of the total gene score for smoking cessation. Dominance analysis was employed to compare the relative importance of individual, heaviness of smoking, psychological and genetic factors on smoking cessation. 415 successful spontaneous smoking quitters served as the cases, and 404 unsuccessful quitters served as the controls. A significant negative association of total DA pathway gene score and smoking cessation was observed (p < 0.001, OR: 0.25, 95% CI 0.16–0.38). Dominance analysis showed that the most important predictor for smoking cessation was heaviness of smoking score (42%), following by individual (40%), genetic (10%) and psychological score (8%). In conclusion, although the DA pathway gene variation was significantly associated with successful smoking cessation, heaviness of smoking and individual factors had bigger effect than genetic factors on smoking cessation.     

赖氨酰氧化酶在动脉粥样硬化中的作用

赖氨酰氧化酶(lysyl oxidase,LOX)是一种铜依赖性氨基氧化酶,在多个组织器官中均有表达,能参与催化细胞外基质(extracellular matrix,ECM)中胶原和弹性纤维的赖氨酸残基交联,以维持细胞外基质的结构和功能正常。新近研究发现LOX与动脉粥样硬化亦有紧密关系。本文就LOX在动脉粥样硬化发生、发展过程中的联系作一综述。     

Anxiogenic-like effects of gamma-hydroxybutyric acid (GHB) in mice tested in the light-dark box

Gamma-hydroxybutyric acid (GHB) is a drug with abuse potential, popularly known as "liquid ecstasy". It is an endogenous compound of the mammalian brain which satisfies many of the criteria for consideration as a neurotransmitter or neuromodulator. In this study, the effects of acute administration of GHB (40, 80 and 120 mg/kg, ip) on anxiety, tested in the light/dark box, were examined in male mice of the OF.1 strain. Likewise, we compared the behavioural profile of GHB with that induced by mCPP (1 mg/kg, ip), a compound with known anxiogenic actions. GHB-treated mice spent notably less time in the lit area (40 and 80 mg/kg) and more time in the dark area (all doses), whereas the total number of 'rearings', transitions and latency were significantly reduced. A very similar behavioural profile was observed in mCPP-treated animals. Overall, these findings indicate that GHB exhibits anxiogenic-like properties in male mice. It is suggested that the anxiogenic effects of GHB could be related to its ability to modulate GABA and/or dopaminergic receptors.     

Do complex models increase prediction of complex behaviours? Predicting driving ability in people with brain disorders

Prediction of complex behavioural tasks via relatively simple modelling techniques, such as logistic regression and discriminant analysis, often has limited success. We hypothesized that to more accurately model complex behaviour, more complex models, such as kernel-based methods, would be needed. To test this hypothesis, we assessed the value of six modelling approaches for predicting driving ability based on performance on computerized sensory-motor and cognitive tests (SMCTests?) in 501 people with brain disorders. The models included three models previously used to predict driving ability (discriminant analysis, DA; binary logistic regression, BLR; and nonlinear causal resource analysis, NCRA) and three kernel methods (support vector machine, SVM; product kernel density, PK; and kernel product density, KP). At the classification level, two kernel methods were substantially more accurate at classifying on-road pass or fail (SVM 99.6%, PK 99.8%) than the other models (DA 76%, BLR 78%, NCRA 74%, KP 81%). However, accuracy decreased substantially for all of the kernel models when cross-validation techniques were used to estimate prediction of on-road pass or fail in an independent referral group (SVM 73-76%, PK 72-73%, KP 71-72%) but decreased only slightly for DA (74-75%) and BLR (75-76%). Cross-validation of NCRA was not possible. In conclusion, while kernel-based models are successful at modelling complex data at a classification level, this is likely to be due to overfitting of the data, which does not lead to an improvement in accuracy in independent data over and above the accuracy of other less complex modelling techniques.     

Do complex models increase prediction of complex behaviours? Predicting driving ability in people with brain disorders

Prediction of complex behavioural tasks via relatively simple modelling techniques, such as logistic regression and discriminant analysis, often has limited success. We hypothesized that to more accurately model complex behaviour, more complex models, such as kernel-based methods, would be needed. To test this hypothesis, we assessed the value of six modelling approaches for predicting driving ability based on performance on computerized sensory–motor and cognitive tests (SMCTests?) in 501 people with brain disorders. The models included three models previously used to predict driving ability (discriminant analysis, DA; binary logistic regression, BLR; and nonlinear causal resource analysis, NCRA) and three kernel methods (support vector machine, SVM; product kernel density, PK; and kernel product density, KP). At the classification level, two kernel methods were substantially more accurate at classifying on-road pass or fail (SVM 99.6%, PK 99.8%) than the other models (DA 76%, BLR 78%, NCRA 74%, KP 81%). However, accuracy decreased substantially for all of the kernel models when cross-validation techniques were used to estimate prediction of on-road pass or fail in an independent referral group (SVM 73–76%, PK 72–73%, KP 71–72%) but decreased only slightly for DA (74–75%) and BLR (75–76%). Cross-validation of NCRA was not possible. In conclusion, while kernel-based models are successful at modelling complex data at a classification level, this is likely to be due to overfitting of the data, which does not lead to an improvement in accuracy in independent data over and above the accuracy of other less complex modelling techniques.