Methylphenidate alters basal ganglia neurotensin systems through dopaminergic mechanisms: a comparison with cocaine treatment

Methylphenidate (MPD) is a psychostimulant widely used to treat behavioral problems such as attention deficit hyperactivity disorder. MPD competitively inhibits the dopamine (DA) transporter. Previous studies demonstrated that stimulants of abuse, such as cocaine (COC) and methamphetamine differentially alter rat brain neurotensin (NT) systems through DA mechanisms. As NT is a neuropeptide primarily associated with the regulation of the nigrostriatal and mesolimbic DA systems, the effect of MPD on NT-like immunoreactivity (NTLI) content in several basal ganglia regions was assessed. MPD, at doses of 2.0 or 10.0 mg/kg, s.c., significantly increased the NTLI contents in dorsal striatum, substantia nigra and globus pallidus; similar increases in NTLI were observed in these areas after administration of COC (30.0 mg/kg, i.p.). No changes in NTLI occurred within the nucleus accumbens, frontal cortex and ventral tegmental area following MPD treatment. In addition, the NTLI changes in basal ganglia regions induced by MPD were prevented when D(1) (SCH 23390) or D(2) (eticlopride) receptor antagonists were coadministered with MPD. MPD treatment also increased dynorphin (DYN) levels in basal ganglia structures. These findings provide evidence that basal ganglia, but not limbic, NT systems are significantly affected by MPD through D(1) and D(2) receptor mechanisms, and these NTLI changes are similar, but not identical to those which occurred with COC administration. In addition, the MPD effects on NT systems are mechanistically distinct from the effects of methamphetamine.     

Action,time and the basal ganglia

The ability to control the speed of movement is compromised in neurological disorders involving the basal ganglia, a set of subcortical cerebral nuclei that receive prominent dopaminergic projections from the midbrain. For example, bradykinesia, slowness of movement, is a major symptom of Parkinson''s disease, whereas rapid tics are observed in patients with Tourette syndrome. Recent experimental work has also implicated dopamine (DA) and the basal ganglia in action timing. Here, I advance the hypothesis that the basal ganglia control the rate of change in kinaesthetic perceptual variables. In particular, the sensorimotor cortico-basal ganglia network implements a feedback circuit for the control of movement velocity. By modulating activity in this network, DA can change the gain of velocity reference signals. The lack of DA thus reduces the output of the velocity control system which specifies the rate of change in body configurations, slowing the transition from one body configuration to another.     

Mephedrone does not damage dopamine nerve endings of the striatum,but enhances the neurotoxicity of methamphetamine,amphetamine, and MDMA

Mephedrone (4‐methylmethcathinone) is a β‐ketoamphetamine stimulant drug of abuse with close structural and mechanistic similarities to methamphetamine. One of the most powerful actions associated with mephedrone is the ability to stimulate dopamine (DA) release and block its re‐uptake through its interaction with the dopamine transporter (DAT). Although mephedrone does not cause toxicity to DA nerve endings, its ability to serve as a DAT blocker could provide protection against methamphetamine‐induced neurotoxicity like other DAT inhibitors. To test this possibility, mice were treated with mephedrone (10, 20, or 40 mg/kg) prior to each injection of a neurotoxic regimen of methamphetamine (four injections of 2.5 or 5.0 mg/kg at 2 h intervals). The integrity of DA nerve endings of the striatum was assessed through measures of DA, DAT, and tyrosine hydroxylase levels. The moderate to severe DA toxicity associated with the different doses of methamphetamine was not prevented by any dose of mephedrone but was, in fact, significantly enhanced. The hyperthermia caused by combined treatment with mephedrone and methamphetamine was the same as seen after either drug alone. Mephedrone also enhanced the neurotoxic effects of amphetamine and 3,4‐methylenedioxymethamphetamine on DA nerve endings. In contrast, nomifensine protected against methamphetamine‐induced neurotoxicity. As mephedrone increases methamphetamine neurotoxicity, the present results suggest that it interacts with the DAT in a manner unlike that of other typical DAT inhibitors. The relatively innocuous effects of mephedrone alone on DA nerve endings mask a potentially dangerous interaction with drugs that are often co‐abused with it, leading to heightened neurotoxicity.     

Manganese exposure is cytotoxic and alters dopaminergic and GABAergic neurons within the basal ganglia

Manganese is an essential nutrient, integral to proper metabolism of amino acids, proteins and lipids. Excessive environmental exposure to manganese can produce extrapyramidal symptoms similar to those observed in Parkinson's disease (PD). We used in vivo and in vitro models to examine cellular and circuitry alterations induced by manganese exposure. Primary mesencephalic cultures were treated with 10–800 μM manganese chloride which resulted in dramatic changes in the neuronal cytoskeleton even at subtoxic concentrations. Using cultures from mice with red fluorescent protein driven by the tyrosine hydroxylase (TH) promoter, we found that dopaminergic neurons were more susceptible to manganese toxicity. To understand the vulnerability of dopaminergic cells to chronic manganese exposure, mice were given i.p. injections of MnCl₂ for 30 days. We observed a 20% reduction in TH-positive neurons in the substantia nigra pars compacta (SNpc) following manganese treatment. Quantification of Nissl bodies revealed a widespread reduction in SNpc cell numbers. Other areas of the basal ganglia were also altered by manganese as evidenced by the loss of glutamic acid decarboxylase 67 in the striatum. These studies suggest that acute manganese exposure induces cytoskeletal dysfunction prior to degeneration and that chronic manganese exposure results in neurochemical dysfunction with overlapping features to PD.     

Towards an executive without a homunculus: computational models of the prefrontal cortex/basal ganglia system

The prefrontal cortex (PFC) has long been thought to serve as an 'executive' that controls the selection of actions and cognitive functions more generally. However, the mechanistic basis of this executive function has not been clearly specified often amounting to a homunculus. This paper reviews recent attempts to deconstruct this homunculus by elucidating the precise computational and neural mechanisms underlying the executive functions of the PFC. The overall approach builds upon existing mechanistic models of the basal ganglia (BG) and frontal systems known to play a critical role in motor control and action selection, where the BG provide a 'Go' versus 'NoGo' modulation of frontal action representations. In our model, the BG modulate working memory representations in prefrontal areas to support more abstract executive functions. We have developed a computational model of this system that is capable of developing human-like performance on working memory and executive control tasks through trial-and-error learning. This learning is based on reinforcement learning mechanisms associated with the midbrain dopaminergic system and its activation via the BG and amygdala. Finally, we briefly describe various empirical tests of this framework.     

Neurotensin and neurotensin receptor 1 mRNA expression in song‐control regions changes during development in male zebra finches

Learned vocalizations are important for communication in some vertebrate taxa. The neural circuitry for the learning and production of vocalizations is well known in songbirds, many of which learn songs initially during a critical period early in life. Dopamine is essential for motor learning, including song learning, and dopamine‐related measures change throughout development in song‐control regions such as HVC, the lateral magnocellular nucleus of the anterior nidopallium (LMAN), Area X, and the robust nucleus of the arcopallium (RA). In mammals, the neuropeptide neurotensin strongly interacts with dopamine signaling. This study investigated a potential role for the neurotensin system in song learning by examining how neurotensin (Nts) and neurotensin receptor 1 (Ntsr1) expression change throughout development. Nts and Ntsr1 mRNA expression was analyzed in song‐control regions of male zebra finches in four stages of the song learning process: pre‐subsong (25 days posthatch; dph), subsong (45 dph), plastic song (60 dph), and crystallized song (130 dph). Nts expression in LMAN during the subsong stage was lower compared to other time points. Ntsr1 expression was highest in HVC, Area X, and RA during the pre‐subsong stage. Opposite and complementary expression patterns for the two genes in song nuclei and across the whole brain suggest distinct roles for regions that produce and receive Nts. The expression changes at crucial time points for song development are similar to changes observed in dopamine studies and suggest Nts may be involved in the process of vocal learning. © 2018 Wiley Periodicals, Inc. Develop Neurobiol 78: 671–686, 2018     

Distinct responses of basal ganglia substance P systems to low and high doses of methamphetamine

Substance P (SP) is a neuropeptide closely associated with basal ganglia dopaminergic neurons. Because some neuropeptide systems in the basal ganglia (i.e. neurotensin and metenkephalin) are differentially affected by treatment with low or high doses of methamphetamine, we determined if basal ganglia SP pathways were also differentially influenced in a dose-dependent manner by this psychostimulant. Employing in vivo microdialysis, it was observed that the low dose (0.5 mg/kg) of methamphetamine increased the extracellular concentration of SP in the substantia nigra, but not in globus pallidus or striatum. In contrast, the high dose (10 mg/kg) of methamphetamine did not increase extracellular SP content in any of these structures. The effect of the low-dose methamphetamine treatment on nigral extracellular SP levels was blocked by pre-treatment with either a D1 or D2 antagonist. In addition, 12 h after similar methamphetamine treatments, a dose-dependent differential response in SP tissue levels occurred in some of the regions examined. When these changes occurred, the low dose of methamphetamine usually reduced, whereas the high dose increased, SP tissue content. This study demonstrated opposite responses of the basal ganglia SP system to low and high doses of methamphetamine and suggested that a combination of dopamine D1 and D2 receptor activity contributed to these effects.     

Mephedrone, an abused psychoactive component of 'bath salts' and methamphetamine congener, does not cause neurotoxicity to dopamine nerve endings of the striatum

Mephedrone (4-methylmethcathinone) is a β-ketoamphetamine with close structural analogy to substituted amphetamines and cathinone derivatives. Abuse of mephedrone has increased dramatically in recent years and has become a significant public health problem in the United States and Europe. Unfortunately, very little information is available on the pharmacological and neurochemical actions of mephedrone. In light of the proven abuse potential of mephedrone and considering its similarity to methamphetamine and methcathinone, it is particularly important to know if mephedrone shares with these agents an ability to cause damage to dopamine nerve endings of the striatum. Accordingly, we treated mice with a binge-like regimen of mephedrone (4 × 20 or 40 mg/kg) and examined the striatum for evidence of neurotoxicity 2 or 7 days after treatment. While mephedrone caused hyperthermia and locomotor stimulation, it did not lower striatal levels of dopamine, tyrosine hydroxylase or the dopamine transporter under any of the treatment conditions used presently. Furthermore, mephedrone did not cause microglial activation in striatum nor did it increase glial fibrillary acidic protein levels. Taken together, these surprising results suggest that mephedrone, despite its numerous mechanistic overlaps with methamphetamine and the cathinone derivatives, does not cause neurotoxicity to dopamine nerve endings of the striatum.     

Contrasting responses by basal ganglia met-enkephalin systems to low and high doses of methamphetamine in a rat model

The influence of methamphetamine (METH) on basal ganglia met-enkephalin (Menk) was studied by determining levels of this peptide in striatal, pallidal and nigral regions after administering a single low (0.5 mg/kg) or high (10 mg/kg) dose of this stimulant. The Menk levels in the striatal and pallidal areas were reduced and increased after the low- and high-dose METH treatments, respectively, 12 h after drug administration in all striatal and pallidal regions examined. The low-dose effect appeared to be principally influenced by increased activation of the dopamine D2-like receptor, while the high-dose effect seemed to result from dominance of D1-like receptor activation. However, both effects required coactivation of D1- and D2-like receptors. For the most part, both low- and high-dose METH-induced changes in Menk tissue content were fully recovered by 24 h. The Menk levels were not significantly altered in the substantia nigra 3-24 h after either METH treatment. Results reported herein indicated that striatal and pallidal Menk pathways respond differently after acute treatment with low or high doses of METH.     

A model of the basal ganglia in voluntary movement and postural reactions

A basal ganglia central pattern generator (CPG) is developed and its role in voluntary movements on the ground and postural reactions on a disturbed platform are studied and analysed by simulation. Biped dynamics and platform kinematics are utilised. The effects of agonist–antagonist muscular co-activation and joint stiffness are formulated. The implementation of the necessary counter-manoeuvres for maintaining balance and postural stability is studied. A control strategy, applicable to large systems, is formulated. The biped manoeuvres and transitions terminate in pre-specified intervals of time. Gravity is included and compensated for. Certain voluntary and postural adjustment strategies are the same but are initiated differently. Further experimental/computational research may identify the central nervous system and sensory paths that lead to the CPG. All actuator forces linearly evolve in time from their original values to their terminal values. There are no central continuous feedback loops present. Monitoring and sensing, however, are ongoing. The counter-manoeuvres are based on learned human-like voluntary movements that are triggered by the disturbance. The required central inputs to the musculoskeletal system are designed in the CPG. A functional structure for the CPG is proposed. The effect of certain disorders and malfunctions of the CPG are studied by simulation.     

Restructuring of basal ganglia circuitry and associated behaviors triggered by low striatal D2 receptor expression: implications for substance use disorders

Dopamine D2 receptors (D2Rs) consistently emerge as a critical substrate for the etiology of some major psychiatric disorders. Indeed, a central theory of substance use disorders (SUDs) postulates that a reduction in D2R levels in the striatum is a determining factor that confers vulnerability to abuse substances. A large number of clinical and preclinical studies strongly support this link between SUDs and D2Rs; however, identifying the mechanism by which low D2Rs facilitate SUDs has been hindered by the complexity of circuit connectivity, the heterogeneity of D2R expression and the multifaceted constellation of phenotypes observed in SUD patient. Animal models are well‐suited for understanding the mechanisms because they allow access to the circuitry and the genetic tools that enable a dissection of the D2R heterogeneity. This review discusses recent findings on the functional role of D2Rs and highlights the distinctive contributions of D2Rs expressed on specific neuronal subpopulations to the behavioral responses to stimulant drugs. A circuit‐wide restructuring of local and long‐range inhibitory connectivity within the basal ganglia is observed in response to manipulation of striatal D2R levels and is accompanied by multiple alterations in dopamine‐dependent behaviors. Collectively, these new findings provide compelling evidence for a critical role of striatal D2Rs in shaping basal ganglia connectivity; even among neurons that do not express D2Rs. These findings from animal models have deep clinical implications for SUD patients with low levels D2R availability where a similar restructuring of basal ganglia circuitry is expected to take place.     

基底节区脑梗塞的神经心理学和听觉事件相关诱发电位的研究

目的：了解基底节区脑梗塞（BGRI）患者发病后记忆力和视空间能力的状况,分析BGRI是否对认知功能产生影响及其特点。方法：通过对21名初发的单侧单灶BGRI及21位年龄、性别、受教育程度相匹配的基本健康志愿者分别进行Rey复杂图形检查（Rey）,临床记忆量表（CMS）、Hospital Anxiety-Depression Scale（HAD）,美国国立卫生研究院卒中量表（NIHSS）、牛津残障量表（OHS）、Barthel指数（BI）及听觉事件相关诱发电位（AERP）的检查。结果：病例组的焦虑及抑郁分值,具有极显著的统计学意义;AERP检查反应时较对照组长,具有显著的统计学意义;在临床记忆量表中,病例组图像自由回忆分测验的量表分和记忆商（MQ）较差,与对照组相比有显著统计学意义。病例组Rey检查中临摹得分、即刻回忆得分和延迟回忆得分与对照组比较无显著性差异。结论：单侧单灶的基底节区脑梗塞可以对执行功能、记忆能力以及情绪造成影响：对视空间功能的影响不大.     

Associative and sensorimotor cortico‐basal ganglia circuit roles in effects of abused drugs

The mammalian forebrain is characterized by the presence of several parallel cortico‐basal ganglia circuits that shape the learning and control of actions. Among these are the associative, limbic and sensorimotor circuits. The function of all of these circuits has now been implicated in responses to drugs of abuse, as well as drug seeking and drug taking. While the limbic circuit has been most widely examined, key roles for the other two circuits in control of goal‐directed and habitual instrumental actions related to drugs of abuse have been shown. In this review we describe the three circuits and effects of acute and chronic drug exposure on circuit physiology. Our main emphasis is on drug actions in dorsal striatal components of the associative and sensorimotor circuits. We then review key findings that have implicated these circuits in drug seeking and taking behaviors, as well as drug use disorders. Finally, we consider different models describing how the three cortico‐basal ganglia circuits become involved in drug‐related behaviors. This topic has implications for drug use disorders and addiction, as treatments that target the balance between the different circuits may be useful for reducing excessive substance use.     

Differential remodeling of subthalamic projections to basal ganglia output nuclei and locomotor deficits in 6-OHDA-induced hemiparkinsonian mice

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Effect of subthalamic nucleus or entopeduncular nucleus lesion on levodopa-induced neurochemical changes within the basal ganglia and on levodopa-induced motor alterations in 6-hydroxydopamine-lesioned rats

Inactivation of the subthalamic nucleus (STN) or the internal segment of the pallidum (GPi)/entopeduncular nucleus (EP) by deep brain stimulation or lesioning alleviates clinical manifestations of Parkinson's disease (PD) as well as reducing the side-effects of levodopa treatment. However, the effects of STN or entopeduncular nucleus (EP) lesion on levodopa-related motor fluctuations and on neurochemical changes induced by levodopa remain largely unknown. The effects of such lesions on levodopa-induced motor alterations were studied in 6-hydroxydopamine (6-OHDA)-lesioned rats and were assessed neurochemically by analyzing the functional activity of the basal ganglia nuclei, using the expression levels of the mRNAs coding for glutamic acid decarboxylase and cytochrome oxidase as molecular markers of neuronal activity. At the striatal level, preproenkephalin (PPE) mRNA levels were analyzed. We found in 6-OHDA-lesioned rats that a unilateral STN or EP lesion ipsilateral to the 6-OHDA lesion had no effect on either the shortening in the duration of the levodopa-induced rotational response or the levodopa-induced biochemical changes in the basal ganglia nuclei. In contrast, overexpression of PPE mRNA due to levodopa treatment was reversed by the STN or EP lesion. Our study thus shows that lesion of the EP or STN may counteract some of the neurochemical changes induced by levodopa treatment within the striatum.     

6-Hydroxydopamine lesions of the medial prefrontal cortex of rats do not affect dopamine metabolism in the basal ganglia at short and long postsurgical intervals

Dopamine (DA) in the medial prefrontal cortex (mPFC) has been implicated in the regulation of subcortical DA function. To further characterize the potential interaction between cortical and subcortical DA systems, the short- and long-term neurochemical consequences of 6-hydroxydopamine (6-OHDA) lesions of the mPFC of rats were investigated in the mPFC and in its subcortical target structures. 4 to 5, 10 to 12 and 32 to 36 days after infusion of 6-OHDA, DA was depleted to a larger extent than noradrenaline and serotonin. No lesion-induced changes of DA and its metabolites were detected in subcortical structures. These results show that prefrontal 6-OHDA lesions produce immediate and long lasting depletions of prefrontal monoamines, especially of DA, without increasing basal DA metabolism in the striatum and nucleus accumbens.     

Striatal CB1 and D2 receptors regulate expression of each other,CRIP1A and delta opioid systems

Although biochemical and physiological evidence suggests a strong interaction between striatal CB₁ cannabinoid (CB₁R) and D₂ dopamine (D₂R) receptors, the mechanisms are poorly understood. We targeted medium spiny neurons of the indirect pathway using shRNA to knockdown either CB₁R or D₂R. Chronic reduction in either receptor resulted in deficits in gene and protein expression for the alternative receptor and concomitantly increased expression of the cannabinoid receptor interacting protein 1a (CRIP1a), suggesting a novel role for CRIP1a in dopaminergic systems. Both CB₁R and D₂R knockdown reduced striatal dopaminergic‐stimulated [³⁵S]GTPγS binding, and D₂R knockdown reduced pallidal WIN55212‐2‐stimulated [³⁵S]GTPγS binding. Decreased D₂R and CB₁R activity was associated with decreased striatal phosphoERK. A decrease in mRNA for opioid peptide precursors pDYN and pENK accompanied knockdown of CB₁Rs or D₂Rs, and over‐expression of CRIP1a. Down‐regulation in opioid peptide mRNAs was followed in time by increased DOR1 but not MOR1 expression, leading to increased [D‐Pen2, D‐Pen5]‐enkephalin‐stimulated [³⁵S]GTPγS binding in the striatum. We conclude that mechanisms intrinsic to striatal medium spiny neurons or extrinsic via the indirect pathway adjust for changes in CB₁R or D₂R levels by modifying the expression and signaling capabilities of the alternative receptor as well as CRIP1a and the DELTA opioid system.