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Following a program of resistance training, there are neural and muscular contributions to the gain in strength. Here, we measured changes in important central motor pathways during strength training in 2 female macaque monkeys. Animals were trained to pull a handle with one arm; weights could be added to increase load. On each day, motor-evoked potentials in upper limb muscles were first measured after stimulation of the primary motor cortex (M1), corticospinal tract (CST), and reticulospinal tract (RST). Monkeys then completed 50 trials with weights progressively increased over 8-9 weeks (final weight ∼6 kg, close to the animal's body weight). Muscle responses to M1 and RST stimulation increased during strength training; there were no increases in CST responses. Changes persisted during a 2 week washout period without weights. After a further 3 months of strength training, an experiment under anesthesia mapped potential responses to CST and RST stimulation in the cervical enlargement of the spinal cord. We distinguished the early axonal volley and later spinal synaptic field potentials, and used the slope of the relationship between these at different stimulus intensities as a measure of spinal input-output gain. Spinal gain was increased on the trained compared with the untrained side of the cord within the intermediate zone and motor nuclei for RST, but not CST, stimulation. We conclude that neural adaptations to strength training involve adaptations in the RST, as well as intracortical circuits within M1. By contrast, there appears to be little contribution from the CST. SIGNIFICANCE STATEMENT We provide the first report of a strength training intervention in nonhuman primates. Our results indicate that strength training is associated with neural adaptations in intracortical and reticulospinal circuits, whereas corticospinal and motoneuronal adaptations are not dominant factors.

Aluminum is a potent neurotoxin used in animal models of neurodegenerative diseases like Alzheimer’s disease (AD), in which oxidative stress mediates tissue pathogenesis in vivo. N-acetyl cysteine (NAC) is a glutathione precursor with reported antioxidant and neuroprotective potentials. Recent therapy for combating AD is known to provide only symptomatic relief thus necessitating the discovery of new drugs and their mechanism of action. This study was aimed to demonstrate the in vivo neuroprotective effect of NAC against aluminum (Al3+)-induced neuro-degeneration in rats (a model for AD). Twenty- five (25) adult male Wistar rats used for this study were divided into 5 groups: Group A = Control, B = Aluminum chloride (200 mg/kg), C = 1000 mg/kg of NAC + Aluminum chloride (200 mg/kg), D = 1000 mg/kg of NAC, E = Aluminum chloride (200 mg/kg) was orally administered daily for 3 weeks and discontinued for one week. Frontal Cortex harvested for histological analysis using Haematoxylin and Eosin stain, Cresyl Fast Violet stain for Nissl granules and Glial fibrillary acidic protein immunohistochemistry specific for astrocytes. Aluminum significantly induced oxidative stress, coupled with marked neurons necrosis, chromatolysis and gliosis in the frontal cortex, upon NAC administration, there was neuro anti-inflammatory response as seen in the significant reduction in astrocytes expression, neuronal cell death and Nissl body aggregation which attenuates neuropathological deficits induced by Al3+. It was shown that aluminum is a neurotoxin mediating AD-like oxidative stress, NAC has a therapeutic potential associated with its potent in vivo interaction with astrocytes in response to Al3+ neuro-inflammation seen in positive expression of Nissl granules and glial cells in addition to possibility of endogenous glutathione neuroprotection after withdrawal of stress mediator in neurodegeneration.

The laminar organization of the motor cortex of the sheep and other large domestic herbivores received scarce attention and is generally considered homologous to that of rodents and primates. Thickness of the cortex, subdivision into layers and organization are scarcely known. In the present study, we applied different modern morphological, mathematical and image-analyses techniques to the study of the motor area that controls movements of the forelimb in the sheep. The thickness of the cortex resulted comparable to that of other terrestrial Cetartiodactyls (but thicker than in marine Cetartiodactyls of similar body mass). The laminar organization showed marked development of layer 1, virtual absence of layer 4, and image analysis suggested prevalence of large irregular neural cells in the deeper layers. Diffusion tensor imaging revealed robust projections from the motor cortex to the pyramids in the brainstem, and well evident tracts descending to the tegmentum of the mesencephalon and dorsal pons. Our data contrast the general representation of the motor system of this species, considered to be predominantly based on extra-pyramidal tracts that originate from central pattern generators in the brainstem. © 2019, Springer-Verlag GmbH Germany, part of Springer Nature.

The caudal fastigial nucleus (FN) is known to be related to the control of eye movements and projects mainly to the contralateral reticular nuclei where excitatory and inhibitory burst neurons for saccades exist [the caudal portion of the nucleus reticularis pontis caudalis (NRPc), and the rostral portion of the nucleus reticularis gigantocellularis (NRG) respectively]. However, the exact reticular neurons targeted by caudal fastigioreticular cells remain unknown. We tried to determine the target reticular neurons of the caudal FN and superior colliculus (SC) by recording intracellular potentials from neurons in the NRPc and NRG of anesthetized cats. Neurons in the rostral NRG received bilateral, monosynaptic excitation from the caudal FNs, with contralateral predominance. They also received strong monosynaptic excitation from the rostral and caudal contralateral SC, and disynaptic excitation from the rostral ipsilateral SC. These reticular neurons with caudal fastigial monosynaptic excitation were not activated antidromically from the contralateral abducens nucleus, but most of them were reticulospinal neurons (RSNs) that were activated antidromically from the cervical cord. RSNs in the caudal NRPc received very weak monosynaptic excitation from only the contralateral caudal FN, and received either monosynaptic excitation only from the contralateral caudal SC, or monosynaptic and disynaptic excitation from the contralateral caudal and ipsilateral rostral SC, respectively. These results suggest that the caudal FN helps to control also head movements via RSNs targeted by the SC, and these RSNs with SC topographic input play different functional roles in head movements.

Repulsive guidance molecule a (RGMa) is a neurite growth inhibitor that is of great interest in the study of CNS neuronal regeneration. We adopted RNA interference (RNAi) as a means of suppressing the expression of RGMa and observed the improvement in axonal regeneration and neurological function of rats after cerebral ischemic injury. Recombinant adenovirus rAd5-shRNA-RGMa was constructed and prepared for animal experimentation. RGMa and neurofilament protein 200 (NF200) in the ischemic cortex and ipsilateral hippocampus were detected by reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. The ischemic regions were examined by triphenyltetrazolium chloride (TTC) staining and the newborn neurite branches by Biotinylated Dextran Amine (BDA) neuronal tracing. Behavior tests were adopted to evaluate neurologic function recovery. Results showed RGMa was down-regulated and axonal growth was improved in the RNAi treated group (P

Manganese (Mn) is an essential element and it acts as a cofactor for a number of enzymatic reactions, including those involved in amino acid, lipid, protein, and carbohydrate metabolism. Excessive exposure to Mn can lead to poisoning, characterized by psychiatric disturbances and an extrapyramidal disorder. Mn-induced neuronal degeneration is associated with alterations in amino acids metabolism. In the present study, we analyzed whole rat brain amino acid content subsequent to four or eight intraperitoneal injections, with 25 mg MnCl₂/kg/day, at 48-h intervals. We noted a significant increase in glycine brain levels after four or eight Mn injections (p 0.05 and p 0.01, respectively) and arginine also after four or eight injections (p 0.001). Significant increases were also noted in brain proline (p 0.01), cysteine (p 0.05), phenylalanine (p 0.01), and tyrosine (p 0.01) levels after eight Mn injections vs. the control group. These findings suggest that Mn-induced alterations in amino acid levels secondary to Mn affect the neurochemical milieu.

Spinal cord injury damaging the rubrospinal tract (RST) interferes with skilled forelimb movement, but identification of the precise role of the RST in this behavior is impeded by the difficulty of surgically isolating the RST from other pathways running within the lateral funiculus (LF). The present study used a skilled reaching task and a behavioral/anatomical dissection method to identify the contribution of the RST to skilled forelimb movement. Rats were trained on the skilled reaching task and subjected to lesions of the LF. Based on histological evaluation, the animals were assigned to large, medium, or small LF lesion size groups. End point and arm/hand/digit movements were subsequently identified for each group. Success was impaired in all groups, but the impairment was not related to lesion size. Frame-by-frame qualitative analysis of the video recordings revealed that large LF lesions abolished the elements of digits close, digits open, arpeggio, grasp, supination 2, and release. Medium LF lesions interfered with a subset of the movement elements that were shown to be affected by the large LF lesions, namely arpeggio and grasp. Only the arpeggio movement was compromised after small LF lesions. The results show that not only does the LF contribute to skilled reaching, but because the RST was likely to have been damaged in all lesion groups, the RST is more involved in hand rotation than in digit use. The results are discussed in relation to the fiber tracts that are likely to be damaged in the different LF lesion groups.

The search for non-narcotic drugs that will enhance the analgesic effects of opiates without enhancing their side effects has included the investigation of psychoactive drugs already approved for other uses. Some research has supported an analgesic effect of risperidone (RIS), an atypical neuroleptic. However, the analysis of the analgesic efficacy of RIS alone or as an adjuvant to morphine (MOR) has not considered the production of adverse motor effects that would limit its usefulness as a treatment for pain. We tested whether low doses of RIS would enhance the analgesic action of opiates without inducing untoward motor effects. The analgesia induced by a range of RIS doses (0.1–1.0 mg/kg, SC) was assessed alone and in combination with MOR (5 mg/kg, IP) in male Long–Evans (hooded) rats using two different algesiometric assays: hotplate and tail-flick test. The presence or absence of ptosis, vacuous chewing, and abnormal stationary postures was recorded to evaluate dyskinetic effects. No dose of RIS alone altered pain threshold. However, the highest dose of RIS, 1.0 mg/kg SC, significantly increased the analgesic effects of MOR. Dyskinetic effects of RIS were dose-dependent and enhanced in RIS + MOR treatment. These results do not support the hypothesis that RIS, alone or in combination with MOR, elevates pain threshold without also inducing motor side effects. These findings suggest caution in the use of RIS as either a primary treatment or opiate adjuvant treatment for pain.

The acetylcholine esterase inhibitor/cholinergic nicotinic receptor (nAChR) allosteric modulator galantamine (Gal) is used against cognitive impairment in Alzheimer's disease. Negative/cognitive and psychotic symptom improvement in schizophrenia by adjunct Gal to antipsychotic drugs (APDs) has been reported. Cognitive symptoms in schizophrenia may involve brain prefrontal hypo-dopaminergia. Experimental data by others indicate nAChR involvement in animal pro-cognitive effects of Gal. The role of nAChRs in antipsychotic effects by Gal has, however, not been elucidated. Using the conditioned avoidance response (CAR) and the catalepsy tests for antipsychotic activity and extrapyramidal side-effect (EPS) liability, respectively, we here investigated the effects of adjunct Gal (1.25 mg/kg) to the typical APD haloperidol (Hal) (0.05 mg/kg), or the atypical APD risperidone (Ris) (0.2 mg/kg), in rats. Adjunct Gal significantly enhanced APD-like effects by low doses of Hal or Ris, but showed a safe EPS liability profile only in combination with Ris. Pretreatment with the muscarinic receptor (mAChR) antagonist scopolamine, but not the nAChR antagonist mecamylamine, completely reversed the enhancing effects of adjunct Gal to Hal treatment, in the CAR test. While the nAChR-modulating properties of Gal probably contribute to pro-cognitive activity, as shown by others, the present data suggest that any contribution to antipsychotic activity by Gal is mediated primarily via mAChRs. This property combination of Gal may offer a unique, favourable therapeutic profile for schizophrenia treatment.

While the era of major advances in understanding and treating parkinsonism seems to be over, steady progress is being made in elucidating physiological and pharmacological aspects of extrapyramidal function. The dramatic impact of levodopa therapy has been followed by the recognition of serious limitations to its long-term use, which provides a continuing stimulus for efforts to analyze the physiological and pharmacological properties of the basal ganglia and substantia nigra. There are reasonable grounds for the hope that this research will lead to significant developments in therapy.

Described the real pyramidal and extrapyramidal neural networks of the mammalian brain, realizing asbehavior, motor control and involved in learning and memory. The algorithm of postsynaptic excitatory glutamatergic synapses plasticity analyzed, which leads to the modification and storage for a long time, the efficiency of synaptic transmission --ong-term potentiation, long-term depression. Analyzed the mechanisms of plasticity allosteric GABAA(-)redcptors. Described the molecular and cellular mechanisms of the trafficking of GABAA(-)receptors and its role in the dynamic modulation of neuronal inhibition. Analyzed molecular and cellular plasticity algorithm of allosteric GABAA(-)receptors. Discussed hypoth-sis update neural networks that is realized on a molecular level with the internalization and recycling mechanism specific GABAA(-)receptor cluster. It is assumed that the process of transfer from the memory stage storage to the stage of working memory. Deactualization of neural network, which is implemented at the molecular level by the mechanism of internalization specific cluster of GABAA(-)receptor, is a pro-ess of transferring from stage of working or random access memory in the storage stage.

The corticospinal and rubrospinal tracts are the predominant tracts for controlling skilled hand function. Injuries to these tracts impair grasping but not gross motor functions such as overground locomotion. The aim of the present study was to determine whether or not, after damage to both the corticospinal and rubrospinal tracts, other spared subcortical motor pathway can mediate the recovery of skilled hand function. Adult rats received a bilateral injury to the corticospinal tract at the level of the medullar pyramids and a bilateral ablation of the rubrospinal axons at C4. One group of rats received, acutely after injury, two injections of chondroitinase-ABC at C7, and starting at 7 days post-injury were enrolled in daily reaching and grasping rehabilitation (CHASE group, n = 5). A second group of rats received analogous injections of ubiquitous penicillinase, and did not undergo rehabilitation (PEN group, n = 5). Compared to rats in the PEN group, CHASE rats gradually recovered the ability to reach and grasp over 42 days after injury. Overground locomotion was mildly affected after injury and both groups followed similar recovery. Since the reticulospinal tract plays a predominant role in motor control, we further investigated whether or not plasticity of this pathway could contribute to the animal’s recovery. Reticulospinal axons were anterogradely traced in both groups of rats. The density of reticulospinal processes in both the normal and ectopic areas of the grey ventral matter of the caudal segments of the cervical spinal cord was greater in the CHASE than PEN group. The results indicate that after damage to spinal tracts that normally mediate the control of reaching and grasping in rats other complementary spinal tracts can acquire the role of those damaged tracts and promote task-specific recovery.

High affinity for serotonin-2A (5-HT(2A)) over dopamine (DA) D(2) receptors is a leading hypothesis for clozapine's favorable therapeutic profile. Recent preclinical studies also indicate that a sufficient antipsychotic effect might be obtained by a combined high 5-HT(2A)/low D(2) receptor blockade. Thus, addition of a 5-HT(2A) receptor antagonist to an ineffective dose of a D(2) receptor antagonist produces a robust antipsychotic-like effect in the conditioned avoidance response (CAR) test. Electrophysiological and biochemical studies also show that 5-HT(2A) receptor antagonists can confer an atypical (clozapine-like) profile on a D(2) receptor antagonist. Improved therapeutic efficacy by adjunctive 5-HT(2A) receptor antagonist treatment to a traditional D(2) receptor blocking regimen has been suggested. However, the ability of 5-HT(2A) receptor blockade to protect against, or ameliorate, parkinsonian symptoms still remains unclear. Using the CAR and the catalepsy (CAT) tests as indices for antipsychotic activity and extrapyramidal side effect (EPS) liability, respectively, the effects of the selective 5-HT(2A) receptor antagonist MDL 100,907 in combination with the DA D(2) receptor antagonists haloperidol or raclopride were studied in rats. Haloperidol (0.025 or 0.1 mg/kg sc, -30 min) produced a dose-dependent suppression of CAR. Pretreatment with MDL 100,907 (0.5, 1.0, or 1.5 mg/kg sc; -60 min) enhanced and prolonged the haloperidol-induced suppression of CAR without escape failures. MDL 100,907 (1 mg/kg sc, -60 min) had no effect on CAT when coadministered with ineffective doses of raclopride. Raclopride (1 mg/kg sc, -30 min) alone produced a submaximal cataleptic response that was significantly enhanced by pretreatment with MDL 100,907. The present results confirm and extend previous results by showing that 5-HT(2A) receptor blockade can enhance the antipsychotic-like effects of a very low dose of a commonly used traditional antipsychotic. 5-HT(2A) receptor blockade does not, however, prevent EPS (CAT). The therapeutic advantage of this combination might, therefore, operate within a fairly narrow window.

Ibogaine is an indolamine found in the West Africa shrub, Tabernanthe iboga, and has been proposed for the treatment of addiction to central nervous system (CNS) stimulants such as cocaine and amphetamine. The mechanism of ibogaine action and its suitability as a treatment for drug addiction still remains unclear. Since previous studies demonstrated differential effects of stimulants of abuse (amphetamines) on neuropeptide systems such as substance P, we examined the impact of ibogaine and cocaine on extrapyramidal (striatum and substantia nigra) and limbic (nucleus accumbens and frontal cortex) substance P-like immunoreactivity. Ibogaine and cocaine treatments altered substance P systems by increasing striatal and nigral substance P-like immunoreactivity concentration 12 h after the last drug treatment. However, substance P-like immunoreactivity content was not significantly increased in nucleus accumbens after treatment with either drug. The ibogaine- and cocaine-induced increases in substance P-like immunoreactivity in striatum and substantia nigra were blocked by coadministration of selective dopamine D(1) receptor antagonist (SCH 23390; R(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4, 5-tetrahydro-1H-3-benzazepine hydrochloride) or dopamine D(2) receptor antagonist (eticlopride; S(-)-3-Chloro-5-ethyl-N-[(1-ethyl-2-pyrrolidinyl)methyl]-6-hydroxy-2- methoxy-benzamide hydrochloride). Most of the responses by substance P systems to ibogaine administration resembled those caused by cocaine, except in cortical tissue where multiple administration of cocaine, but not ibogaine increased substance P-like immunoreactivity. These data suggest that substance P systems may contribute to the effects of ibogaine and cocaine treatment.

Changes in extrapyramidal dopamine (DA) function significantly alter the activity of striatal neurotensin (NT) systems. Specifically, stimulation of DA D-1 or D-2 receptors increases or decreases striatal NT tissue levels, respectively. In contrast, removal of D-2 receptor basal activity with either an antagonist or lesion of the nigrostriatal DA projection increases striatal NT content. To understand better the significance of these changes in the levels of NT peptide, we determined the effects of treatment with the selective D-1 agonist, SKF 82958, alone or in combination with a lesion of the nigrostriatal DA pathway, on the levels of NT mRNA in various regions of the caudate nucleus. Removal of at least 90% of this DA pathway significantly increased NT mRNA in most, but not all, regions throughout the caudate nucleus. In contrast, four, but not one, administrations of SKF 82958 (2 mg kg-1 dose-1) increased NT mRNA levels in principally middle, but not rostral, caudate regions. Lesioning the nigrostriatal DA pathway enhanced the effects of SKF 82958 so that a lower, single dose (1 mg/kg) of this D-1 agonist also increased NT mRNA levels predominantly in the middle caudate sections. These findings demonstrate that DA D-1 receptors profoundly regulate the striatal expression of NT mRNA in a regionally selective fashion, which appears to be unique from that principally influenced by DA D-2 regulation.

Ibogaine (Endabuse) is a psychoactive indole alkaloid found in the West African shrub, Tabernanthe iboga. This drug interrupts cocaine and amphetamine abuse and has been proposed for treatment of addiction to these stimulants. However, the mechanism of action that explains its pharmacological properties is unclear. Since previous studies demonstrated differential effects of psychotomimetic drugs (cocaine and methamphetamine) on neuropeptides such as neurotensin (NT), the present study was designed to determine: (1) the effects of ibogaine on striatal, nigral, cortical, and accumbens neurotensin-like immunoreactivity (NTLI); (2) the effects of selective dopamine antagonists on ibogaine-induced changes in NT concentrations in these brain areas; and (3) the effects of ibogaine pretreatment on cocaine-induced changes in striatal, nigral, cortical and accumbens NTLI content. Ibogaine treatments profoundly affected NT systems by increasing striatal, nigral, and accumbens NTLI content 12 h after the last drug administration. In contrast, NTLI concentrations were not significantly increased in the frontal cortex after ibogaine treatment. The ibogaine-induced increases in NTLI in striatum, nucleus accumbens and substantia nigra were blocked by coadministration of the selective D1 receptor antagonist, SCH 23390. The D2 receptor antagonist, eticlopride, blocked the ibogaine-induced increase in nigral NTLI, but not in striatum and nucleus accumbens. Ibogaine pretreatment significantly blocked the striatal and nigral increases of NTLI resulting from a single cocaine administration. Whereas many of the responses by NT systems to ibogaine resembled those which occur after cocaine, there were also some important differences. These data suggest that NT may contribute to an interaction between ibogaine and the DA system and may participate in the pharmacological actions of this drug.

Classic neuroleptic drugs produce a syndrome of vacuous jaw movements in rats, and this syndrome has been offered as an animal model of early onset extrapyramidal side effects. The atypical antipsychotics do not produce elevations in vacuous jaw movements, or do so only at very high doses. The purpose of the present study was to determine the impact of the putative antipsychotic, amperozide, on vacuous jaw movements in rats. Groups of rats received daily injections of haloperidol (0.2, 0.4, or 0.8 mg/kg), clozapine (2.0, 4.0, 8.0 mg/kg), amperozide (2.0, 4.0, 8.0 mg/kg) or vehicle for 4 weeks. Once per week, rats were observed for the presence of vacuous jaw movements. Haloperidol increased vacuous jaw movements with increasing doses. Clozapine only produced elevations in vacuous jaw movements at the highest dose. In contrast, increasing doses of amperozide resulted in decreasing vacuous jaw movements for this portion of the dose-response curve. This is the first report of the effect of amperozide on vacuous jaw movements and results are discussed in terms of a potentially unique behavioral profile with respect to this behavior.

We have examined the conduction pathways of motor evoked potentials (MEPs) elicited by transcranial magnetic stimulation, and their correlation with locomotor function in rats. MEPs were concomitantly recorded from the spinal cord (sMEPs) and the limb muscles (mMEPs) before and after various spinal tract ablations. Motor function was also examined using an inclined plane test. sMEPs were composed of four negative peaks (N1-N4) and mMEPs of high-voltage, biphasic waves. Ventral funiculus transection reduced the N1-N3 peaks and abolished mMEPs. Contrarily, dorsal funiculus transection including the pyramidal tract did not alter these MEPs. Motor performance on an inclined plane was worse after ventral funiculus transection than after other transections. These findings indicate that, in rats, the N1-N3 peaks of magnetic sMEPs conduct ventral funiculus activity, and that magnetic mMEPs mainly reflect extrapyramidal activities and are correlated with locomotor function.

Evidence indicates that the antipsychotic drug clozapine has a low propensity for the induction of extrapyramidal motor symptoms, and also that clozapine has therapeutic effects in patients with idiopathic Parkinson's disease. Because tacrine-induced tremulous jaw movements in rats have been suggested as a possible model of extrapyramidal motor dysfunctions, including parkinsonian tremor, the present work was undertaken to investigate the effects of clozapine on tremulous jaw movements. Clozapine decreased tacrine-induced tremulous jaw movements in a dose-related manner, with an ED50 of approximately 3.3 mg/kg. In order to determine the relative potency of this effect compared to other behavioral effects of clozapine, suppression of lever pressing was also studied. Clozapine reduced lever pressing in a dose-related manner, with an ED50 of approximately 5.4 mg/kg. This indicates that clozapine suppressed jaw movements at or below the doses required for suppression of lever pressing. In contrast, the typical antipsychotic drug haloperidol failed to suppress tacrine-induced tremulous jaw movements in doses up to 1.0 mg/kg, which is about 11-fold higher than the ED50 for suppression of lever pressing with that drug. Thioridazine and risperidone also suppressed tremulous jaw movements in roughly the same dose range at which lever pressing was reduced. It is possible that the suppression of tacrine-induced tremulous jaw movements by clozapine in rats is related to the unique behavioral and motor effects of clozapine. The ratio of potencies of these effects (i.e., suppression of tremulous jaw movements versus suppression of lever pressing) could be used as a behavioral procedure for assessing clozapine-like activity in novel compounds.

The effect of the antipsychotic drug haloperidol on extracellular neurotensin-like immunoreactivity was investigated by microdialysis and compared with the time-dependent response of tissue neurotensin-like immunoreactivity content in brain structures containing dopamine nerve cell bodies and terminals. A single administration of haloperidol (1 mg/kg) increased the extracellular neurotensin-like immunoreactivity levels in nucleus accumbens as measured by microdialysis, but decreased its extracellular concentration in the caudate regions surrounding the probe. The same treatment increased the tissue content of neurotensin-like immunoreactivity in both the nucleus accumbens core and all caudate regions examined within 24 h after the injection. Interestingly, although the neurotensin-like immunoreactivity concentration in the substantia nigra was not altered by the haloperidol treatment, neurotensin-like immunoreactivity levels decreased significantly in the ventral tegmental area. These findings suggest that varied neurotensin systems are associated with nigrostriatal and mesolimbic dopamine pathways and these systems have different responses to haloperidol. The changes in the release of neurotensin may contribute to altered caudate and accumbens neurotensin-like immunoreactivity tissue content induced by haloperidol treatment, but other factors, such as variation in synthesis also likely influence these effects. Differential actions of haloperidol on neurotensin release might be due to regional differences in dopamine or sigma receptor subtypes associated with the neurotensin-containing neurons.

Recent developments in understanding the pathophysiology of disordered motor control in cerebral palsy are reviewed. In spastic cerebral palsy, evidence for abnormal segmental as well as supraspinal control of motor neuron output exists. Impaired Ia inhibition of antagonist muscles has been suggested but recently contested. Evidence also supports the role of decreased presynaptic inhibition of Ia afferents and decreased nonreciprocal Ib inhibition. Furthermore, early cerebral injury results in reorganization of supraspinal (corticospinal) inputs to motor neuron pools. In extrapyramidal cerebral palsy, injury of basal ganglia or thalamus has been demonstrated. A scheme for understanding the neurochemical circuitry of the extrapyramidal system is discussed. Animal models and certain specific human diseases provide examples of how this circuitry may be disturbed, thereby resulting in an imbalance between the direct and indirect striatal output systems and in impaired motor control. Future studies employing postmortem neurochemical analysis, functional magnetic resonance imaging, and positron emission tomographic scanning may foster progress in this area. (J Child Neurol 1996;11(Suppl 1):S5-S 12).

The pharmacological mechanism underlying metabolic activation of the rat extrapyramidal system by acute cocaine was examined using the quantitative 2-deoxyglucose autoradiographic method. Pretreatment with a selective dopamine D1-like receptor antagonist, SCH 23390, prevented cocaine-induced metabolic activation in the entopeduncular nucleus and substantia nigra pars reticulata in a dose-dependent manner. These results suggest that activity in striatonigral circuits is induced by stimulation of D1-like receptors by dopamine in the presence of acute cocaine.

Contradictory immunohistochemical data have been reported on the localization of N-acetylaspartylglutamate in the rat forebrain, using different carbodiimide fixation protocols and antibody purification methods. In one case, N-acetylaspartylglutamate immunoreactivity was observed in apparent interneurons throughout all allocortical and isocortical regions, suggesting possible colocalization with GABA. In another case, strong immunoreactivity was observed in numerous pyramidal cells in neocortex and hippocampus, suggesting colocalization with glutamate or aspartate. Reconciling these disparate findings is crucial to understanding the role of N-acetylaspartylglutamate in nervous system function. Antibodies to N-acetylaspartylglutamate and a structurally related molecule, N-acetylaspartate, were purified in stages, and their cross-reactivities with protein conjugates of N-acetylaspartylglutamate and N-acetylaspartate were monitored at each stage by solid-phase immunoassay. Reduction of the cross-reactivity of the anti-N-acetylaspartylglutamate antibodies of N-acetylaspartate-protein conjugates to about 1% eliminated significant staining of most pyramidal neurons in the rat forebrain. Utilizing highly purified antibodies, the distributions of N-acetylaspartylglutamate and N-acetylaspartate were examined in several major telencephalic and diencephalic regions of the rat, and were found to be distinct. N-acetylaspartylglutamate-immunoreactivity was observed in specific neuronal populations, including many groups thought to use GABA as a neurotransmitter. Among these were the globus pallidus, ventral pallidum, entopeducular nucleus, thalamic reticular nucleus, and scattered non-pyramidal neurons in all layers of isocortex and allocortex. N-acetylaspartate-immunoreactivity was more broadly distributed than N-acetylaspartylglutamate-immunoreactivity in the rat forebrain, appearing strongest in many pyramidal neurons. Although N-acetylaspartate-immunoreactivity was found in most neurons, it exhibited a great range of intensities between different neuronal types.

Modeling spinal cord injury (SCI) in animals is challenging because an appropriate combination of lesion location, lesion severity and behavioral testing is essential to analyze recovery of motor function. For particular tests such as single pellet reaching, the contribution of individual descending tracts to recovery has been investigated using specific tract ablation or graded lesions. However, it has not been established whether single pellet reaching is sufficiently sensitive for assessing the efficacy of treatments for cervical SCI (e.g., one of the currently most successful treatment approaches: rehabilitative training). To address this issue, we trained adult rats in single pellet reaching before and after a cervical (C4) spinal lesion. Animals with lesions of increasing severity were grouped into categories based on damage to anatomical structures such as the corticospinal tract (CST) and the rubrospinal tract (RST), two descending motor tracts that have been implicated in fine motor control of the forelimb. We related lesion extent to spontaneous recovery and plasticity-promoting post injury training and found that reaching performance was not correlated with lesion size or the extent of CST or RST injury. Interestingly, the dorsolateral quadrant (DLQ) lesion category, in which the unilateral dorsal CST and most of the unilateral RST are lesioned, was the only category that showed a clear effect of plasticity-promoting treatment (i.e., training), indicating its usefulness as a lesion model for this testing paradigm. The DLQ lesion likely strikes a balance between tissue sparing and functional impairment and is, therefore, best suited to maximize the potential to observe treatment effects of plasticity-promoting treatments using single pellet reaching. Because of the specific lesion size that is necessary to observe treatment effects, the single pellet skilled reaching task can be considered a stringent behavioral test and therefore may be useful for predicting translational success of potential treatments. However, due to the variability in the success rate, the labor-intensive nature, and the limited usefulness to test functional outcome of a wide range of lesion severities, we are hesitant to continue to use single pellet reaching to assess the effectiveness of currently available treatments for cervical SCI.

Information on the location of the major spinal cord tracts in the mouse is sparse. We have collected published data on the position of these tracts in the mouse and have used data from other mammals to identify the most likely position of tracts for which there is no mouse data. We have plotted the position of six descending tracts (corticospinal, rubrospinal, medial and lateral vestibulospinal, rostral and caudal reticulospinal) and eight ascending tracts (gracile; cuneate; postsynaptic dorsal columns; dorsolateral, lateral, and anterior spinothalamic; dorsal and ventral spinocerebellar) on diagrams of transverse sections of all mouse spinal cord segments from the first cervical to the third coccygeal segment.

In this study we evaluated the effects of multiple administrations of selective dopamine D1 and D2 receptor agonists and antagonists on striatal, nigral, accumbens, pallidal and cortical neuropeptide Y systems. Treatment with the D1 receptor agonist, SKF 38393, decreased, while that with the D1 receptor antagonist, SCH 23390, increased neuropeptides Y-like immunoreactivity in the globus pallidus and several regions within the caudate-putamen. SCH 23390 did not change accumbens neuropeptide Y-like immunoreactivity levels but SKF 38393 increased neuropeptide Y-like immunoreactivity levels in anterior and decreased neuropeptide Y-like immunoreactivity levels in the posterior nucleus accumbens. Interestingly, reductions in neuropeptide Y-like immunoreactivity content occurred in response to administrations of both D2 receptor agonist, quinpirole, or antagonist, sulpiride, in all identified regions of eacj structure at some time point. These data suggest that the neuropeptide Y systems studied may be regulated by selective activity at postsynaptic or presynaptic dopamine receptors. They further suggest that within structures such as the caudate-putamen and nucleus accumbens are multiple distinct neuropeptide Y systems which are uniquely influenced by dopamine receptors.

The present study investigates the extrapyramidal effects of co-administration of enalapril (angiotensin-converting enzyme inhibitor) or losartan (angiotensin receptor blocker) with haloperidol in mice. Enalapril/losartan (as a suspension in 1% gum acacia) was administered by oral gavage and haloperidol was administered as an intraperitoneal injection to all the animals for seven days. Catalepsy was measured 30 min after the administration of haloperidol (1 mg/kg i.p.) on days 1 and 7. Observations on day 1 constituted the acute study (single dose administration) and observations on day 7, constituted the chronic study (repeated dose administration). Both acute and chronic administration of enalapril/losartan produced an increase in the duration of haloperidol induced catalepsy at the highest dose (20 mg/kg). Enalapril produced a more pronounced increase in the duration of catalepsy as compared to losartan on both acute and chronic administration. Results of our study suggest that co-administration of anti-psychotics and drugs affecting the angiotensin system can lead to an increase in motor side effects and therefore should be used with caution in patients with these co-morbid conditions.

The rodent rubrospinal tract (RST) has been studied extensively to investigate regeneration and remodeling of central nervous system (CNS) axons. Currently no retrograde tracers can specifically label rubrospinal axons and neurons (RSNs). The RST can be anterogradely labeled by injecting tracers into the red nucleus (RN), but accurately locating the RN is a technical challenge. Here we developed a recombinant adenovirus carrying a green fluorescent protein reporter gene (Adv-GFP) which can preferentially, intensely, and bi-directionally label the RST. When Adv-GFP was injected into the second lumbar spinal cord, the GFP was specifically transported throughout the entire RST, with peak labeling seen at 2 weeks post-injection. When Adv-GFP was injected directly into the RN, GFP was anterogradely transported throughout the RST. Following spinal cord injury (SCI), injection of Adv-GFP resulted in visualization of GFP in transected, spared, or sprouted RST axons bi-directionally. Thus Adv-GFP could be used as a novel tool for monitoring and evaluating strategies designed to maximize RST axonal regeneration and remodeling following SCI.

The present study provides data on fresh volumes of 39 anatomically defined brain regions after a 10 min transient forebrain ischemia in the rat. Ischemia was induced by occlusion of the carotid arteries and simultaneous hypotension. After a survival period of 3 months the rats were transcardially perfusion-fixed with Bodian's solution, and the brains processed for paraffin embedding and serially sectioned. The sections were Nissl-stained for delineation of the brain regions. The volume of a brain region was calculated from 8–10 equidistant sections, using the Cavalieri method and corrected for shrinkage of the brain. Fresh volumes were reduced by 27–50% in the layers of the hippocampal CA1 sector, by 40–46% in the substantia nigra, by 19% in the caudate nucleus, by 13% in the subiculum and the cingulate areas 1–3, by 12–14% in the retrosplenial and temporal areas. The results show that determination of fresh volumes is a sensitive method for quantification and localization of ischemic brain damage in the whole brain.

Acrylamide, an occupational neurotoxicant, reduced MAP1 and MAP2 distribution in different regions of rat brain. Different components of the extrapyramidal system (caudate-putamen, globus pallidus, substantia nigra and red nucleus) revealed differential distribution of MAP1 and MAP2 in acrylamide-treated animals. Rats were treated with acrylamide (estimated mean dose: 15 mg/kg/day) for 2 weeks and MAP1 and MAP2 were localized according to Sternberger's peroxidase-anti-peroxidase technique. MAP1 labelled neuronal perikarya and dendrites almost with a similar intensity, but MAP2 immunostaining was more intense in dendrites than neuronal perikarya. Acrylamide caused a near-total loss of MAP1 and MAP2 immunoreactivity in caudate-putamen. Other components of the extrapyramidal system were relatively less affected by acrylamide. These results indicate that caudate-putamen is more susceptible to the action of acrylamide than other components of the extrapyramidal system studied. The depletion of MAP1 and MAP2 immunoreactivity by acrylamide appears to be an early biochemical event preceding peripheral neuropathy. The loss of MAPs immunoreactivity occurs first in dendrites and proceeds toward the perikarya. This study indicates that acrylamide not only causes axonal damage but may also induce dendritic degeneration.

Dose-related effects of clozapine and risperidone on the pattern of brain regional serotonin and dopamine metabolism and on tests related to extrapyramidal functions in rats The present study was designed to evaluate the behavioral and neurochemical profiles of clozapine and risperidone in rats in a dose-dependent manner. Animals injected intraperitoneally (i.p.) with clozapine (2.5, 5.0 and 10.0 mg kg-1) or risperidone (1.0, 2.5 and 5.0 mg kg-1) were sacrificed 1 h later to collect brain samples. Hypolocomotive effects (home cage activity and catalepsy) were successively monitored in each animal after the drug or saline administration. Both drugs significantly (p < 0.01) decreased locomotor activity at high doses and in a dose-dependent manner. Maximum (100%) cataleptic potential was achieved at a high dose (5.0 mg kg-1) of risperidone. Neurochemical estimations were carried out by HPLC with electrochemical detection. Both drugs, at all doses, significantly (p < 0.01) increased the concentration of homovanillic acid (HVA), a metabolite of dopamine (DA), in the striatum. Dihydroxyphenylacetic acid (DOPAC) levels increased in the striatum and decreased in the rest of the brain, particularly in clozapine-injected rats. 5-Hydroxyindoleacetic acid (5-HIAA), the predominant metabolite of serotonin, significantly (p < 0.01) decreased in the striatum. 5-Hydroxytryptamine (5-HT) was significantly (p < 0.01) increased by risperidone and decreased by clozapine in the rest of the brain. Striatal tryptophan (TRP) was significantly (p < 0.01) decreased by risperidone and increased in the rest of the brain. The striatal HVA/DA ratio increased and the 5-HT turnover rate remained unchanged in the rest of the brain. Results suggest that the affinity of the two drugs towards D2/5-HT1A receptors interaction is involved in lower incidence of extrapyramidal side effects. Role of 5-HT1A receptors in the treatment of schizophrenia is discussed.

Bromocriptine and a series of experimental ergoline D2 partial agonists (SDZ-208-911, SDZ-212-327, SDZ-208-912) were evaluated for their interactions with exogenous dopamine (DA, at ED50 = 16 micrograms) stereotaxically injected unilaterally into a limbic (superior-medial nucleus accumbens septi) or extrapyramidal (central corpus striatum) target site in rat brain. Behavioral measures to quantify responses were locomotor arousal induced by DA in accumbens and contralateral head turning with striatum. All agents, given systemically (i.p.), induced dose-dependent inhibition of behavioral responses to DA from both brain sites. In both accumbens and striatum, SDZ-212-327 was most potent and bromocriptine, least; however, bromocriptine was relatively much more potent in accumbens, and SDZ-208-912 somewhat more potent in striatum. These results add to the growing impression that agents with partial agonist actions at central DA receptors can show behaviorally inhibitory effects that may reflect paradoxical antidopaminergic actions against the full, natural agonist of DA receptors and that such effects can be regionally selective.

Haloperidol increases the expression of Fos, the protein product of the proto-oncogene c-fos, in some parts of the central nervous system. Haloperidol also produces catalepsy in rodents and extrapyramidal side effects in humans, both of which are reduced by muscarinic receptor antagonists. In order to gain insight into the neurochemical and neuroanatomical substrates of haloperidol-induced catalepsy we examined the effects of the muscarinic receptor antagonist scopolamine on haloperidol-induced Fos expression in the striatum, nucleus accumbens and lateral septal nucleus. At a dose that reduced the cataleptic effect of haloperidol, scopolamine decreased the neuroleptic-induced Fos expression in the striatum and lateral septal nucleus but not the nucleus accumbens. These results indicate that haloperidol may increase c-fos expression in medium spiny striatal neurons indirectly by enhancing striatal acetylcholine release. They are also consistent with the hypothesis that neuroleptic-induced increases in striatal c-fos expression are predictive of extrapyramidal side effects produced by these compounds.

Little is known about the in vivo function of the GTP-binding protein-coupled "metabotropic" excitatory amino acid (EAA) receptor. In vitro studies on agonist-induced brain phosphoinositide hydrolysis have shown that (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid is a highly selective and efficacious metabotropic EAA agonist. We have recently reported that in vivo unilateral intrastriatal injection of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid induces transient extrapyramidal motor activation that manifests itself as contralateral turning. In this study, we fully characterized the onset of turning behavior following intrastriatal (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid injection and the possible involvement of striatal dopamine neurons in the mediation of this effect. Rats were anesthetized with the short-acting agent halothane to allow for rapid surgical recovery and thus early behavioral measurements. Intrastriatal (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1 mumol/2 microliters) produced an incremental increase in contralateral turning starting at 1 h and plateauing 3-6 h after injection (peak effect, 39.1 +/- 6.7 rotations per 5 min). Dopamine depletion with alpha-methyl-DL-p-tyrosine (250 mg/kg i.p., 80% depletion) resulted in greater than 85% inhibition of (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid-induced contralateral turning. The dopamine antagonist haloperidol (0.3 mg/kg i.p.) produced 48% inhibition of the (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid response. In time course studies, turning behavior correlated with increases in levels of the dopamine metabolites 3,4-dihydroxyphenylacetic acid and homovanillic acid. These results suggest a functional interaction between the metabotropic EAA receptor and the dopaminergic system in the striatum.

The hypothesis that cannabinoids potentiate the motor effects of neuroleptics and produce their abuse potential by stimulating dopaminergic activity was tested by measuring the ability of THC to increase extracellular dopamine concentrations. Male Long-Evans rats were implanted with guide cannulae for the striatum or nucleus accumbens. Fifteen hours prior to testing, removable microdialysis probes were inserted through the guide cannulae. Dialysis samples were collected during resting baseline, after 1.0 mg/kg, 10 mg/kg THC, or vehicle of olive oil with 5% ETOH (by gavage) followed by amphetamine (1.5 mg/kg) or fluphenazine (0.3 mg/kg). THC produced no change in the extracellular concentrations of DA, DOPAC, and HVA, nor in 5-HIAA. THC also had no effect on the enhancement of extracellular DA produced by amphetamine nor on the transient increase in DA, DOPAC, and HVA produced by fluphenazine. There were also no behavioral differences between groups during any of these treatments.

Spinal cord evoked potentials were elicited in cats by transcranial electrical stimulation with electrodes on the vertex and hard palate. Vertex motor evoked potentials (V-MEP) were also recorded. An extracellular microelectrode recording technique was then used to analyze the results by isopotential mapping. The relationship between the distribution of field potentials and the stimulation polarity was studied using the field potential distribution of the V-MEP in the lower thoracic spinal cord that had been represented on the isopotential maps. The first negative wave of the V-MEP showed maximal amplitude distribution in the anterior funiculus, which corresponds to the extrapyramidal tracts. This pattern was seen with both stimulation polarity arrangements: 1) stimulation with the cathode at the vertex and the anode at the hard palate, and 2) stimulation with the anode at the vertex and the cathode at the hard palate. When the cathode was at the vertex, the stimulation threshold was lower, and the response had higher amplitude than when the anode was at the vertex. Recording V-MEPs elicited by vertex cathode stimulation could provide an excellent method of monitoring the extrapyramidal tracts in cats.

The levels of neurotensin-like immunoreactivity (NTLI) and dynorphin-like immunoreactivity (DLI) in the neostriatum, nucleus accumbens and substantia nigra were increased 18 h after a single administration of MDMA (3,4-methylenedioxymethamphetamine, 10 mg/kg). Coadministration of SCH 23390, a dopamine D 1 receptor antagonist, or MK-801, a non-competitive antagonist of the NMDA (N-methyl-D-aspartate) receptor complex, prevented the MDMA-induced increase of NTLI and DLI in all three brain structures while the administration of sulpiride, a dopamine D 2 receptor antagonist, failed to alter the MDMA effects. These findings suggest that MDMM-induced changes in neurotensin and dynorphin involve both the dopaminergic and the glutamatergic systems.

Cervical spinal cord injury (SCI) can severely impair reaching and grasping ability, and several descending systems, including the rubrospinal tract and corticospinal tract, have been implicated in the control of reach-to-grasp movements. The primary aim of this study was to characterize further the forelimb deficits associated with a cervical dorsolateral funiculotomy, which ablates the rubrospinal tract but spares the dorsal and ventral corticospinal tract in the rat. Adult female rats that preferred to use their right forelimb to reach for single pellets received a lesion to the right cervical dorsolateral funiculus between the C3-4 dorsal roots. Gross forelimb motor function was assessed by measuring spontaneous forelimb usage during exploration in a cylinder, and fine motor function was assessed using staircase and single pellet reaching tests. Single pellet reaching was further evaluated by qualitative and quantitative kinematic scoring of the movement components. Histological analysis included the quantification of spared white matter. Cervical dorsolateral funiculotomy produced marked deficits in reaching performance on both the single pellet and staircase reaching tests, with transient deficits in gross forelimb usage in the cylinder. Quantitative kinematics also revealed a reduction in digit abduction during the reach, which persisted throughout the 8-week post-SCI period. Tests of reach-to-grasp function, therefore, were more sensitive than a test of gross forelimb usage after cervical dorsolateral funiculotomy and did not show recovery over the 8-week survival period. We suggest that the staircase test is a useful screening tool for intervention studies because of its ease of implementation, and that the single pellet test is valuable for examining reaching accuracy and detailed kinematics.

Neuropeptides are linked to the psychopathology of stimulants of abuse, principally through dopamine mechanisms. Substance P (SP) is one of these neuropeptides and is associated with both limbic and extrapyramidal dopaminergic pathways and likely contributes to the pharmacology of these stimulants. The effects of nicotine on these dopamine systems have also been extensively studied; however, its effects on the associated SP pathways have received little attention. In the present study, we elucidated the effects of nicotine treatment on limbic and extrapyramidal SP systems by measuring changes in associated SP tissue concentrations. Male Sprague–Dawley rats received (±)nicotine 4.0 mg/kg/day (0.8 mg/kg, intraperitoneally; five injections at 2-h intervals) in the presence or absence of selective dopamine D1 and D2 receptor antagonists or a nonselective nicotinic acetylcholine receptor antagonist. The nicotine treatment significantly but temporarily decreased substance P-like immunoreactivity (SPLI) content in the ventral tegmental area (VTA) and substantia nigra 12–18 h after drug exposure. The nicotine-mediated changes in SPLI were selectively blocked by pretreatment with mecamylamine as well as a dopamine D1, D2, or both receptor antagonists. Other brain areas that also selectively demonstrated nicotine-related declines in SPLI content included prefrontal cortex, the nucleus accumbens shell, and the very posterior caudate. These findings indicate that some limbic and basal ganglia SP systems are significantly affected by exposure to nicotine through processes mediated by nicotinic and dopaminergic receptors, suggesting a role for SP pathways in nicotine’s limbic and extrapyramidal effects.

In the feline model of the motor evoked potential (MEP) test, a multiphasic spinal cord signal can be elicited in response to bipolar or transcranial brain stimulation. Previous studies have shown that signals produced by threshold stimulation travel mostly in the corticospinal tract. However, from this study we show that suprathreshold stimulation produces very large amplitude MEPs which travel in the ventral funiculus and therefore are most likely associated with extrapyramidal tract activation. The data supporting this conclusion are: (1) apparent conduction velocities of the first two large amplitude peaks are at least 80 m/s with transcranial stimulation; (2) latency of the transcranial MEP at L2 in the cord is less than or equal to 3.50 ms; (3) large amplitude, positive monophasic potentials are recorded in the ventral but not dorsal-lateral funiculus for either bipolar or transcranial MEPs; (4) both bipolar and transcranial MEPs are significantly reduced or abolished by selective lesion of the ventral funiculus. The two tracts which we believe are responsible for mediating the suprathreshold MEP in the cat are the reticulospinal and vestibulospinal tracts. This is significant because suprathreshold MEPs can be used to monitor feline ventral cord function. Furthermore, combining the use of threshold and suprathreshold MEPs may provide a differential diagnostic test for pyramidal vs. extrapyramidal motor function.

Remoxipride blocks dopamine agonist-induced effects in the rat, mediated by dopamine D2 receptors with an in-vivo potency less than that of haloperidol but greater than that of chlorpromazine, thioridazine, and sulpiride. Unlike haloperidol and sulpiride, remoxipride has weaker antagonistic effects towards presynaptic dopamine activity compared to its effects on postsynaptically mediated activity. Remoxipride causes a preferential inhibition of dopamine agonist-induced locomotion as compared to stereotyped behaviour, suggesting that it may exert a preferential blockade of mesolimbic dopamine neurotransmission. The low tendency of remoxipride to cause catalepsy in the rat is indicative of a weak effect on striatal dopamine neurotransmission and predicts a low liability to induce extrapyramidal side effects in man. Remoxipride causes a smaller elevation of prolactin than sulpiride at doses producing central dopamine receptor blockade. The results suggest that remoxipride, unlike haloperidol, can discriminate between different types of dopamine mediated functions probably by having a preferential action on subpopulations of functionally coupled dopamine D2 receptors.

Common flowering quince (FQ) is the fruit of Chaenomeles speciosa (Sweet) Nakai. FQ-containing cocktails have been applied to the treatment of neuralgia, migraine, and depression in traditional Chinese medicine. The present study assessed whether FQ is effective in dopamine transporter (DAT) regulation and antiparkinsonism by utilizing in vitro and in vivo assays, respectively. FQ at concentrations of 1–1000 μg/ml concentration-dependently inhibited dopamine uptake by Chinese hamster ovary (CHO) cells stably expressing DAT (D8 cells) and by synaptosomes. FQ had a slight inhibitory action on norepinephrine uptake by CHO cells expressing the norepinephrine transporter and no inhibitory effect on γ-aminobutyric acid (GABA) uptake by CHO cells expressing GABA transporter-1 or serotonin uptake by the serotonin transporter. A viability assay showed that FQ mitigated 1-methyl-4-phenylpyridinium-induced toxicity in D8 cells. Furthermore, in behavioral studies, FQ alleviated rotational behavior in 6-hydroxydopamine-treated rats and improved deficits in endurance performance in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. Furthermore, immunohistochemistry revealed that FQ markedly reduced the loss of tyrosine hydroxylase-positive neurons in the substantia nigra in MPTP-treated mice. In summary, FQ is a selective, potent DAT inhibitor and has antiparkinsonian-like effects that are mediated possibly by DAT suppression. FQ has the potential to be further developed for Parkinson's disease treatment.

Case Description—4 racehorses were examined because of markedly abnormal behavior following administration of fluphenazine decanoate. Clinical Findings—Clinical signs included restlessness, agitation, profuse sweating, hypermetria, aimless circling, intense pawing and striking with the thoracic limbs, and rhythmic swinging of the head and neck alternating with episodes of severe stupor. Fluphenazine was detected in serum or plasma from all 4 horses. The dose of fluphenazine decanoate administered to 3 of the 4 horses was within the range (25 to 50 mg) routinely administered to adult humans. Treatment and Outcome—In 2 horses, there was no response to IV administration of diphenhydramine hydrochloride, but the abnormal behavior in these 2 horses appeared to resolve following administration of benztropine mesylate, and both horses returned to racing. The other 2 horses responded to diphenhydramine administration. One returned to racing. The other was euthanized because of severe neurologic signs, respiratory failure, and acute renal failure. Clinical Relevance—Findings indicate that adverse extrapyramidal effects may occur in horses given fluphenazine decanoate. These effects appear to be unpredictable and may be severe and life threatening. Use of fluphenazine decanoate as an anxiolytic in performance horses is not permitted in many racing and horse show jurisdictions, and analytic procedures are now available to detect the presence of fluphenazine in serum or plasma.

Neurodegenerative disorders are characterised by cell damage due to accumulation of toxic, pathologic proteins. Mutations in genes coding different cell proteins result in conformational disturbances of the protein structure, their accumulation and aggregation manifested at the level of light microscope as various intracellular inclusions. This paper is an attempt of approach to cellular mechanisms underlying neurodegenerative diseases of the extrapyramidal system with special attention to ubiquitin-proteasome pathway -- the pathway whose discoverers received the 2004 Nobel Prize in chemistry.

The aminoergolines SDZ-208–911, -208–912, and -212–327, weak partial D 2 agonists with agonist/antagonist properties, are proposed as potential atypical antipsychotic agents with limited risk of extrapyramidal effects or hyperprolactinemia. The in vivo effects on dopamine (DA) metabolism in limbic (accumbens) and extrapyramidal (striatum) regions of rat brain were evaluated by measuring the accumulation of l -dihydroxyphenylalanine (DOPA) after inhibiting decarboxylation alone (“open-loop” model) or with added γ-butyrolactone (GBL, autoreceptor model). All three aminoergolines markedly increased DOPA in both regions, dose-dependently, with only minor decreases when GBL was included, and so evidently lack appreciable agonist activity at D 2 -like autoreceptors and resemble typical neuroleptics in stimulating DA synthesis, without regional selectivity.

Among the enteroviruses, polioviruses and enterovirus 71 (EV71) are two major neurotropic viruses causing serious neurological manifestations. While polioviruses are being eradicated globally by vaccination, EV71 still has the potential to cause a large outbreak such as that in Taiwan in 1998, in which there were many fatalities. In this study, we determined the neurovirulence of EV71 by neuropathological analysis of cynomolgus monkeys after experimental infection with five EV71 strains, which were isolated from individual patients with fatal encephalitis; meningitis; and hand, foot, and mouth disease. After intraspinal inoculation, the monkeys developed neurological manifestations within 1-6 days post-inoculation, irrespective of the inoculated strains. These manifestations included not only pyramidal tract signs such as flaccid paralysis, but also extrapyramidal tract signs such as tremor and ataxia. Histological and viral examinations confirmed virus replication in the spinal cord, brainstem, cerebellar cortex, and dentate nuclei, and cerebrum. The strains isolated during the 1970s and 1990s showed no particular differences with respect to neurotropism. Thus, it is clear that EV71 has a wider neurotropism than that of polioviruses.

The effect of manganese (Mn) exposure on the behavior and extrapyramidal system of offspring were studied. Pregnant rats and their offspring in the experimental group were exposed to manganese from drinking water containing 2 g/L (low Mn-exposed group) or 10 g/L (high Mn-exposed group) of MnCl2 respectively. The latent period for running from the center field to any arm of Elevated Plus Arm Maze of both low and high Mn-exposed group was significantly reduced. But the latent period for reaching the platform above the water in Morris Water Maze of the Mn-exposed group was not different from that of control group. There was a significant increase in the areas, glial fibrillary acid protein(GFAP) immunoreactivity and the average proportional densities of GFAP-positive elements in nucleus caudate and accumbens in the high Mn-exposed group, and a significant reduction in the tyrosine hydroxylase immunoreactivity (TH) and average proportional densities of TH-positive elements in substantia nigra, ventral tegmentum area of midbrain and nucleus caudate in the high Mn-exposed group.

Clozapine has superior effects in treating negative symptoms of schizophrenia and causes less extrapyramidal side effects than traditional antipsychotics. In this study, we investigated the effects of acute and long-term clozapine administration on [14C]2-deoxyglucose uptake (2-DG uptake) in rats, as measured using the [14C]2-deoxy-D-glucose method. The 2-DG uptake was reduced in fewer regions after chronic clozapine (46%) than after acute clozapine (97%). After chronic clozapine treatment, the 2-DG uptake was reduced in the shell, but not the core, of the nucleus accumbens. In addition, long-term clozapine treatment remained affecting 2-DG uptake in several regions of the extrapyramidal system and the thalamus. The pattern of 2-DG uptake changes after long-term clozapine administration may provide information for the regions related to the therapeutic effect of clozapine.