Bacillus Calmette-Guerin vaccine-mediated neuroprotection is associated with regulatory T-cell induction in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease.

We previously showed that, in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease (PD), vaccination with bacillus Calmette-Guerin (BCG) prior to MPTP exposure limited the loss of striatal dopamine (DA) and dopamine transporter (DAT) and prevented the activation of nigral microglia. Here, we conducted BCG dose studies and investigated the mechanisms underlying BCG vaccination's neuroprotective effects in this model. We found that a dose of 1 × 10(6) cfu BCG led to higher levels of striatal DA and DAT ligand binding (28% and 42%, respectively) in BCG-vaccinated vs.

Alterations in the striatal dopamine system during intravenous methamphetamine exposure: effects of contingent and noncontingent administration.

The continuing spread of methamphetamine (METH) abuse has stimulated research aimed at understanding consequences of its prolonged exposure. Alterations in nigrostriatal dopamine (DA) system parameters have been characterized in experimental studies after discontinuation of long-term METH but fewer studies have included similar assessments during METH exposure. Here, we report METH plasma pharmacokinetics and striatal DA system alterations in rat after noncontingent and contingent METH administration for 7.

A prototype stimulator system for noninvasive Low Intensity Focused Ultrasound delivery.

A prototype Low Intensity Focused Ultrasound (LIFU) stimulator system was developed to evaluate non-invasive neuromodulation in a large animal model. We conducted a feasibility study on a Göttingen minipig, demonstrating reversible, targeted transcranial neuromodulation. The hypothalamus of the minipig was repeatedly stimulated with LIFU which evoked temporally correlated increases in both heart rate and blood pressure.

Hypothalamic deep brain stimulation reduces weight gain in an obesity-animal model.

Prior studies of appetite regulatory networks, primarily in rodents, have established that targeted electrical stimulation of ventromedial hypothalamus (VMH) can alter food intake patterns and metabolic homeostasis. Consideration of this method for weight modulation in humans with severe overeating disorders and morbid obesity can be further advanced by modeling procedures and assessing endpoints that can provide preclinical data on efficacy and safety. In this study we adapted human deep brain stimulation (DBS) stereotactic methods and instrumentation to demonstrate in a large animal model the modulation of weight gain with VMH-DBS.

BCG vaccine-induced neuroprotection in a mouse model of Parkinson's disease.

There is a growing interest in using vaccination with CNS antigens to induce autoreactive T cell responses that home to damaged areas in the CNS and ameliorate neurodegenerative disease. Neuroprotective vaccine studies have focused on administering oligodendrocyte antigens or Copaxone® in complete Freund's adjuvant (CFA). Theoretical considerations, however, suggest that vaccination with a neuronal antigen may induce more robust neuroprotective immune responses.

Human methamphetamine pharmacokinetics simulated in the rat: behavioral and neurochemical effects of a 72-h binge.

Bingeing is one pattern of high-dose methamphetamine (METH) abuse, which involves continuous drug taking over several days and can result in psychotic behaviors for which the brain pathology remains poorly defined. A corresponding animal model of this type of METH exposure may provide novel insights into the neurochemical and behavioral sequelae associated with this condition. Accordingly, to simulate the pharmacokinetic profile of a human METH binge exposure in rats, we used a computer-controlled, intravenous METH procedure (dynamic infusion, DI) to overcome species differences in METH pharmacokinetics and to replicate the human 12-h plasma METH half-life.

Cyclosporine, a P-glycoprotein modulator, increases [18F]MPPF uptake in rat brain and peripheral tissues: microPET and ex vivo studies.

Purpose: Pretreatment with cyclosporine, a P-glycoprotein (P-gp) modulator increases brain uptake of 4-(2'-methoxyphenyl)-1-[2'-(N-2"-pyridinyl)-p-[(18)F]fluorobenzamido]ethylpiperazine ([(18)F]MPPF) for binding to hydroxytryptamine(1A) (5-HT(1A)) receptors. Those increases were quantified in rat brain with in vivo microPET and ex vivo tissue studies.

Materials And Methods: Each Sprague-Dawley rat (n = 4) received a baseline [(18)F]MPPF microPET scan followed by second scan 2-3 weeks later that included cyclosporine pretreatment (50 mg/kg, i.

Modulation of food intake following deep brain stimulation of the ventromedial hypothalamus in the vervet monkey. Laboratory investigation.

Object: Deep brain stimulation (DBS) has become an effective therapy for an increasing number of brain disorders. Recently demonstrated DBS of the posterior hypothalamus as a safe treatment for chronic intractable cluster headaches has drawn attention to this target, which is involved in the regulation of diverse autonomic functions and feeding behavior through complex integrative mechanisms. In this study, the authors assessed the feasibility of ventromedial hypothalamus (VMH) DBS in freely moving vervet monkeys to modulate food intake as a model for the potential treatment of eating disorders.

Mitochondrial dysfunction, oxidative stress, and apoptosis revealed by proteomic and transcriptomic analyses of the striata in two mouse models of Parkinson's disease.

The molecular mechanisms underlying the changes in the nigrostriatal pathway in Parkinson's disease (PD) are not completely understood. Here, we use mass spectrometry and microarrays to study the proteomic and transcriptomic changes in the striatum of two mouse models of PD, induced by the distinct neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and methamphetamine (METH). Proteomic analyses resulted in the identification and relative quantification of 912 proteins with two or more unique peptides and 86 proteins with significant abundance changes following neurotoxin treatment.

Methamphetamine increases basal ganglia iron to levels observed in aging.

Increases in basal ganglia iron are well documented for neurodegenerative diseases but have not been associated with methamphetamine (METH). In this study, vervet monkeys that received two doses of METH (2 mg/kg, intramuscularly, 6 h apart) showed at 1 month, iron increases in substantia nigra pars reticulata and globus pallidus, with concurrent increases of ferritin-immunoreactivity and decreases of tyrosine hydroxylase-immunoreactivity in substantia nigra. At 1.

Architectonic distribution of the serotonin transporter within the orbitofrontal cortex of the vervet monkey.

To elucidate the organization of the serotoninergic innervation within the orbitofrontal cortex (OFC), serotonin transporter (SERT) density was quantified by autoradiography using [(3)H]cyanoimipramine binding. In six adult vervet monkeys, 15 architectonic areas were delineated according to cytoarchitectonic (Nissl), myeloarchitectonic (Gallyas) and chemoarchitectonic (acetylcholinesterase) criteria to assess SERT distribution at two levels of organization: cortical area and cortical type. For cortical type, the 15 areas were evenly divided into three different categories primarily based upon the degree of granularization of layer IV: agranular, dysgranular, and granular.

Long-term methamphetamine administration in the vervet monkey models aspects of a human exposure: brain neurotoxicity and behavioral profiles.

Methamphetamine (METH)-associated alterations in the human striatal dopamine (DA) system have been identified with positron emission tomography (PET) imaging and post-mortem studies but have not been well correlated with behavioral changes or cumulative METH intake. Animal studies that model some aspects of human long-term METH abuse can establish dose-dependency profiles of both behavioral changes and potential brain neurotoxicities for identifying consequences of particular cumulative exposures. Based on parameters from human and our monkey pharmacokinetic studies, we modeled a prevalent human METH exposure of daily multiple doses in socially housed vervet monkeys.

Methamphetamine blood concentrations in human abusers: application to pharmacokinetic modeling.

Characterization of methamphetamine's (METH) dose-dependent effects on brain neurochemistry may represent a critical component for better understanding the range of resultant behavioral pathologies. Most human studies, however, have assessed only the effects of long term, high dose METH abuse (e.g.

Escalating dose pretreatment induces pharmacodynamic and not pharmacokinetic tolerance to a subsequent high-dose methamphetamine binge.

A major feature of human methamphetamine (METH) abuse is the gradual dose escalation that precedes high-dose exposure. The period of escalating doses (EDs) is likely associated with development of tolerance to aspects of METH's pharmacologic and toxic effects but the relative contributions of pharmacokinetic and pharmacodynamic factors have not been well defined. In our prior studies in rats, we showed that pretreatment with an ED-METH regimen (0.

Endogenously nitrated proteins in mouse brain: links to neurodegenerative disease.

Increased abundance of nitrotyrosine modifications of proteins have been documented in multiple pathologies in a variety of tissue types and play a role in the redox regulation of normal metabolism. To identify proteins sensitive to nitrating conditions in vivo, a comprehensive proteomic data set identifying 7792 proteins from a whole mouse brain, generated by LC/LC-MS/MS analyses, was used to identify nitrated proteins. This analysis resulted in the identification of 31 unique nitrotyrosine sites within 29 different proteins.

Functional stereotactic radiosurgery involving a dedicated linear accelerator and gamma unit: a comparison study.

Object: The purpose of this work was to investigate the targeting and dosimetric characteristics of a linear accelerator (LINAC) system dedicated for stereotactic radiosurgery compared with those of a commercial gamma knife (GK) unit.

Methods: A phantom was rigidly affixed within a Leksell stereotactic frame and axial computerized tomography scans were obtained using an appropriate stereotactic localization device. Treatment plans were performed, film was inserted into a recessed area, and the phantom was positioned and treated according to each treatment plan.

Development and evaluation of an automated atlas-based image analysis method for microPET studies of the rat brain.

An automated method for placement of 3D rat brain atlas-derived volumes of interest (VOIs) onto PET studies has been designed and evaluated. VOIs representing major structures of the rat brain were defined on a set of digitized cryosectioned images of the rat brain. For VOI placement, each PET study was registered with a synthetic PET target constructed from the VOI template.

Radiosurgery performed with the aid of a 3-mm collimator in the subthalamic nucleus and substantia nigra of the vervet monkey.

Object: Radiosurgery for functional neurosurgery performed using a linear accelerator (LINAC) has not been extensively characterized in preclinical studies. In the present study, the properties of a newly designed 3-mm-diameter collimator were evaluated in a dedicated LINAC, which produced lesions in the basal ganglia of vervet monkeys. Lesion formation was determined in vivo in three animals by examining magnetic resonance (MR) images to show the dose-delivery precision of targeting and the geometry and extent of the lesions.

Brain mediation of Anolis social dominance displays. II. Differential forebrain serotonin turnover, and effects of specific 5-HT receptor agonists.

Serotonin (5-HT) functions are associated with social dominance status in diverse species, but to date the brain regions wherein 5-HT exerts such effects are uncertain. Here, we indexed 5-HT turnover in male Anolis carolinensis as the ratio of 5-HT to its metabolite, 5-hydroxy-indol-acetic acid, and also as the accumulation of the in vivo tracer 14C-alpha-methyl-tryptophan (14C-AMT). After patching one eye, displaying dominant animals increased both measures of 5-HT turnover in the forebrain hemisphere receiving display-evocative visual stimuli, compared to control, contralateral brain, whereas both 5-HT turnover indices were decreased when animals displayed submissively.

[(18)F]p-MPPF: aA radiolabeled antagonist for the study of 5-HT(1A) receptors with PET.

This paper summarizes the present status of the researches conducted with [(18)F]4-(2'-methoxyphenyl)-1-[2'-[N-(2"-pyridinyl)-p-fluorobenzamido ]ethyl]-piperazine known as [(18)F]p-MPPF, a new 5-HT(1A) antagonist for the study of the serotonergic neurotransmission with positron emission tomography (PET). This includes chemistry, radiochemistry, animal data (rats, cats, and monkeys) with autoradiography and PET, human data with PET, toxicity, and metabolism.

Regional heterogeneity of dopaminergic deficits in vervet monkey striatum and substantia nigra after methamphetamine exposure.

Methamphetamine (METH)-induced neurotoxicity within the striatum and substantia nigra of the vervet monkey was characterized by heterogeneous decreases in immunoreactivity (IR) for dopamine system phenotypic markers. Decreases in IR for tyrosine hydroxylase (TH), dopamine transporter (DAT), and the vesicular monoamine transporter (VMAT2) were observed 1 week after METH HCI (2x2 mg/kg; 24 h apart). Regional changes throughout the rostrocaudal extent of the striatum were characterized by a gradient of neurotoxic effect (lateral greater than medial) and the preservation of patches of IR.

Recovery from methamphetamine induced long-term nigrostriatal dopaminergic deficits without substantia nigra cell loss.

After administration of methamphetamine (METH) (2x2 mg/kg, 6 h apart) to vervet monkeys, long term but reversible dopaminergic deficits were observed in both in vivo and post-mortem studies. Longitudinal studies using positron emission tomography (PET) with the dopamine transporter (DAT)-binding ligand, [11C]WIN 35,428 (WIN), were used to show decreases in striatal WIN binding of 80% at 1 week and only 10% at 1.5 years.

Long-term methamphetamine-induced decreases of [(11)C]WIN 35,428 binding in striatum are reduced by GDNF: PET studies in the vervet monkey.

The effects of glial cell line-derived neurotrophic factor (GDNF) pretreatment on methamphetamine (METH)-induced striatal dopamine system deficits in the vervet monkey were characterized with [(11)C]WIN 35,428 (WIN)-positron emission tomography (PET). WIN, a cocaine analog that binds to the dopamine transporter (DAT), was used to provide an index of striatal dopamine terminal integrity. In two subjects, GDNF (200 microg/40 microl) was injected into the caudate and putamen unilaterally vs.