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Background: NYX-458 is a N-methyl-d-aspartate receptor (NMDAR) modulator that enhances synaptic plasticity. Dopaminergic cell loss in Parkinson's disease (PD) leads to NMDAR dysregulation in the cortico-striato-pallidal-thalmo-cortical network and altered plasticity in brain regions important to cognitive function. We hypothesize that targeting the NMDAR may be an efficacious approach to treating cognitive impairment in PD., Objectives: NYX-458 was evaluated in 2 nonhuman primate models of PD. The first, a chronic low-dose 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-administration model, was used to assess the effects of NYX-458 on cognitive domains impacted early in PD including attention, working memory, executive function, and visuospatial learning. The second, a high-dose MPTP-administration model, was used to assess potential for NYX-458 induced change in motor symptoms., Methods: NYX-458 was evaluated in the chronic low-dose MPTP model using the variable delayed response measure to assess attention and working memory and simple discrimination reversal to assess executive function. NYX-458 was also assessed in the high-dose MPTP model as a monotherapy and in combination with low-dose or high-dose levodopa to assess potential impact on motor symptoms., Results: NYX-458 administration resulted in rapid and long-lasting improvement in cognitive function across the domains of attention, working memory, and executive function. Dose levels effective in improving cognitive performance had no effect on PD motor symptoms, the antiparkinsonian benefit of levodopa, or dyskinesia., Conclusions: NYX-458 provides benefit in specific domains known to be impaired in PD in a dopamine depletion model of PD-like cognitive impairment. These data support the continued evaluation of NYX-458 as a potential therapeutic for cognitive decline in PD. © 2020 International Parkinson and Movement Disorder Society., (© 2020 International Parkinson and Movement Disorder Society.)

Sex differences in the risk for and expression of various brain disorders have been known for some time. Yet, the molecular underpinnings of these sex differences as well as how sex modifies normal brain development are still poorly understood. It has recently become known that epigenetic mechanisms play an essential role in establishing and maintaining sex differences in neurodevelopment and disease susceptibility. Epigenetic mechanisms such as post-translational modifications of histones (histone PTMs) integrate various hormonal and external environmental influences to affect genomic output, and this appears to occur in a sex-dependent manner. The present review aims to highlight current understanding of the role of histone PTMs in the sexual differentiation of the brain under normal conditions and how sex-specific modulation of histone PTMs may be involved in psychiatric conditions including autism spectrum disorder (ASD), schizophrenia, and major depressive disorder (MDD). The role of sex chromosome genes as sex-specific histone modifiers and their importance in sexually differentiating the brain will be discussed. Further, the contribution of sex-specific histone PTM marks in the placenta in programming the sexually dimorphic developmental course of the brain and susceptibility to diseases/disorders will be reviewed. Prenatal programming may have a long-lasting effect on the adult brain and behavior but due to the interaction of histone PTMs and its modifiers with fluctuating hormone levels and external influences over the lifespan, the process remains dynamic. Although a few studies indicate an association between sex and histone PTM-related mechanisms in ASD, schizophrenia, and MDD, more research is needed to fully appreciate the interactive effects of histone PTMs and sex in the development and manifestation of these disorders. Understanding the interactions between sex and histone PTMs will advance our understanding of psychiatric disorders and potentially guide development of future treatments tailored specifically to each sex., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Developmental lead (Pb) exposure results in persistent cognitive/behavioral impairments as well as an elevated risk for developing a variety of diseases in later life. Environmental exposures during development can result in a variety of epigenetic changes, including alterations in DNA methylation, that can influence gene expression patterns and affect the function and development of the nervous system. The present promoter-based methylation microarray profiling study explored the extent to which developmental Pb exposure may modify the methylome of a brain region, hippocampus, known to be sensitive to the effects of Pb exposure. Male and female Long Evans rats were exposed to 0 ppm, 150 ppm, 375 ppm, or 750 ppm Pb through perinatal exposures (gestation through lactation), early postnatal exposures (birth through weaning), or long-term postnatal exposures (birth through postnatal day 55). Results showed a significant contribution of sex to the hippocampal methylome and effects of Pb exposure level, with non-linear dose response effects on methylation. Surprisingly, the developmental period of exposure contributed only a small amount of variance to the overall data and gene ontology (GO) analysis revealed the largest number of overrepresented GO terms in the groups with the lowest level of exposure. The highest number of significant differentially methylated regions was found in females exposed to Pb at the lowest exposure level. Our data reinforce the significant effect that low level Pb exposure may have on gene-specific DNA methylation patterns in brain and that this occurs in a sex-dependent manner., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Over a lifetime, early developmental exposures to neurocognitive risk factors, such as lead (Pb) exposures and prenatal stress (PS), will be followed by multiple varied behavioral experiences. Pb, PS and behavioral experience can each influence brain epigenetic profiles. Our recent studies show a greater level of complexity, however, as all three factors interact within each sex to generate differential adult variation in global post-translational histone modifications (PTHMs), which may result in fundamentally different consequences for life-long learning and behavioral function. We have reported that PTHM profiles differ by sex, brain region and time point of measurement following developmental exposures to Pb±PS, resulting in different profiles for each unique combination of these parameters. Imposing differing behavioral experience following developmental Pb±PS results in additional divergence of PTHM profiles, again in a sex, brain region and time-dependent manner, further increasing complexity. Such findings underscore the need to link highly localized and variable epigenetic changes along single genes to the highly-integrated brain functional connectome that is ultimately responsible for governing behavioral function. Here we advance the idea that increased understanding may be achieved through iterative reductionist and holistic approaches. Implications for experimental design of animal studies of developmental exposures to neurotoxicants include the necessity of a 'no behavioral experience' group, given that epigenetic changes in response to behavioral testing can confound effects of the neurotoxicant itself. They also suggest the potential utility of the inclusion of salient behavioral experiences as a potential effect modifier in epidemiological studies.

Lead (Pb) exposure during development impairs a variety of cognitive, behavioral and neurochemical processes resulting in deficits in learning, memory, attention, impulsivity and executive function. Numerous studies have attempted to model this effect of Pb in rodents, with the majority of studies focusing on hippocampus-associated spatial learning and memory processes. Using a different paradigm, trace fear conditioning, a process requiring coordinated integration of both the medial prefrontal cortex and the hippocampus, we have assessed the effects of Pb exposure on associative learning and memory. The present study examined both female and male long evans rats exposed to three environmentally relevant levels of Pb (150 ppm, 375 ppm and 750 ppm) during different developmental periods: perinatal (PERI; gestation-postnatal day 21), early postnatal (EPN; postnatal days 1-21) and late postnatal (LPN; postnatal days 1-55). Testing began at postnatal day 55 and consisted of a single day of acquisition training, and three post training time points (1, 2 and 10 days) to assess memory consolidation and recall. All animals, regardless of sex, developmental window or level of Pb-exposure, successfully acquired conditioned-unconditioned stimulus association during training. However, there were significant effects of Pb-exposure on consolidation and memory recall at days 1-10 post training. In females, EPN and LPN exposure to 150 ppm Pb (but not PERI exposure) significantly impaired recall. In contrast, only PERI 150 ppm and 750 ppm-exposed males had significant recall deficits. These data suggest a complex interaction between sex, developmental window of exposure and Pb-exposure level on consolidation and recall of associative memories., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Manganese (Mn) is an essential trace metal nutrient, however, excess Mn can be neurotoxic. The degree to which chronic environmental or occupational exposures to Mn in adults cause neuropsychological dysfunction is of considerable interest. Descriptions of neuropsychological dysfunction following chronic Mn exposure have been somewhat inconsistent though, likely owing to different measures of exposure in different populations, complicated by factors of mixed exposures and differences in neuropsychological tests administered. We previously described up-regulation of the mRNA expression for amyloid-beta (A-beta) precursor-like protein 1 (APLP1) and the presence of A-beta diffuse plaques in frontal cortex of Mn-exposed monkeys. The present study examined Mn-induced changes in performance on a paired associate learning (PAL) task that has been suggested as a marker for preclinical Alzheimer's disease. Aspects of performance of this task were affected early following initiation of Mn exposure. Thus, PAL performance may be a sensitive and valuable tool for the early, preclinical detection of incipient dementia and it may also be a sensitive tool for detecting cognitive dysfunction from Mn exposure. The current cognitive data, combined with our previous findings, suggest that frontal cortex may be a particularly sensitive target for the effects of Mn on cognition and that chronic Mn exposure may initiate or accelerate a process that could lead to or predispose to Alzheimer's like pathology and cognitive dysfunction., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Developmental exposure to lead (Pb) has adverse effects on cognitive functioning and behavior that can persist into adulthood. Exposures that occur during fetal or early life periods may produce changes in brain related to physiological re-programming from an epigenetic influence such as altered DNA methylation status. Since DNA methylation is regulated by DNA methyltransferases and methyl cytosine-binding proteins, this study assessed the extent to which developmental Pb exposure might affect expression of these proteins in the hippocampus. Long Evans dams were fed chow with or without added Pb acetate (0, 150, 375, 750 ppm) prior to breeding and remained on the same diet through weaning (perinatal exposure group). Other animals were exposed to the same doses of Pb but exposure started on postnatal day 1 and continued through weaning (early postnatal exposure group). All animals were euthanized on day 55 and hippocampi were removed. Western blot analyses showed significant effects of Pb exposure on DNMT1, DNMT3a, and MeCP2 expression, with effects often seen at the lowest level of exposure and modified by sex and developmental window of Pb exposure. These data suggest potential epigenetic effects of developmental Pb exposure on DNA methylation mediated at least in part through dysregulation of methyltransferases., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

The use of animal models (including the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine [MPTP] mouse model) to mimic dopaminergic (DAergic) cell loss and striatal dopamine (DA) depletion, as seen in Parkinson's disease (PD), has implicated a multitude of factors that might be associated with DAergic cell death in PD including excitotoxicity, inflammation, and oxidative stress. All of these factors have been shown to be reduced by administration of histone deacetylase (HDAC) inhibitors (HDACis) resulting in some degree of neuroprotection in various models of neurodegenerative disease including in Huntington's disease and amyotrophic lateral sclerosis. However, there is limited information of effects of HDACis in PD models. We have previously shown HDACis to be partially protective against 1-methyl-4-phenylpyridinium (MPP(+))-mediated cell loss in vitro. The present study was conducted to extend these findings to an in vivo PD model. The HDACi valproic acid (VPA) was co-administered with MPTP for 5 days to male FVBn mice and continued for an additional 2 weeks, throughout the period of active neurodegeneration associated with MPTP-mediated DAergic cell loss. VPA was able to partially prevent striatal dopamine depletion and almost completely protect against substantia nigra DAergic cell loss. These results suggest that VPA may be a potential disease-modifying therapy for PD., (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.)

While levodopa therapy for Parkinson's disease (PD) may effectively relieve motor symptoms, many of the cognitive deficits experienced by PD patients (and in animal models of PD) are not effectively managed by this treatment. In contrast, previous work has shown positive effects of nicotinic therapies on cognition in PD models. The present study evaluated the effects of levodopa, nicotine and the nicotinic acetylcholine receptor agonist SIB-1553A alone and in combination on cognition in a non-human primate model of early PD. Three adult male Rhesus monkeys, previously administered low doses of the neurotoxin MPTP over several months to produce cognitive deficits, were trained to perform a modified spatial delayed response task in which the attentional demands of the task were manipulated by varying the duration of the cue presentation while keeping the memory demands of the task low and constant. Task performance was assessed after administration of levodopa, nicotine ditartrate, or SIB-1553A and after administration of drug combinations. Animals performed normally when task attentional load was low (i.e., with long cue durations) but performance was significantly impaired on short cue duration trials. Levodopa further impaired performance on short cue duration trials and induced a deficit on long cue duration trials. Nicotine and SIB-1553A improved performance on short cue trials and when co-administered with levodopa, counteracted levodopa-induced deficits. These results confirm that nicotinic therapies may be useful for treating cognitive deficits associated with PD and suggest that negative effects of levodopa on cognition may be amenable to correction with adjunctive nicotinic therapies.

Human exposure to manganese (Mn) has been associated with a variety of cognitive deficits including learning and memory deficits. However, results from epidemiological studies have been inconsistent in describing the nature of such cognitive deficits. The present study was conducted to evaluate the effects of chronic Mn exposure on memory functioning in non-human primates and to correlate behavioral outcome with brain Mn levels in an attempt to explain outcome variability seen in prior studies. Cynomolgus macaque monkeys were trained to perform memory-related tasks (spatial working memory, non-spatial working memory, reference memory) and exposed to manganese sulfate (15-20 mg/kg/week) over an exposure period lasting 227.5+/-17.3 days. Blood manganese levels were in the upper range of levels reported for human environmental, medical or occupational exposures. By the end of the manganese exposure period, animals developed mild deficits in spatial working memory, more significant deficits in non-spatial working memory and no deficits in reference memory. Linear regression analyses showed that for most brain regions sampled, there was a significant inverse relationship between working memory task performance and brain Mn concentration. These results suggest that chronic exposure to levels of manganese achieved in this study may have detrimental effects on working memory and that Mn levels achieved in several brain regions are inversely related to working memory performance.

Transgenic mice in which the tetracycline transactivator (tTA) is driven by the forebrain-specific calcium-calmodulin-dependent kinase II alpha promoter (CaMKII alpha-tTA mice) are used to study the molecular genetics of many behaviors. These mice can be crossed with other transgenic mice carrying a transgene of interest coupled to the tetracycline-responsive promoter element to produce mice with forebrain-specific expression of the transgene under investigation. The value of using CaMKII alpha-tTA mice to study behavior, however, is dependent on the CaMKII alpha-tTA mice themselves lacking a behavioral phenotype with respect to the behaviors being studied. Here we present data that suggest CaMKII alpha-tTA mice have a behavioral phenotype distinct from that of their wild-type (WT) littermates. Most strikingly, we find that CaMKII alpha-tTA mice, both those with a C57BL/6NTac genetic background (B6-tTA) and those with a 129S6B6F1/Tac hybrid genetic background (F1-tTA), exhibit decreased locomotor activity compared with WT littermates that could be misinterpreted as altered anxiety-like behavior. Despite this impairment, neither B6-tTA nor F1-tTA mice perform differently than their WT littermates in two commonly used learning and memory paradigms - Pavlovian fear conditioning and Morris water maze. Additionally, we find data regarding motor coordination and balance to be mixed: B6-tTA mice, but not F1-tTA mice, exhibit impaired performance on the accelerating rotarod and both perform as well as their WT littermates on the balance beam.

Lead is a potent developmental neurotoxicant that affects many aspects of cognition and behavior. The hippocampus and striatum are among the areas particularly sensitive to the effects of lead and cholinergic neurons in both regions depend upon nerve growth factor (NGF) for their survival and maturation. The present study examined the extent to which postnatal lead exposure may affect the survival and expression of neuroptrophin receptors of septo-hippocampal cholinergic projection neurons in the medial septum/vertical limb of the diagonal band of Broca (MS/VDB) and cholinergic neurons of the striatum. Weanling rats were fed chow containing lead acetate for 30 days and effects on cholinergic cell number and the number of cells expressing neurotrophin receptors p75(NGFR) and trkA were assessed. A decrease in the number of cells expressing p75(NGFR) and an increase in the number of cells expressing trkA receptor was observed in the MS/VDB of lead-exposed rats, without a loss of cholinergic cell number or alteration in cell size. Lead-exposure resulted in a significant decrease in trkA-expressing cells in the striatum but no change in the number or size of cholinergic neurons. These results suggest that a brief postnatal lead exposure does not result in loss of MS/VDB or striatal cholinergic neurons but does modify the expression of neurotrophin receptors in these regions. The significance of these effects on the septo-hippocampal and striatal functioning remains to be studied.

A number of previous studies have demonstrated a positive effect of exogenously administered monosialoganglioside GM1 on striatal dopamine (DA) levels and DA neuron survival in animal models of parkinsonism. However, due to low bioavailability of peripherally administered GM1, the present study investigated the neuroprotective/neurorestorative potential of enhancing endogenous GM1 biosynthesis by administration of the synthetic ceramide analog L-threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (L-PDMP) in two mouse models of Parkinsonism produced by acute or subacute 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration. L-PDMP treatment caused an increase in brain GM1 levels in both Parkinson models and resulted in a partial sparing of striatal DA levels in the subacute MPTP model but not in the acute MPTP model. L-PDMP treatment had no effect on DA neuron survival in either model. These data suggest that the administration of L-PDMP as a means to enhance endogenous brain GM1 levels may hold limited promise as a potential neuroprotective or neurorestorative therapeutic strategy for Parkinson's disease.

Chronic low dose MPTP-treated monkeys develop difficulty in performing spatial working memory tasks. Since these tasks have both attentional and memory components, the extent to which task performance deficits are attentional or memory in nature was examined. Using a modified variable delayed response (VDR) task, employment of an attentional cue prior to stimulus presentation significantly improved task performance, suggesting a strong attentional component to the deficit in spatial working memory task performance. These findings suggest that procedures to enhance attention may be useful in ameliorating some of the "memory" deficits associated with early Parkinson's disease., (Copyright 2003 Elsevier B.V.)

Oxidative injury is believed to be a major factor in the pathogenesis of a variety of neurodegenerative diseases. Additionally, the mode of cell death in oxidant-stressed cells can vary. The present study was conducted to evaluate the use of a primary neuronal cell-based bioassay in which different modes of oxidant-induced cell death could be studied and in which putative neuroprotective agents could be screened. Addition of 50 microM H(2)O(2) to primary cortical neuronal cultures for 1 h under normal ATP conditions resulted in approximately 40% cell death, almost exclusively of an apoptotic nature. In this condition, cell death was effectively blocked by GM1 ganglioside, the semi-synthetic ganglioside derivative LIGA20, the dopamine receptor agonist pramipexole (PPX) and the caspase inhibitor Z-VAD-FMK but not by the poly (ADP-ribose) polymerase (PARP) inhibitor 3-aminobenzamide (3-AB). Pretreatment of cells with 0.01 microM oligomycin for 45 min prior to addition of 50 microM H(2)O(2) caused significant ATP depletion and approximately the same amount of cell death as H(2)O(2) alone. However, under these conditions, cell death was primarily non-apoptotic in nature and GM1, LIGA20 and Z-VAD-FMK had no protective effects. In contrast, AB and PPX effectively blocked cell death. These results suggest that cellular ATP plays a critical role in determining the mode of cell death in primary neurons and that these types of in vitro models may provide a useful system for screening putative neuroprotective agents.

Levodopa-induced dyskinesias (LIDs) present a major problem for the long-term management of Parkinson's disease (PD) patients. Due to the interdependence of risk factors in clinical populations, it is difficult to independently examine factors that may influence the development of LIDs. Using macaque monkeys with different types of MPTP-induced parkinsonism, the current study evaluated the degree to which rate of symptom progression, symptom severity, and response to and duration of levodopa therapy may be involved in the development of LIDs. Monkeys with acute (short-term) MPTP exposure, rapid symptom onset and short symptom duration prior to initiation of levodopa therapy developed dyskinesia between 11 and 24 days of daily levodopa administration. In contrast, monkeys with long-term MPTP exposure, slow symptom progression and/or long symptom duration prior to initiation of levodopa therapy were more resistant to developing LIDs (e.g., dyskinesia developed no sooner than 146 days of chronic levodopa administration). All animals were similarly symptomatic at the start of levodopa treatment and had similar therapeutic responses to the drug. These data suggest distinct differences in the propensity to develop LIDs in monkeys with different rates of symptom progression or symptom durations prior to levodopa and demonstrate the value of these models for further studying the pathophysiology of LIDs.

The effects of low-level lead exposure on survival and neurite length of rat E15 primary ventral mesencephalic dopaminergic neurons were studied. Lead acetate (0.001-10 microM) added to primary cultures for 48 h (in serum-free defined media [DM]) caused a loss of tyrosine hydroxylase (TH)-positive neurons only at the highest concentrations (1 and 10 microM). In contrast, significant effects on neurite length were observed at concentrations as low as 0.001 microM. Lead-induced decrease in neurite length became more apparent at concentrations of 0.01 microM (mean 37.9% decrease) and 0.10 microM lead acetate (mean 43.9% decrease). These data show that very low concentrations of lead, well below the level necessary to adversely affect neuronal survival, can have dramatic effects on neurite growth. These results support recent clinical findings of detrimental effects of low-level lead exposure on brain development.

A number of neuropeptides are affected in Parkinson's disease and the enzyme proline endopeptidase contributes to the degradation of many of these neuropeptides, some of which are linked to a variety of cognitive functions. In the present study, the effects of the highly potent proline endopeptidase inhibitor S 17092 on cognitive deficits in monkeys induced by chronic low dose 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration were examined. Chronic low dose MPTP administration resulted in deficits in performance of variable delayed response, delayed matching-to-sample, and delayed alternation tasks. Seven day oral administration of S 17092 followed by single dose administration of the same dose on the day of testing significantly improved overall performance on these tasks. The most effective dose of S 17092 was 3 mg/kg. These results indicate that S 17092 has cognition-enhancing properties in this model of early parkinsonism.

1-Methyl-4-phenyl-1,2,3,6-tetrahyrdropyridine (MPTP)-exposed cats develop severe Parkinsonism that spontaneously resolves in 4-6 weeks. The present study examined the extent to which compensatory changes in tyrosine hydroxylase (TH) and dopamine transporter (DAT) gene and protein expression may underlie this behavioral recovery. In normal cats, TH and DAT protein levels were higher in the dorsal vs. ventral striatum. Expression of DAT and TH mRNA was higher in substantia nigra pars compacta (SNc) than in the ventral tegmental area (VTA). In symptomatic parkinsonian animals, DAT and TH protein levels were significantly decreased in all striatal areas studied. TH and DAT mRNA expression in residual SNc neurons were decreased a mean 32% and 38%, respectively. DAT gene expression in residual VTA neurons in symptomatic animals was decreased 30% whereas TH gene expression was unaffected. In spontaneously recovered cats, TH protein levels were significantly higher than the levels in symptomatic cats only in the ventral striatum, whereas no increase in DAT protein levels were observed in any striatal area. Residual neurons in most ventral mesencephalic regions of recovered cats had increased TH mRNA expression but not increased DAT gene expression, compared with symptomatic animals. Thus, increased TH protein and mRNA and suppression of DAT protein and mRNA expression in the striatum and ventral mesencephalon were associated with functional recovery from MPTP-induced parkinsonism., (Copyright 2001 Wiley-Liss, Inc.)

Striatal preprotachykinin (PPT) gene expression and [(3)H]mazindol binding were examined in monkeys exposed to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Some animals (n = 5) became moderately to severely parkinsonian after receiving large doses of MPTP over 9-30 d and remained symptomatic for a relatively short time (3 weeks to 3 months; acutely symptomatic group). A second group of animals (n = 5) received low doses of MPTP (1.5-12 months), developed cognitive impairments but displayed no gross motor deficits (asymptomatic group), and were killed 3-12 months after their final dose of MPTP. Other animals became moderately to severely parkinsonian after receiving escalating doses of MPTP (>6 months; n = 4) or high doses of MPTP (<1 month; n = 1) and remained symptomatic for 2.5-5.75 years (chronically symptomatic group). All MPTP-treated animals had extensive losses of [(3)H]mazindol binding in dorsal striatal sensorimotor regions with asymptomatic animals generally having a lesser degree of damage. However, PPT mRNA levels differed sharply among treatment groups. Symptomatic animals (acutely and chronically parkinsonian) had significantly decreased PPT mRNA levels in most striatal regions. In asymptomatic animals, PPT mRNA expression was not significantly different from that measured in control animals, despite decreases in [(3)H]mazindol binding in some striatal regions of similar magnitude to those observed in symptomatic animals. These observations suggest that PPT gene expression may be directly related to expression of parkinsonian motor symptomatology regardless of duration of MPTP exposure, duration of the parkinsonism, or extent of dopamine denervation. These results imply that the direct striatal output circuit may have a greater contribution to expression of parkinsonian symptomatology than proposed previously.

Intracellular progesterone receptors (PRs) are ligand-inducible transcription factors that mediate the majority of the effects of progesterone (P) on neuroendocrine functions. During the past decade, evidence has accumulated which suggest that PRs can also be activated independently of P, by signals propagated through membrane-bound receptors to the interior of cells. The activation of PRs by this type of "cross-talk" mechanism has been implicated in the physiological regulation of several important neuroendocrine processes, including estrous behavior and periovulatory hormone secretions. We review evidence that both ligand-dependent and ligand-independent activation of PRs occurs in central neurons and in anterior pituitary cells and that the convergence and summation of these signals at the PR serves to integrate neural and endocrine signals which direct several critically important neuroendocrine processes. An integrative function for PRs is reviewed in several physiological contexts, including the display of lordosis behavior in female rodents, the neurosecretion of gonadotropin-releasing hormone surges, secretion of preovulatory gonadotropin surges, and release of periovulatory follicle stimulating hormone surges. The weight of evidence indicates that cross talk at the intracellular PR is an essential component of the integrative mechanisms that direct each of these neuroendocrine events. The recurrence of PR's integrative actions in several different physiological contexts suggests that other intracellular steroid receptors similarly function as integrators of neural and endocrine signals in other neuroendocrine processes., (Copyright 2001 Academic Press.)

Loss of striatal dopamine has been associated with an increase in striatal enkephalin expression. However, the relationship between increased striatal enkephalin expression and the manifestation of parkinsonian motor deficits is not clear. Administration of MPTP to cats produces a severe parkinsonian condition from which the animals spontaneously recover. Using in situ hybridization histochemistry, preproenkephalin (PPE) mRNA expression was examined in the striatum of cats when normal, symptomatic for or spontaneously recovered from MPTP-induced parkinsonism. In all areas of the striatum, PPE mRNA levels were significantly elevated in animals exhibiting severe parkinsonian motor deficits and remained elevated even after recovery of gross motor functioning. These results show that striatal PPE gene expression and parkinsonian motor deficits are not directly correlated.

GM1 ganglioside administration has previously been shown to increase striatal dopamine levels and to enhance the density of tyrosine hydroxylase-positive fibers in the striatum of monkeys made parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The present study examined the extent to which GM1 administration promotes recovery of dopamine terminals and reverses lesion-induced changes in postsynaptic receptors in the striatum of MPTP-treated monkeys. All MPTP-treated animals developed severe parkinsonism. GM1-treated monkeys exhibited significant functional recovery after 6 weeks of treatment, whereas saline-treated controls remained parkinsonian over the same time period. MPTP exposure resulted in profound decreases in [(3)H]-mazindol binding to dopamine transporters in the caudate and putamen and increased D1 and D2 receptor binding in several striatal regions. GM1 treatment resulted in significant increases in striatal [(3)H]-mazindol binding and decreases in D1 binding compared to control animals in many striatal regions. GM1 treatment did not significantly affect D2 binding. These results show that GM1 treatment can partially restore striatal dopaminergic terminals and partially reverse postsynaptic changes in dopamine receptors in a nonhuman primate model of parkinsonism., (Copyright 2000 Wiley-Liss, Inc.)

Unlabelled: [99mTc]TRODAT-1 is a radiolabeled tropane that binds dopamine transporters. The primary goal of this study was to determine whether its regional cerebral distribution could differentiate between patients with Parkinson's disease and healthy human volunteers., Methods: The sample consisted of 42 patients with Parkinson's disease, 23 age-matched controls, and 38 healthy adults younger than 40 y old. SPECT scans of the brain were acquired on a triple-head gamma camera 3-4 h after the intravenous injection of 740 MBq (20 mCi) [99mTc]TRODAT-1. Mean counts per pixel were measured manually in subregions of the basal ganglia and normalized to the mean background counts to give specific uptake values ([SUVs] approximately k3/k4). Patient and control groups were also compared with automated statistical parametric mapping techniques. Logistic discriminant analyses were performed to determine the optimum uptake values for differentiating patients from age-matched controls., Results: Quantitative image analysis showed that the group mean SUVs in patients were less than the mean values in controls for all regions (all Ps < 0.000001). There was overlap in the caudate as well as in the anterior-most portion of the putamen, but not in the posterior putamen, even when the asymptomatic sides of 5 patients with clinically defined hemi-Parkinson's disease were factored in., Conclusion: The findings indicate that Parkinson's disease can be detected with [99mTc]TRODAT by simply inspecting the images for uptake in the posterior putamen. Appropriate asymmetries seem to be visible with quantification in patients with clinically defined hemi-Parkinson's disease, even though changes in the putamen contralateral to the clinically unaffected side in these patients appear to precede the development of symptoms.

The contribution of the duration of the striatal dopamine (DA) depletion and the expression of parkinsonian signs to changes in D(1) and D(2) receptor number was investigated in the present study. Some animals (N=4) received large doses of 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP) over short periods of time and were symptomatic for a short period of time (1-3 months; acute parkinsonian group). Other animals (N8 months; chronic parkinsonian group). Despite similar symptomatology and similar degrees of striatal DA denervation, only acute parkinsonian animals had significantly increased numbers of D(1) receptors in most striatal regions. Striatal D(2) receptor binding was elevated in acute parkinsonian monkeys but only in some lateral striatal subregions at mid and caudal levels. These findings further suggest that the duration of parkinsonism is a critical factor in modulating changes in striatal neurochemistry.

Persisting insomnia secondary to traumatic brain injury, rarely reported and documented, is described in an adult male following head injury. The neuronal mechanisms underlying this sleep disorder as well as the neuropsychological concomitants and therapeutic approaches are discussed.

It is well known that estrogen (E2) stimulates expression of progesterone receptors (PRs), thereby inducing responsiveness of several tissues to the actions of progesterone (P). Recent studies have also suggested, however, that biological actions previously ascribed to E2 alone may also be mediated by activation of E2-induced PRs, even independently of signal changes in P concentrations. In the present experiments, the progesterone receptor knockout (PRKO) mice were used to assess the role of PR activation in the positive feedback actions of E2 on gonadotropin release. Ovariectomized (OVX) PRKO mice were tested for their capacity to mount primary gonadotropin surges in response to exogenous E2, and to exhibit a GnRH self-priming effect in response to sequential injections of the decapeptide. Wild-type (WT) and PRKO mice were OVX, treated with both 17beta-estradiol and estradiol benzoate (EB), and then killed at 1900 h on day 7 postOVX. Plasma LH RIA revealed that WT mice exhibited surges in response to the E2 treatment; the PRKO mice, however, showed no elevation in plasma LH above untreated controls. Instead, plasma LH levels in E2-treated, OVX PRKO mice decreased significantly in comparison to untreated OVX PRKO mice, suggesting that E2 can exert a negative feedback influence on LH release in PRKO mice, despite the absence of positive feedback effects. A slight but significant rise in plasma FSH was observed in E2-treated OVX WT mice in comparison to untreated controls: an effect not seen in E2-treated OVX PRKO mice, reinforcing the observation that estrogen's positive feedback effects are compromised in PRKO mice. In a second experiment, E2-treated OVX WT and PRKO mice were given either one or two pulses of GnRH 60 min apart, and killed 10 min later. The WT mice were found to exhibit a robust GnRH self-priming effect, as WT mice receiving two GnRH pulses displayed LH responses approximately 2-fold greater than those receiving only one pulse. By contrast, PRKO mice receiving two GnRH pulses exhibited no additional increase in plasma LH levels. We conclude that PR activation is obligatory for expression of the GnRH self-priming effect as well as for generation of E2-induced LH and FSH surges. The extent to which failure of LH surge secretion in PRKO mice is due to the absence of GnRH self-priming, lack of hypothalamic GnRH surges, and/or defects in other processes remains to be determined. These observations clearly demonstrate, however, that the presence of PR is an absolute requirement for the transmission of E2-induced signals leading to gonadotropin surges.

Monkeys that receive chronic low-dose 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP) administration have difficulty performing numerous cognitive tasks. This study further examines the extent to which chronic low-dose MPTP exposure affects performance of a visual memory task [variable delayed response (VDR)] with both attentional and short-term memory components and assesses the effects of the novel neuronal nicotinic acetylcholine receptor agonist SIB-1508Y and levodopa on cognitive task performance. Before MPTP treatment, these monkeys displayed a delay-dependent decrement in performance on the VDR task and performed well on delayed matching-to-sample and visual pattern discrimination tasks. Chronic low-dose MPTP treatment caused a shift to a delay-independent pattern of responding on the VDR task, such that short-delay trials were performed as poorly as long-delay trials. There were also deficits in performing the delayed matching-to-sample task, whereas visual discrimination performance remained intact. SIB-1508Y normalized the pattern of response on the VDR task by significantly improving performance on short-delay trials and on the delayed matching-to-sample task. These effects lasted up to 24 to 48 h after SIB-1508Y administration. Neither levodopa nor nicotine significantly improved task performance. These results suggest that chronic low-dose MPTP exposure results in a cognitive disturbance that can be corrected by the nicotinic acetylcholine receptor agonist SIB-1508Y but not by levodopa. Thus, SIB-1508Y may be useful in the treatment of the cognitive deficits in Parkinson's disease.

This study examined the extent of striatal dopamine (DA) denervation and coincident expression of preproenkephalin (PPE) mRNA in monkeys made parkinsonian by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration. Some animals (n = 4) became moderately parkinsonian after receiving large doses of MPTP over short periods of time and were symptomatic for only a short period of time (1-3 months; acute parkinsonian group). Other animals became moderately parkinsonian after receiving either escalating doses of MPTP over long periods (4-6 months; n = 5) or a high dose of MPTP over a short period (<1 month; n = 1) and remained symptomatic for an extended period (>8 months; chronic parkinsonian group). Despite similar symptomatology and similar degrees of striatal DA denervation at the time of their deaths, only acute parkinsonian animals had significantly increased PPE expression in sensorimotor striatal regions. PPE expression in chronic parkinsonian animals was either not changed or significantly decreased in most striatal regions. These findings suggest that the duration and not the extent of striatal DA denervation is a critical factor in modulating changes in striatal PPE expression. Furthermore, these results question the role of increased activity in the enkephalin-containing indirect striatopallidal pathway in the expression of parkinsonian symptoms.

The potential antiparkinsonian effects of the centrally acting, subtype-selective neuronal nicotinic acetylcholine receptor agonist (S)-(-)-5-ethynyl-3-(1-methyl-2-pyrrolidinyl)-pyridine (SIB-1508Y) was assessed on motor symptoms and disability scale ratings in three monkeys previously made parkinsonian by chronic exposure to the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Compared with levodopa (L-dopa), SIB-1508Y exerted only mild antiparkinsonian effects when administered alone. Emetic effects of this drug interfered with potential therapeutic effects at higher doses. However, when a low, ineffective dose of SIB-1508Y was combined with low, ineffective doses of L-dopa, a significant clinical effect was observed. These data suggest that subtype-selective nicotinic acetylcholine receptor agonists may hold promise as antiparkinsonian agents, and when administered in combination with L-dopa may allow a reduction in the dose of L-dopa needed to achieve a significant clinical effect.

GM1 ganglioside has been shown to stimulate repair of the nigrostriatal dopamine system after injury. This has been particularly evident in the mouse MPTP model of Parkinsonism. Systemic administration of GM1 has been shown to increase striatal dopamine levels and lead to increased density of substantia nigra pars compacta neurons after MPTP administration versus mice treated with MPTP and saline. The purpose of the present study was to assess regional changes in dopaminergic innervation of the striatum of mice treated with MPTP then GM1. Studies consisted of [3H] mazindol binding of dopamine uptake sites, postmortem striatal tissue dopamine levels, and peak dopamine release in response to KCl stimulation measured in vivo. Results showed that measures of dopamine innervation were significantly increased in most striatal areas in MPTP+GM1-treated mice compared to MPTP+saline-treated controls. The results indicate that GM1 treatment increases measures of dopaminergic innervation after an MPTP lesion, possibly through sprouting of new terminals or increased dopamine production and release from remaining terminals.

The ability of a single intranigral infusion of glial cell line-derived neurotrophic factor (GDNF) to reverse deficits in skilled paw usage and sensorimotor orientation and to ameliorate apomorphine-induced rotational asymmetry in unilateral 6-hydroxydopamine-lesioned rats was examined. After lesioning, all rats developed sensory inattention on the side contralateral to the lesion, rotational asymmetry in response to apomorphine administration and significant deficits in successfully performing a forelimb reaching task dependent upon the use of somatosensory and proprioceptive feedback. A single intranigral injection of GDNF (300 micro g) made 4 wks. after the 6-OHDA lesion, significantly decreased the number of drug-induced rotations at 1 and 2 wks. after GDNF administration. At the same time however, no improvements were noted in performance of the paw reaching task or in sensorimotor orienting. Post mortem analyses showed that the GDNF treatment did not cause any increase in striatal dopamine levels but did increase tyrosine hydroxylase-positive immunohistochemical staining in the substantia nigra on the side of the GDNF infusion. These results demonstrate the need for multiple behavioral measures of efficacy when evaluating treatments for parkinsonism in the unilateral 6-hydroxydopamine lesion model in the rat.

During 1972 to 1977, the Lawrence Livermore National Laboratory (LLNL) experienced increased diagnosis of malignant melanoma among employees. In 1984, a report on the results of a case-control study of 39 cases concluded that occupational factors, including exposures to ionizing radiation and to chemicals, caused the excess incidence. The study reported here, based on results from 69 case-control pairs, re-examines the role of the occupational factors implicated by the earlier study in melanoma causation. Results from this study suggest that constitutional factors, including skin reactivity to sunlight, sunbathing frequency, and number of moles, explain most of the excess melanoma. Exposures to occupational factors, including ionizing radiation and chemicals, were found to be no different in cases than in controls.

Recent studies have found that the basal ganglia are involved in diverse behavioral activities and suggest that they have executive functions. Highlights from the past year include anatomical and clinical studies that have used sophisticated, novel methods to confirm a role for the basal ganglia in somatosensory discrimination, visual perception, spatial working memory and habit learning.

Therapeutic treatment of parkinsonian monkeys by chronic administration of levodopa (l-DOPA) leads to the development of dyskinesias and other motor fluctuations. It is unclear whether there are alterations in the dopamine system that are related to the induction of dyskinesias by l-DOPA, but recent attention has focused on the D1 receptor system. The present study assessed the consequences of chronic l-DOPA treatment in monkeys made parkinsonian with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on indices of the pre- and post-synaptic dopamine (DA) system. Treatment with therapeutic doses of l-DOPA led to the induction of dyskinesias in the MPTP-treated monkeys. High-pressure liquid chromatography was used for measurement of tissue levels of DA and its metabolites, and quantitative autoradiography was used to examine the regional integrity of the presynaptic DA system (by measuring [3H]mazindol binding to DA uptake sites). Quantitative autoradiography was used to measure the number of postsynaptic D1 receptors (using [3H] SCH 23390) in the striatum and pallidum of normal, MPTP alone, and MPTP monkeys treated chronically with l-DOPA. In both MPTP-treated monkeys, levels of DA and metabolites as well as [3H]mazindol binding were greatly reduced in the caudate and putamen, slightly more in dorsal than in ventral areas. However, the lack of increase in striatal DA levels along with higher [3H]mazindol binding in MPTP-plus-l-DOPA-treated monkeys suggested differences in the way DA was used after l-DOPA treatment In MPTP-treated monkeys, a significant increase (141-170% of normals) of D1 receptor numbers was observed in putamen and dorsal caudate. With l-DOPA treatment, the number of D1 receptor numbers was further elevated in caudal putamen (119-123%), dorsal caudate (110-130%), and in the internal segment of the globus pallidus (GPi; 164% of normals) of MPTP-treated monkeys as compared with MPTP treatment alone. This suggested that in MPTP-treated monkeys made dyskinetic by chronic pulsatile delivery of l-DOPA, there was enhanced production of D1 receptors in the direct striatal output to the GPi.

The response of central median/central lateral (CM/CL) and ventral anterior/ventral lateral (VA/VL) thalamic neurons to tactile sensory stimulation of the face and electrical stimulation of the striatum was assessed in awake cats before and after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) exposure. When cats exhibited Parkinson-like motor deficits, there was a significant decrease in the number of CM/CL and VA/VL neurons responsive to tactile stimulation of the face. Mean spontaneous firing rates decreased by 58% in the CM/CL nuclei, 65% in the VA, and 49% in the VL. The number of thalamic neurons responding to electrical stimulation of the striatum was also significantly decreased in parkinsonian animals. Approximately 6 weeks after MPTP exposure, when cats had spontaneously recovered gross motor function, thalamic responses to peripheral sensory stimulation, electrical stimulation of the CD, and spontaneous activity rates, returned to approximately normal levels in all thalamic areas studied. These findings support the concept that abnormalities in the transmission of information through the thalamus, and in particular, a decrease in sensory responsiveness in intralaminar and motor thalamic regions subsequent to nigrostriatal dopamine depletion, may contribute to the generation of Parkinson-like motor and sensorimotor deficits.

The spontaneous activity, responses to peripheral sensory and ipsilateral caudate nucleus stimulation of globus pallidus (GP) and entopeduncular nucleus (ENTO) neurons were studied in cats while normal, symptomatic for 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced parkinsonism, and when spontaneously recovered from gross parkinsonian motor deficits. Administration of MPTP resulted in parkinsonian motor symptoms that spontaneously recovered approximately 4-6 weeks after the MPTP administration. Post-mortem dopamine levels in recovered animals was approximately 95% below levels previously measured in normal animals. In symptomatic animals, the mean spontaneous firing rate for GP units was decreased by 50% and increased by 55% for ENTO units recorded. Spontaneous firing rates for GP and ENTO units in recovered cats were not significantly different from those observed in normal cats. In normal cats, 31.4% of GP and 29% of ENTO units tested responded to tactile stimulation of the face. Only 12.2% of GP and 13% of ENTO units responded to such stimulation in parkinsonian animals while the responses were generally less specific (larger receptive fields, more bilateral receptive fields, and more responses to multiple stimulation types) than normal. In recovered cats GP and ENTO responses resembled those observed in normal cats. There was no difference in the overall percentage of pallidal units responding to striatal stimulation across the 3 experimental conditions. There was, however, an increase in the percentage of units responding with complex response sequences (i.e. decrease in activity followed by an increase in activity) in symptomatic animals as compared to normal and recovered animals. The results suggest that loss of striatal dopamine in parkinsonian animals has profound effects on the sensory responsiveness of GP and ENTO neurons and that these effects coincide with the appearance of and recovery from parkinsonian motor deficits. These data further support the notion that sensory information processing by the basal ganglia may play an important role in influencing motor output.

Five adult Macaca fascicularis monkeys were trained to perform tests of cognitive and motor functioning that included a complex visual pattern discrimination task, an object retrieval task, a test of task persistence, and a timed motor task. Once stable baseline performance was achieved, monkeys were administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at doses of 0.05 to 0.075 mg/kg, 2 to 3 times per week for a total of 24 weeks. Animals were assessed weekly for performance on the previously learned tasks. All monkeys developed performance deficits in a predictable pattern with behavioural and cognitive deficits (i.e. deficits in task persistence and the cognitive component of object retrieval) appearing in advance of measurable motor deficits. Deficits in visual pattern discrimination never appeared. These results show that specific cognitive dysfunction pre-dates motor dysfunction in a chronic, slowly progressing parkinson model in monkeys and support the contention that cognitive deficits in Parkinson's disease may precede the motor signs of the disorder and may not be caused by them.

Repeated daily administration of haloperidol produces changes in striatal neurochemistry (decreased dopamine synthesis, upregulation of D2 receptors) and behavior (increasing catalepsy). Coadministration of taurine greatly attenuated these neuroleptic-induced changes. Possible mechanisms of taurine's mitigating effects are its attenuating influences on glutamatergic transmission and its actions as a GABAA agonist. The possibility was discussed of adding taurine to chronic antipsychotic regimens to block the side-effects typically accompanying such therapy.

GM1 ganglioside, administered to young C57/B16J mice with moderate (approx 85%) 1-methyl-4-phenyl-1,2,3,6-terahydropyridine (MPTP)-induced striatal dopamine depletions, caused a dose-dependent increase in striatal dopamine levels. This effect was maximal between 7.0 and 30.0 mg/kg and was not apparent at higher and lower doses of GM1. GM1 ganglioside treatment had no effect on striatal dopamine levels in mice with more extensive lesions of the dopamine system (i.e. approx 93% loss of striatal dopamine). The semisynthetic ganglioside derivative LIGA 20, administered orally, also increased striatal dopamine levels in moderately lesioned animals, albeit at lower doses than GM1. LIGA 20 administration also resulted in increased striatal dopamine levels in animals with more extensive dopamine lesions, where GM1 had no effect. These results show that both GM1 and its semisynthetic derivative LIGA 20 can partially restore striatal dopamine levels in MPTP-treated mice and that LIGA 20 is more potent and not subject to the same dose-limiting effects as GM1.

Intraperitoneal injection of GM1 ganglioside or intracerebroventricular infusion of basic fibroblast growth factor (FGF-2) or epidermal growth factor (EGF) partially restored dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the striatum of young MPTP-treated mice. Combined treatments of GM1 ganglioside with FGF-2 or EGF produced a greater restoration of striatal dopamine levels than treatments with GM1 or either of the neurotrophic factors alone. GM1 treatment, but not trophic factor treatments caused significant sparing of substantia nigra pars compacta (SNc) tyrosine hydroxylase (TH)-positive neurons. These results confirm previous findings that GM1 provides trophic support for damaged dopamine neurons and suggests that GM1, FGF-2, and EGF may also enhance dopaminergic function in residual neurons. The results also suggest that a potentially fruitful approach to treating degenerative disorders of the dopamine system may be the use of combined trophic factor therapies.

The effects of additional MPTP injections on striatal neurochemistry and tyrosine hydroxylase positive cell populations within the ventral mesencephalon in cats recovered from parkinson-like motor deficits resulting from previous MPTP administration was studied. A second or third series of MPTP injections in recovered cats initially reinstated parkinson-like motor deficits. All cats again recovered normalized motor function two to three weeks after MPTP administration. Neurochemical analysis of striatal tissue showed no or only minor differences in dopamine and metabolite levels within most striatal regions sampled between cats which received single or multiple sets of MPTP injections. Cell count results showed no significant differences between the two MPTP conditions for the majority of the regions studied. These results suggest that the mechanisms responsible for motor recovery from MPTP intoxication in cats can be transiently disrupted by further exposure to MPTP and that cats do not develop a permanent parkinsonian syndrome from repeated MPTP exposure.

The administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to adult cats severely disrupts the dopaminergic innervation of the striatum. Animals display a parkinson-like syndrome, consisting of akinesia, bradykinesia, postural instability, and rigidity, which spontaneously recovers by 4-6 weeks after the last administration of MPTP. In this study we used quantitative receptor autoradiography to examine changes in DA uptake sites and DA receptors in the basal ganglia of normal, and symptomatic and recovered MPTP-treated cats. Consistent with the destruction of the nigrostriatal DA pathway, there was a severe loss of DA uptake sites, labeled with [3H]-mazindol, in the caudate nucleus (64-82%), nucleus accumbens (44%), putamen (63%), and substantia nigra pars compacta (SNc, 53%) of symptomatic cats. Following behavioral recovery, there were no significant changes in DA uptake site density. Significant increases of [3H]-SCH 23390 binding to D1 DA receptors were observed in the dorsal caudate (> 24%; P < 0.05) of symptomatic cats and in all regions of the caudate-putamen (> 30%; P < 0.05) of recovered animals. [3H]-SCH 23390 binding in the substantia nigra pars reticulata was half of that in the striatum and showed no changes in symptomatic or recovered animals. No alterations in the binding of [125I]-epidepride to D2 receptors was observed in any region of the striatum in either symptomatic or recovered animals. [125I]-Epidepride binding in the SNc was decreased by > 36% (P < 0.05) following MPTP treatment. These data show that cats made parkinsonian by MPTP exposure have a significant decrease in the number of DA reuptake sites throughout the striatum and that recovery of sensorimotor function in these animals is not correlated with an increase in the number of striatal reuptake sites. Behavioral recovery, however, does seem to be correlated with a general elevation of D1 receptors throughout the striatal complex. The present data also show that direct correlations between changes in DA receptor regulation after a large DA depleting lesion and behavioral deficits or recovery from those deficits are difficult and that the relationships between DA receptors/transporters and behavior require further study.

Background: The number of total body nevi is a major risk marker for malignant melanoma. No previous study has evaluated the accuracy of whole body large nevus (> or = 5 mm) self-counts., Objective: Our purpose was to evaluate the accuracy of large nevus self-counts by sex, age, educational level, body site, family history of skin cancer, and nevus characteristics., Methods: Self-counting of large nevi by 125 patients was compared with physician counting, with attention to nevus characteristics., Results: Overall, 79% of the self-counts agreed to within +/- 3 nevi of the physician's count. Analysis of variance revealed that the presence of nonpigmented or flat nevi significantly increased the chance of subject undercount, as did male sex., Conclusion: Self-counts of large nevi are comparable to physician's counts and may be useful for melanoma screening.

Administration of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to cats results in a parkinsonian syndrome that spontaneously recovers by 6 weeks after induction. Striatal dopamine depletions in these animals are heterogenous with more extensive damage dorsolaterally than ventromedially. Measures of extracellular dopamine levels by in vivo microdialysis showed that dopamine released from a relatively preserved ventral striatal innervation can diffuse over a distance of 5.5 mm to 7.0 mm to the more extensively denervated dorsolateral striatum, where it may influence sensorimotor activities and contribute to functional recovery. Diffusion of dopamine through a large volume of striatal tissue was observed in cats 6 weeks after an MPTP-induced lesion and in normal cats with pharmacologically induced dopamine reuptake inhibition, but not in normal animals without reuptake inhibition. In cats recovered from MPTP-induced parkinsonism, a greater amount of dopamine was recovered from the extracellular fluid in the dorsolateral caudate following stimulated release of dopamine from the ventromedial striatum than after stimulated release locally in the dorsolateral caudate. These results suggest volume transmission of dopamine over large distances is possible and perhaps an important contributor to functional recovery from a large dopamine-depleting lesion. These results may also form the basis for understanding how limited reinnervation of the striatum by grafts or trophic factor therapies may lead to significant functional improvement.

Numerous in vitro and in vivo experimental animal studies have demonstrated that gangliosides, particularly GMI ganglioside (siagoside), may stimulate or accelerate the repair of peripheral and central nervous system neurons after various types of damage. Clinical studies of GMl in peripheral neuropathies and stroke, disorders in which the effects of GM 1 have been studied most extensively, have yielded inconsistent results. Problems of inadequate study design, inclusion of heterogenous clinical popUlations and variations in dosage, duration of treatment and timing of initial administration make it difficult to compare results from individual studies and to conclusively assess efficacy of GMl treatment. Therefore, further clinical studies of gangliosides seem warranted.Despite efforts to link gangliosides with the development of Guillain-Barre syndrome, there are no valid data to support such an association. Gangliosides, in particular GM I, are well tolerated after repeated administration to humans and do not appear to be immunogenic.GM1 may be a useful therapeutic agent if administered to particular patients with a specific spectrum of symptoms and disease severity. In addition, to be effective the agents need to be administered in appropriate dosages and at an appropriate time after neuronal injury. Human clinical trials of gangliosides should continue cautiously and with restraint.

Administration of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to aged (12 months) C57 black mice results in a striatal dopamine depletion that can be partially reversed only by long-term (i.e. 8 weeks) intraperitoneal administration of GM1 ganglioside. The present study shows that the semi-synthetic sphingolipid LIGA 20 (II3Neu5AcGgOse4-2-d-erythro-1,3-dihydroxy-2-dichloro-acetrylam ide-4- transoctadene) can partially reverse MPTP-induced striatal dopamine depletions in aged mice after being administered orally for only 4 weeks. GM1 ganglioside administered for 4 weeks had no effect on striatal dopamine levels. These results suggest that LIGA 20 is more potent than the parent GM1 ganglioside and may exert effects on the damaged nervous system under conditions in which GM1 is ineffective.

Cat caudate nucleus (CD) neurons were tested for changes in spontaneous activity, response to peripheral sensory stimuli (tactile, auditory, and visual), and electrical stimulation of monosynaptic afferents (pericruciate cortex and nucleus centralis lateralis) in normal cats and in the same cats after induction of and spontaneous recovery from parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). After normal baseline data were collected, cats were given MPTP (7.5 mg/kg, 5-7 d) to induce a parkinsonian syndrome consisting of rigidity, akinesia, and decreased orienting to sensory stimuli. During this symptomatic period, the mean spontaneous activity of CD units increased (6.20 spikes/sec vs 2.25 spikes/sec in normal cats). In these same animals, the percentage of units responding to peripheral sensory stimulation was significantly decreased (compared to normal) while the percentage of units responding to electrical stimulation of monosynaptic afferents increased. By 6 weeks after MPTP administration, cats had recovered gross motor and sensorimotor function and CD unit recordings were reinitiated. In functionally recovered animals, all electrophysiological measures returned to levels resembling those seen in normal animals. These data suggest that the processing of peripheral sensory information is an important part of basal ganglia function and that the sensory responsiveness of the CD may reflect the overall motor condition of the animal. The changes observed in the responsiveness of CD neurons to direct electrical stimulation of monosynaptic afferents may indicate that the defect in the processing of polysynaptic sensory information observed in the striatum in parkinsonian animals may be occurring, at least in part, extrastriatally.