BACKGROUND: Norepinephrine (NE) plays a central role in post-traumatic stress disorder (PTSD). Dopamine beta-hydroxylase (DbetaH) converts dopamine (DA) to NE and its activity varies widely across individuals. Mustapic et al. (2007) reported a PTSD-associated deficit in serum DbetaH activity (sDbetaH) in a genotype-controlled analysis of combat veterans. We tested whether such a deficit would occur in a sample of civilians. METHODS: The severity of current adult PTSD symptoms and current DSM-IV diagnosis of PTSD were determined by the PTSD Symptom Scale (PSS). Adulthood trauma exposure was assessed using the Traumatic Experience Inventory (TEI). sDbetaH was assayed by HPLC with electrochemical detection and genotypes were determined using the Taqman(R) platform. RESULTS: Two hundred and twenty seven African American (AA) subjects were enrolled in this study, with a mean age (+/- SD) of 42.9 (+/-12.9) years. We found a strong association between rs1611115 genotype and sDbetaH (p<0.0001). After controlling for adulthood trauma exposure, there were no significant differences of sDbetaH between subjects who met a PTSD diagnosis and those who did not (p>0.05) in any genotype group. No significant correlations were found between sDbetaH and PTSD severity, but sDbetaH significantly associated with the status of comorbid depression based on the cutoff of HAMD (p=0.014) in subjects with PTSD. CONCLUSIONS: We have replicated in this sample the prior finding that DBH rs1611115 genotype strongly associates with sDbetaH. No associations between sDbetaH and PTSD diagnosis or symptom severity in this civilian sample. Copyright © 2010. Published by Elsevier Inc.

SUBJECT: The aim of this study was to present our institutional experience with the pediatric intensive care unit (PICU) stays of liver recipients to understand prevention of complications. METHODS: This retrospective review included 22 infants who weighed 8.8 kg or less and underwent 23 transplantations. No grafts were from executed prisoners. We summarized the diagnosis, evaluation, medicine usage, and therapeutic intervention associated with subjects experiencing complications of rejection episodes, surgery, or infection during their ICU stay. RESULTS: There was one perioperative death from primary graft nonfunction. The most common postoperative complications were infections, gastrointestinal bleeding, and vascular complications. Rejection episodes occurred among 25% of patients. The most common isolated pathogenic bacteria was Staphylococcus epidermidis. Median initial ICU stay was 10 days. Mean requirement for artificial ventilation was 37.6 hour. Mean times of use of dobutamine, prostaglandin E1, and dopamine was 3.3, 7.5, and 8.8 days, respectively. Parenteral nutrition was started at a mean of 12 hours and oral food intake at a mean of 72 hours. CONCLUSIONS: Although challenging, orthotopic liver transplantation (OLT) in small infants can be successfully performed with meticulous surgical technique and keen postoperative surveillance.

Catecholamines modulate endocrine stress reactivity by affecting regulatory influences of extra-hypothalamic brain structures on hypothalamus-pituitary-adrenal (HPA)-axis. Therefore, we aimed to investigate combined effects of functional allelic variations that affect dopamine availability in both cortical (COMT Val(158)Met polymorphism) and subcortical (DAT1 VNTR) brain regions on HPA-axis reactivity to psychosocial stress. By using a standardized laboratory stress task (public speaking) we obtained saliva cortisol samples during stress exposure and an extended recovery period in 100 healthy male adults. We report for the first time significant epistasis between COMT Val(158)Met and DAT1 VNTR on cortisol response patterns. Subjects homozygous for both the Met(158) and the 10-repeat allele of DAT1 VNTR were characterized by markedly elevated cortisol reactivity and impaired stress recovery compared to all other groups. Our results indicate a crucial role of functional genetic variants within the dopaminergic system in the modulation of HPA-axis response patterns and highlight the need to investigate combined effects of specific candidate genes on stress-related endophenotypes. Copyright © 2010. Published by Elsevier B.V.

parkin is the most frequent causative gene among familial Parkinson’s disease (PD). Although parkin deficiency induces autosomal recessive juvenile parkinsonism (AR-JP, PARK2) in humans, parkin knockout (PKO) mice consistently show few signs of dopaminergic degeneration. We aimed to directly measure evoked extracellular DA overflow in the striatum with in vivo voltammetry. The amplitude of evoked DA overflow was low in PKO mice. The half-life time of evoked DA overflow was long in PKO mice suggesting lower release and uptake of dopamine. Facilitation of DA overflow by repetitive stimulation enhanced in the older PKO mice. Decreased dopamine release and uptake in young PKO mice suggest early pre-symptomatic changes in dopamine neurotransmission, while the enhanced facilitation in the older PKO mice may reflect a compensatory adaptation in dopamine function during the late pre-symptomatic phase of Parkinson’s disease. Our results showed parkin deficiency may affect DA release in PKO mice, although it does not cause massive nigral degeneration or parkinsonian symptoms as in humans. Copyright © 2010. Published by Elsevier B.V.

Parkinson’s disease (PD) and atypical Parkinsonian syndromes (aPS) belong to the most common neurologic illnesses. Diagnosis and differential diagnosis of these syndromes is primarily based on well-defined clinical criteria, however, may be difficult in early and particular preclinical/premotor stages. Molecular imaging with PET offers here a broad variety of tools supporting the classification of Parkinsonian syndromes including their early and differential diagnosis, assessment of disease progression and evaluation of the efficacy of therapies. The more widely applied PET imaging techniques have focused on the assessment of neurotransmitter systems, here predominantly the pre- and postsynaptic dopaminergic functions, but also others like the serotonergic and cholinergic system. Beyond, refined methods depict distinct patterns of glucose metabolism in the various Parkinsonian syndromes, and focus on further targets such as neuroinflammation, load of amyloid plaques, and cardiac sympathetic denervation. This overview discusses the important PET applications in the field with a main emphasis on their clinical utilization but also highlights scientific applications which may grant further insights in the pathophysiology of PD and aPS. Copyright © 2010 S. Karger AG, Basel.

Neurturin (NTN), a member of the glial cell line-derived neurotrophic factor (GDNF) family, has substantial effects on normal and lesioned nigrostriatal dopamine systems. However, its ability to protect against toxin-induced loss of striatal dopamine release has not been previously reported. The goal of the present study was to determine if NTN could protect against 6-hydroxydopamine (6-OHDA)-induced reductions in striatal dopamine overflow and tissue levels of dopamine, and to compare the effects of NTN with those of GDNF. Male Fischer-344 rats were given a single injection of vehicle, or 5mug NTN or GDNF, into the right striatum. The following day the animals were given a single injection of 12mug 6-OHDA into the striatum at the same site where the trophic factor was injected. Microdialysis experiments conducted three weeks later indicated that the 6-OHDA decreased basal levels of dopamine and metabolites in the lesioned striatum compared to the contralateral striatum, and NTN was able to partially protect against the 6-OHDA-induced reductions. Injection of NTN one day prior to 6-OHDA also led to significant protection against loss of both potassium and amphetamine evoked overflow of dopamine. The NTN treatments partially protected against 6-OHDA-induced reductions in striatal tissue levels of dopamine, and completely protected against loss of nigral dopamine content. The protective effects of NTN were similar in magnitude to those of GDNF. These results support that within the experimental parameters used in this study, NTN is as effective as GDNF in protecting against the dopamine-depleting effects of intrastriatal 6-OHDA. Copyright © 2010. Published by Elsevier Ltd.

Various factors are discussed in the pathophysiology of anxiety disorders, including dysfunctions of the (DA)ergic, serotonin (5-HT)ergic and GABAergic system. We assessed the contribution of the individual synaptic constituents by subjecting all available in vivo imaging studies on patients with anxiety disorders to a retrospective analysis. On a total of 504 patients with obsessive-compulsive disorder (OCD), generalized anxiety disorder (GAD), panic disorder (PD), phobia, or posttraumatic stress-disorder (PTSD) and 593 controls, investigations of VMAT2, DAT, SERT, D1, D2, 5-HTIA, 5-HT2A, GABA(A), and NK1 receptor binding in neostriatum, ventral striatum, thalamus, neocortex, limbic system, cingulate, midbrain/ pons or cerebellum were performed using either PET or SPECT. Separate analyses of the individual disorders showed significant decreases of striatal D2 receptors in OCD (-18%), mesencephalic SERT in OCD (-13%), frontocortical GABAA receptors in PD (-13%) and temporocortical GABAA receptors in GAD (-16%). Pooling of all disorders yielded a significant reduction of mesencephalic SERT (-13%), mesencephalic (-27%) as well as cingulate 5-HT1A receptors (-18%), striatal D2 receptors (-21%) and frontal (-14%), temporal (-14%), occipital (-13%) and cingulate GABAA receptors (-15%). The results show that DA, 5-HT, and GABA play a major role in all subtypes of anxiety disorders. In particular, the findings imply that the regulation state of DA as modulated by GABA and 5-HT may be crucial for the development of anxiety- and compulsion-related disorders. As GABA and 5-HT inhibit DAergic neurotransmission, the reductions of GABAA, 5-HT1A and SERT can be assumed to result in an enhanced activity of the mesolimbic DAergic system. This notion is also reflected by the decrease of striatal D2 receptor binding, which is indicative of an increased availability of synaptic DA.

The substantia nigra pars reticulata (SNr) is a key basal ganglia output nucleus critical for movement control. A hallmark of the SNr gamma-aminobutyric acid (GABA)-containing projection neurons is their depolarized membrane potential, accompanied by rapid spontaneous spikes. Parkinsonian movement disorders are often associated with abnormalities in SNr GABA neuron firing intensity and/or pattern. A fundamental question is the molecular identity of the ion channels that drive these neurons to a depolarized membrane potential. Recent data show that SNr GABA projection neurons selectively express type 3 canonical transient receptor potential (TRPC3) channels. Such channels are tonically active and mediate an inward, Na(+)-dependent current, leading to a substantial depolarization and ensuring appropriate firing intensity and pattern in SNr GABA projection neurons. Equally important, TRPC3 channels in SNr GABA neurons are up-regulated by dopamine (DA) released from neighboring nigral DA neuron dendrites. Co-activation of D1 and D5 DA receptors leads to a TRPC3 channel-mediated inward current and increased firing in SNr GABA neurons, whereas D1-like receptor blockade reduces SNr GABA neuron firing frequency and increases their firing irregularity. TRPC3 channels serve as the effector channels mediating an ultra-short SNc–>SNr DA pathway that regulates the firing intensity and pattern of the basal ganglia output neurons.

PURPOSE OF REVIEW: The on-going quest for potentially disease-modifying therapies in Parkinson’s disease has prompted the development of methods that can differentiate direct disease effects from compensatory processes. RECENT FINDINGS: PET studies have suggested a number of changes at the synaptic level to maintain integrity of dopaminergic systems. Functional MRI studies support the long-held belief that relatively intact cerebellar circuits may compensate for impaired basal ganglia function. Altered connectivity and increased spatial extent of activation also appear to be mechanisms through which motor and cognitive performance can be maintained. SUMMARY: Ascertaining which changes in brain activation in Parkinson’s disease are, in fact, compensatory represents a serious challenge. Compensatory mechanisms have been demonstrated from the microscopic, synaptic level to the macroscopic, system level. Augmentation of compensatory mechanisms, in addition to ameliorating the loss of dopaminergic neurons, may represent a joint strategy for overall minimization of disability.

Signaling mechanisms involving Wnt/beta-catenin and sonic hedgehog (Shh) are known to regulate the development of ventral midbrain (vMB) dopamine neurons. However, the interactions between these two mechanisms and how such interactions can be targeted to promote a maximal production of dopamine neurons are not fully understood. Here we show that conditional mouse mutants with region-specific activation of beta-catenin signaling in vMB using the Shh-Cre mice show a marked expansion of Sox2-, Ngn2-, and Otx2-positive progenitors but perturbs their cell cycle exit and reduces the generation of dopamine neurons. Furthermore, activation of beta-catenin in vMB also results in a progressive loss of Shh expression and Shh target genes. Such antagonistic effects between the activation of Wnt/beta-catenin and Shh can be recapitulated in vMB progenitors and in mouse embryonic stem cell cultures. Notwithstanding these antagonistic interactions, cell-type-specific activation of beta-catenin in the midline progenitors using the tyrosine hydroxylase-internal ribosomal entry site-Cre (Th-IRES-Cre) mice leads to increased dopaminergic neurogenesis. Together, these results indicate the presence of a delicate balance between Wnt/beta-catenin and Shh signaling mechanisms in the progression from progenitors to dopamine neurons. Persistent activation of beta-catenin in early progenitors perturbs their cell cycle progression and antagonizes Shh expression, whereas activation of beta-catenin in midline progenitors promotes the generation of dopamine neurons.