The medial shell region of the nucleus accumbens (msNAc) is a key center for the regulation of goal-directed behavior and is likely to be dysfunctional in neuropsychiatric disorders such as addiction, depression and schizophrenia. Nitric oxide (NO)-producing interneurons in the msNAc are potently modulated by dopamine (DA) and may play an important role in synaptic integration in msNAc networks. In this study, neuronal NO synthase (nNOS) activity was measured in anesthetized rats using amperometric microsensors implanted into the msNAc or via histochemical techniques. In amperometric studies, NO oxidation current was recorded prior to and during electrical stimulation of the ipsilateral fimbria. Fimbria stimulation elicited a frequency and intensity-dependent increase in msNAc NO efflux which was attenuated by systemic administration of the nNOS inhibitor NG-propyl-l-arginine. Parallel studies using NADPH-diaphorase histochemistry to assay nNOS activity produced highly complementary outcomes. Moreover, systemic administration of either a DA D1 receptor agonist or a DA D2 receptor antagonist potentiated nNOS activity in the msNAc elicited by fimbria stimulation. These observations demonstrate for the first time that NO synthesis in nNOS expressing interneurons in the msNAc is facilitated by robust activation of hippocampal afferents in a manner that is differentially modulated by DA D1 and D2 receptor activation.

1426 Objectives Yttrium-90 intra-arterial radioembolization is an effective therapy in patients with both unresectable hepatocellular carcinoma and metastatic disease to the liver, demonstrated to prolong survival. Recently, PET-CT has emerged as a promising technique for investigation of yttrium-90 dosimetry within the targeted neoplasm. The yttrium-90 decay to zirconium-90, a nearly pure β- particle emission, has been well described. Traditionally, post-procedural yttrium-90 microsphere distribution is imaged using SPECT through detection of indirect Bremsstrahlung radiation. However, a small percentage of yttrium-90 decay occurs through internal production of a β+/β- from the 0+/0+ transition state. Although a proportionally very small event, this positron emission can be captured with PET imaging. Recent advancements in post-processing software have allowed for quantification of detailed dose distribution. However, a variety of technical factors pertaining to image acquisition, postprocessing and dosimetric analysis potentially influence the reported dosimetric profile. Methods During initial investigations, a phantom is used with clinically appropriate dose deposited within the phantom liver. PET-CT is acquired of the phantom and data is post processed using a systematic variety of different reconstruction algorithms. Constructed data is then analyzed with MIM processing software (MIM Software Inc, Cleveland, OH) to validate volumetric and dosimetric analysis of the phantom. In a small cohort of patients receiving yttrium-90 radioembolization, PET-CT is then performed immediately following therapy. Volumetric regional analysis of tumor, liver and all imaged intra-abdominal solid organs is obtained using phantom validated methods. Results are compared with pre-procedure FDG PET-CT, correlated with a variety of other available imaging modalities and followed with post procedure FDG PET-CT, in order to assess for tumor recurrence and establish tumoricidal dosimetry. Results Initial phantom measurements document the wide influences and artificial variation that different PET-CT post processing techniques may potentially have upon acquired data. This work details the different strengths and weaknesses of each post-processing technique and elucidates methods to achieve the greatest accuracy in dosimetric analysis. Clinical data illustrates tumor imaging with multimodality comparison (illustrating correlation of PET-CT images with CT, MRI and ultrasonography). Pre and postprocedural imaging as well as clinical assessment are compared with yttrium-90 radioembolization dosimetric profile of each clinical case. Cases of both tumor recurrence and tumoricidal dosimetry are discussed. Furthermore, biodsitribution of yttrium-90 and assessment of dose heterogeneity is assessed. Experimental metrics are compared with more traditional measurements including tumor volume, and SUVmax/mean. Conclusions This translational research provides a critical initial analysis of yttrium-90 PET-CT techniques using phantom measurements to establish validated methods for image acquisition, post processing and dosimetric analysis. Validated methods are then directly applied to a clinical case series to demonstrate the potential value of detailed volumetric dosimetry in evaluating treatment response and potentially predicting tumor recurrence.

Gliomas comprise 80% of primary brain neoplasms, with glioblastoma multiforme being the most commonly diagnosed glioma. The annual incidence is 5.26 per 100,000, or 17,000 newly diagnosed cases per year in the United States. The incidence increases with age, peaking between the 6th and 8th decades. Gliomas are more common among Caucasians and occur more often in men. They can be associated with certain rare hereditary syndromes including Cowden, Turcot, Li-Fraumeni, neurofibromatosis type 1 and type 2, tuberous sclerosis, and familial schwannomatosis. Known risk factors include a history of ionizing radiation, family history of glioma, and certain genetic susceptibility variants that are weakly associated with glioma. Preventative measures have not been shown to decrease the risk of later development. In addition, screening tests are unwarranted since early diagnosis and treatment have not been shown to improve outcome.

Nitric oxide (NO) is a gaseous neurotransmitter that plays a significant role in the establishment and refinement of functional neural circuits. Genetic and post-mortem studies have suggested that neuronal NO synthase (NOS-1) activity may be compromised in frontal and temporal lobes, and related structures, in schizophrenia. The goal of this study was to determine if there is a link between neonatal disruptions in NO signalling and disturbances in the development and function of prefrontal-temporolimbic circuits. Neonatal rats were injected on postnatal days PD3-5 with the selective NOS-1 inhibitor Nω-propyl-L-arginine (NPA) and tested in adulthood (≥PD60) or as juveniles (PD30). Adult rats treated with NPA as neonates exhibited increased amphetamine-induced locomotion compared to animals receiving vehicle as neonates, whereas this was not observed in juvenile rats treated with NPA as neonates. Adult rats exposed to NPA as neonates also exhibited deficits in social interaction and short-term recognition memory, as well as reduced brain weight, compared to vehicle-treated controls. Finally, neonatal NPA exposure increased the responsiveness of nucleus accumbens neurons to prefrontal cortical input and disrupted the modulation of cortico-accumbens circuits by hippocampal afferents that is normally observed in adult animals. These results show for the first time that neonatal inhibition of NOS-1 during a critical neurodevelopmental period leads to aberrant behaviours that manifest in adulthood, as well as electrophysiological abnormalities in prefrontal-temporolimbic circuits. Greater understanding of the role of NOS-1 in the development of these circuits will shed light on how developmental insults translate to pathophysiology associated with schizophrenia.

Nitric oxide (NO) is a gaseous neurotransmitter synthesized in the nucleus accumbens (NAc) by aspiny interneurons containing neuronal NO synthase (nNOS). nNOS activity is readily assayed using nicotinamide adenine dinucleotide phosphate‐diaphorase (NADPH‐d) staining and is believed to be regulated by activation of dopamine (DA) D1‐ and D2‐like receptors. However, the role of DA transmission in the regulation of nNOS activity in identified subregions of the NAc remains unexplored. In this study, the impact of pharmacological manipulations of D1, D2, and NMDA receptors on nNOS activity was determined using optical density measures of NADPH‐d staining preformed in multiple subdivisions (core, medial shell, intermediate shell, and lateral shell) of the NAc. Awake behaving rats received systemic administration of vehicle and/or the following drugs ∼25 min prior to tissue harvesting: the nNOS inhibitor N G ‐propyl‐ L ‐arginine (NPA), the D1 receptor agonist SKF 81297, the D1 receptor antagonist SCH 23390, the D2 receptor agonist quinpirole (QNP), the D2 receptor antagonist eticlopride (ETI), or the NMDA receptor antagonist 3‐((±)2‐carboxypiperazin‐4‐yl)propyl‐1‐phosphonic acid (CPP). In vehicle‐treated animals, a distinct medial‐lateral histochemical gradient of NADPH‐d staining was observed, which was characterized by moderate staining in the core and medial shell and more robust staining in the intermediate and lateral shell. Administration of NPA, SCH 23390, QNP, and CPP attenuated staining preferentially in the intermediate and lateral shell. SKF 81297 and ETI administration consistently increased staining in the medial shell in a manner, which was attenuated following pretreatment with SCH 23390, QNP, NPA, and CPP. These observations demonstrate that nNOS activity measured in distinct subregions of the NAc is differentially modulated by DA D1 and D2 receptor activation. Moreover, these findings demonstrate for the first time that DA D1 and D2 receptor activation regulates the facilitatory influence of glutamatergic transmission on nNOS activity in the NAc medial shell via facilitation (D1) or suppression (D2) of NMDA receptor function. Synapse, 2012. © 2011 Wiley Periodicals, Inc.

Rationale It is known that dopamine (DA) D1 receptor activation stimulates striatal nitric oxide (NO) synthesis, whereas D2 receptor activation produces the opposite effect. However, the mechanisms involved in the dopaminergic modulation of nitric oxide synthase (NOS) are unknown. Objectives We hypothesized that the effects of DA on striatal NO signaling are dependent on ongoing glutamatergic activation of NOS. Therefore, the current study examined whether intact N -methyl- d -aspartic acid (NMDA) receptor activation is required for the dopaminergic modulation of NOS activity. Methods We assessed the impact of pharmacological manipulations of D1, D2, and NMDA receptors on NOS activity in the dorsal striatum and motor cortex using nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) histochemistry. Drugs were administered systemically to conscious animals and NADPH-d staining was quantified in these regions using ex vivo measurements of tissue optical density. Results Administration of the neuronal NOS inhibitor N G -propyl- l -arginine (NPA), the D1 receptor antagonist SCH 23390, and the NMDA receptor antagonist 3-phosphonopropyl-piperazine-2-carboxylic acid (CPP) all attenuated staining selectively in the striatum. Administration of the D2 receptor agonist quinpirole decreased NADPH-d staining in both the striatum and cortex. Striatal NADPH-d staining elicited by administration of the D1 receptor agonist SKF 81297 or the D2 receptor antagonist eticlopride was attenuated by NPA, SCH 23390, and CPP pretreatment. Quinpirole pretreatment also abolished the facilitatory effect of SKF 81297. Conclusions These studies show for the first time that ongoing NMDA receptor activation is necessary for the modulation of striatal NOS activity by both facilitatory (D1 receptor activation) and inhibitory (D2 receptor activation) dopaminergic signaling mechanisms.

The gaseous neurotransmitter nitric oxide plays an important role in the modulation of corticostriatal synaptic transmission. This study examined the impact of frontal cortex stimulation on striatal nitric oxide efflux and neuron activity in urethane-anesthetized rats using amperometric microsensor and single-unit extracellular recordings, respectively. Systemic administration of the neuronal nitric oxide synthase inhibitor 7-nitroindazole decreased spontaneous spike activity without affecting activity evoked by single-pulse stimulation of the ipsilateral cortex. Train (30 Hz) stimulation of the contralateral frontal cortex transiently increased nitric oxide efflux in a robust and reproducible manner. Evoked nitric oxide efflux was attenuated by systemic administration of 7-nitroindazole and the non-selective nitric oxide synthase inhibitor N-G-nitro-L-arginine methyl ester. Train stimulation of the contralateral cortex, in a manner identical to that used to evoke nitric oxide efflux, had variable effects on spike activity assessed during the train stimulation trial, but induced a short-term depression of cortically evoked activity in the first post-train stimulation trial. Interestingly, 7-nitroindazole potently decreased cortically evoked activity recorded during the train stimulation trial. Moreover, the short-term depression of spike activity induced by train stimulation was enhanced following pretreatment with 7-nitroindazole and attenuated after systemic administration of the dopamine D2 receptor antagonist eticlopride. These results demonstrate that robust activation of frontal cortical afferents in the intact animal activates a powerful nitric oxide-mediated feed-forward excitation which partially offsets concurrent D2 receptor-mediated short-term inhibitory influences on striatal neuron activity. Thus, nitric oxide signaling is likely to play an important role in the integration of corticostriatal sensorimotor information in striatal networks.