ANSTO :: Browsing by Author "Callaghan, PD"

Browsing by Author "Callaghan, PD"

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4D PET iterative deconvolution with spatiotemporal regularization for quantitative dynamic PET imaging
(Elsevier, 2015-09-01) Reilhac, A; Charil, A; Wimberley, CA; Angelis, GI; Hamze, H; Callaghan, PD; Garcia, MP; Boisson, F; Ryder, W; Meikle, SR; Grégoire, MC
Quantitative measurements in dynamic PET imaging are usually limited by the poor counting statistics particularly in short dynamic frames and by the low spatial resolution of the detection system, resulting in partial volume effects (PVEs). In this work, we present a fast and easy to implement method for the restoration of dynamic PET images that have suffered from both PVE and noise degradation. It is based on a weighted least squares iterative deconvolution approach of the dynamic PET image with spatial and temporal regularization. Using simulated dynamic [11C] Raclopride PET data with controlled biological variations in the striata between scans, we showed that the restoration method provides images which exhibit less noise and better contrast between emitting structures than the original images. In addition, the method is able to recover the true time activity curve in the striata region with an error below 3% while it was underestimated by more than 20% without correction. As a result, the method improves the accuracy and reduces the variability of the kinetic parameter estimates calculated from the corrected images. More importantly it increases the accuracy (from less than 66% to more than 95%) of measured biological variations as well as their statistical detectivity. © 2015 Elsevier Inc.
5-HT1A Receptor
(Springer-Verlag Berlin Heidelberg, 2010) Callaghan, PD; McGregor, IS; Thompson, MR
Not available
Adolescent rats find repeated Δ9-THC less aversive than adult rats but display greater residual cognitive deficits and changes in hippocampal protein expression following exposure
(Springer Nature, 2007-06-20) Quinn, HR; Matsumoto, I; Callaghan, PD; Long, LE; Arnold, JC; Gunasekaran, N; Thompson, MR; Dawson, B; Mallet, PE; Kashem, MA; Matsda-Matsumoto, H; Iwazki, T; McGregor, IS
The current study examined whether adolescent rats are more vulnerable than adult rats to the lasting adverse effects of cannabinoid exposure on brain and behavior. Male Wistar rats were repeatedly exposed to Δ9-tetrahydrocannabinol (Δ(9)-THC, 5 mg/kg i.p.) in a place-conditioning paradigm during either the adolescent (post-natal day 28+) or adult (post-natal day 60+) developmental stages. Adult rats avoided a Δ(9)-THC-paired environment after either four or eight pairings and this avoidance persisted for at least 16 days following the final Δ(9)-THC injection. In contrast, adolescent rats showed no significant place aversion. Adult Δ(9)-THC-treated rats produced more vocalizations than adolescent rats when handled during the intoxicated state, also suggesting greater drug-induced aversion. After a 10-15 day washout, both adult and adolescent Δ(9)-THC pretreated rats showed decreased social interaction, while onlyΔ (9)-THC pretreated adolescent rats showed significantly impaired object recognition memory. Seventeen days following their last Δ(9)-THC injection, rats were euthanised and hippocampal tissue processed using two-dimensional gel electrophoresis proteomics. There was no evidence of residual Δ(9)-THC being present in blood at this time. Proteomic analysis uncovered 27 proteins, many involved in regulating oxidative stress/mitochondrial functioning and cytoarchitecture, which were differentially expressed in adolescent Δ(9)-THC pretreated rats relative to adolescent controls. In adults, only 10 hippocampal proteins were differentially expressed in Δ(9)-THC compared to vehicle-pretreated controls. Overall these findings suggest that adolescent rats find repeated Δ(9)-THC exposure less aversive than adults, but that cannabinoid exposure causes greater lasting memory deficits and hippocampal alterations in adolescent than adult rats. © 2018 Springer Nature
Aggregation in quads but not pairs of rats exposed to cat odor or bright light
(Elsevier Science BV, 2012-07-01) Bowen, MT; Keats, K; Kendig, MD; Cakic, V; Callaghan, PD; McGregor, IS
In many prey species aggregation of individuals is a defensive strategy commonly employed in response to predators and predator-related cues. However, very little work has explored this adaptive response in laboratory rats. It is known that individual rats show characteristic defensive responses to predator odors, such as hiding, avoidance, inhibition of foraging, feeding and reproduction, and risk assessment directed toward the odor source. However, whether these species-typical responses in individuals are altered in the presence of other conspecifics is yet to be characterized. The present study therefore examined the defensive response of groups of two rats (dyads) or four rats (quads) to two unconditioned stressors: bright ambient light and cat odor (a 2 g ball of cat fur). The dyads and quads were formed from familiar cage mates and test sessions (20 min) occurred in a large open arena (1200 mm(2)) to which the rats had been extensively habituated under dark conditions. The results showed that when quads of rats were exposed to either cat odor or bright light in this arena, they showed characteristic increases in close social proximity, termed "huddling". A tight grouping of 3 (triplet) or 4 (quad) rats was commonly seen in response to cat fur, while triplets were more commonly seen in response to bright light. Interestingly there was no evidence for increased social proximity in dyads exposed to either stressor, only in quads. However, cat odor caused other signs of fear (such as decreased locomotor activity and increased defecation) in both quads and dyads. It is concluded that huddling is a rodent defensive strategy in rats when anxiogenic stimuli are encountered by larger groups of rats.© 2012, Elsevier Ltd.
Assessment of neuroinflammation in transferred EAE via a translocator protein ligand
(IntechOpen, 2012-02-03) Mattner, F; Staykova, M; Callaghan, PD; Berghofer, PJ; Ballantyne, P; Grégoire, MC; Fordham, S; Pham, TQ; Rahardjo, GL; Jackson, TW; Linares, D; Katsifis, A
Neuroinflammation is involved in the pathogenesis and progression of neurological disorders such as Alzheimer's disease and multiple sclerosis (MS) (Doorduin et al., 2008). MS has been considered a T cell-mediated autoimmune disorder of the central nervous system (CNS), characterized by inflammatory cell infiltration and myelin destruction (Hauser et al., 1986) and focal demyelinated lesions in the white matter are the traditional hallmarks of MS. However more recent evidence suggests more widespread damage to the brain and spinal cord, to areas of white matter distant from the inflammatory lesions and demyelination of deep and cortical grey matter (McFarland & Martin, 2007). Experimental autoimmune encephalomyelitis (EAE) is an extensively used model of T-cell mediated CNS inflammation; modelling disease processes involved in MS. EAE can be induced in several species by immunization with myelin antigens or via adoptive transfer of myelin-reactive T cells. The models of EAE in rodents [actively induced and transferred] provide information about different phases [inflammation, demyelination and remyelination] and types [monophasic, chronic-relapsing and chronic-progressive] of the human disease multiple sclerosis and a vast amount of clinical and histopathologic data has been accumulated through the decades. A key aim of current investigations is developing the ability to recognise the early symptoms of the disease and to follow its course and response to treatment. Molecular imaging is a rapidly evolving field of research that involves the evaluation of biochemical and physiological processes utilising specific, radioactive, fluorescent and magnetic resonance imaging probes. However, it is positron emission tomography (PET) and single photon emission computer tomography (SPECT) which, due to their exquisite sensitivity involving specifically designed radiolabelled molecules, that is leading the way in molecular imaging and has greatly enabled the non-invasive “visualisation” of many diseases in both animal models and humans. Furthermore, PET and SPECT molecular imaging are providing invaluable imaging data based on a biochemical-molecular biology interaction rather than from the traditional anatomical view. Increasingly, PET and SPECT radiotracers have been exploited to study or identify molecular biomarkers of disease, monitor disease progression, determining the effects of a drug on a particular pathology and assess the pharmacokinetic behaviour of pharmaceuticals in vivo. Significantly, these new imaging systems provide investigators with an unprecedented ability to examine and measure in vivo biological and pharmacological processes over time in the same animals thus reducing experimental variability, time and costs. Molecular imaging based on the radiotracer principle allows chemical processes ranging from cellular events, to cellular communication and interaction in their environment, to the organisation and function of complete tissue and organs to be studied in real time without perturbation. One of the key benefits of molecular imaging is a technique that allows longitudinal studies vital for monitoring intra-individual progression in disease, or regression with supplementary pharmacotherapies. This is key in animal models of diseases such as MS, where there is significant intra-individual variability in the disease course and severity. Recent investigations have proposed the translocator protein (TSPO; 18 kDa), also known as the peripheral benzodiazepine receptor (PBR), as a molecular target for imaging neuroinflammation (Chen & Guilarte, 2008; Doorduin et al., 2008; Papadopoulos et al., 2006). TSPO (18 kDa) is a multimeric protein consisting of five transmembrane helices, which, in association with a 32 kDa subunit that functions as a voltage dependent anion channel and a 30 kDa subunit that functions as an adenine nucleotide carrier forms part of a hetero-oligomeric complex (McEnery et al., 1992) responsible for cholesterol, heme and calcium transport in specific tissue. TSPO is primarily located on the outer mitochondrial membrane and is predominantly expressed in visceral organs (kidney, heart) and the steroid hormone producing cells of the adrenal cortex, testis and ovaries. In the central nervous system (CNS), TSPO is sparsely expressed under normal physiological conditions, however its expression is significantly upregulated following CNS injury (Chen et al., 2004; Papadopoulos et al., 1997; Venneti et al., 2006; Venneti, et al., 2008). Several studies have identified activated glial cells as the cells responsible for TSPO upregulation in inflamed brain tissue, both in humans and in experimental models (Mattner et al., 2011; Myers et al., 1991a; Stephenson et al., 1995; Vowinckel et al., 1997) and the TSPO ligand [11C]-PK11195 was one of the first PET ligands used for imaging activated microglia in various neurodegenerative diseases (Venneti et al., 2006). Although [11C]-(R)-PK11195 is widely used for imaging of microglia, its considerable high plasma protein binding, high levels of nonspecific binding, relatively poor blood–brain barrier permeability and short half-life, limits its use in brain imaging (Chauveau et al., 2008). Recently, alternative PET radioligands for TSPO including the phenoxyarylacetamide derivative [11C]-DAA1106 and its analogues (Gulyas et al., 2009; Takano et al., 2010; Venneti et al., 2008), the imidazopyridines (PBR111) and its analogues (Boutin et al., 2007a; Fookes et al., 2008) and the pyrazolo[1,5-a]pyrimidine derivatives [18F]-DPA-714 and [11C]-DPA-713 (Boutin et al., 2007b; James et al., 2008) have been investigated. In addition to imaging with PET, recent advances in new generation of hybrid SPECT imaging systems enabling increased resolution and morphological documentation with associated computed tomography have been made for use clinically and preclinically. These advances have created a need and an opportunity for SPECT tracers; particularly those incorporating the longer lived radiotracer iodine-123 (t ½ = 13.2 h), to facilitate extended longitudinal imaging studies. In this study the recently developed high-affinity TSPO, SPECT ligand, 6-chloro-2-(4′-iodophenyl)-3-(N,N-diethyl)-imidazo[1,2-a]pyridine-3-acetamide or CLINDE , was used to explore the expression of activated glia in a model of transferred EAE (tEAE). [123I]-CLINDE has demonstrated its potency and specificity for TSPO binding, its ability to penetrate the blood-brain barrier and suitable pharmacokinetics for SPECT imaging studies (Mattner et al., 2008). It has also been shown that [123I]-CLINDE was able to detect in vivo inflammatory processes characterized by increased density of TSPO in several animal models (Arlicot et al., 2008; Arlicot et al., 2010; Mattner et al., 2005; Mattner et al., 2011; Song et al., 2010), thus representing a promising SPECT radiotracer for imaging neuroinflammation. The present study aimed to investigate the effectiveness of [123I]-CLINDE to detect and quantify the activated glia and consequently correlate the intensity of TSPO upregulation with the severity of disease in a model of tEAE. © 2022 IntechOpen (Open Access).
Bioaccumulation and biodistribution of selenium in metamorphosing tadpoles
(American Chemical Society, 2017-04-19) Lanctôt, CM; Cresswell, T; Callaghan, PD; Melvin, SD
Selenium is an important macronutrient with a very narrow margin between essentiality and toxicity. Amphibians are hypothesized to be particularly sensitive due to the potential for metamorphosis-driven mobilization, which could transfer or concentrate contaminant burdens within specific organs. We explored the potential role of tissue degeneration and remodeling during anuran metamorphosis as a mechanism for altering tissue-specific Se burdens. Limnodynastes peronii tadpoles were exposed to dissolved 75Se (as selenite) for 7 days and depurated until completion of metamorphosis. Bioaccumulation and retention kinetics were assessed in whole tadpoles and excised tissues using gamma spectroscopy, and temporal changes in biodistribution were assessed using autoradiography. Tadpoles retained Se throughout metamorphosis, and partitioned the element predominantly within digestive and excretory tissues, including livers > mesonephros > guts > gallbladder. Importantly, our results demonstrate that Se biodistribution varies significantly throughout development. This is indicative of tissue transference, and particularly in tissues developing de novo after depuration. To the best of our knowledge, this is the first study demonstrating Se transference during metamorphic tissue remodelling. Further research is warranted to explore the fate and metabolism of Se (and other metal and metalloids) during anuran development and the implications of transference for influencing toxicity. © 2017 American Chemical Society
Bioaccumulation kinetics and internal distribution of the fission products radiocaesium and radiostrontium in an estuarine crab
(Elsevier, 2021-04-15) Cresswell, T; Prentice, E; Howell, NR; Callaghan, PD; Metian, M; Johansen, MP
Crab has been designated by the ICRP as one of twelve reference/model organisms for understanding the impacts of radionuclide releases on the biosphere. However, radionuclide-crab interaction data are sparse compared with other reference organisms (e.g. deer, earthworm). This study used an estuarine crab (Paragrapsus laevis) to investigate the contribution of water, diet and sediment sources to radionuclide (134Cs and 85Sr) bioaccumulation kinetics using live-animal radiotracing. The distribution of each radionuclide within the crab tissues was determined using dissection, whole-body autoradiography and synchrotron X-ray Fluorescence Microscopy (XFM). When moulting occurred during exposure, it caused significant increases in 85Sr bioaccumulation and efflux of 134Cs under constant aqueous exposure. Dietary assimilation efficiencies were determined as 55 ± 1% for 134Cs and 49 ± 3% for 85Sr. 85Sr concentrated in gonads more than other organs, resulting in proportionally greater radiation dose to the reproductive organs and requires further investigation. 134Cs was found in most soft tissues and was closely associated with S and K. Biodynamic modelling suggested that diet accounted for 90–97% of whole-body 137Cs, while water accounted for 59–81% of 90Sr. Our new data on crab, as a representative invertebrate, improves understanding of the impacts of planned or accidental releases of fission radionuclides on marine ecology. Crown Copyright © 2020 Published by Elsevier B.V.
Bioaccumulation kinetics and organ distribution of cadmium and zinc in the freshwater decapod crustacean macrobrachium australiense
(ACS Publications, 2014-12-24) Cresswell, T; Simpson, SL; Mazumder, D; Callaghan, PD; Nguyen, AP
This study used the radioisotopes 109Cd and 65Zn to explore the uptake, retention and organ distribution of these nonessential and essential metals from solution by the freshwater decapod crustacean Macrobrachium australiense. Three treatments consisting of cadmium alone, zinc alone, and a mixture of cadmium and zinc were used to determine the differences in uptake and efflux rates of each metal individually and in the metal mixture over a three-week period, followed by depuration for 2 weeks in metal-free water using live-animal gamma-spectrometry. Following exposure, prawns were cryosectioned and the spatial distribution of radionuclides visualized using autoradiography. Metal uptake and efflux rates were the same in the individual and mixed-metal exposures, and efflux rates were close to zero. The majority of cadmium uptake was localized within the gills and hepatopancreas, while zinc accumulated in the antennal gland at concentrations orders of magnitude greater than in other organs. This suggested that M. australiense may process zinc much faster than cadmium by internally transporting the accumulated zinc to the antennal gland. The combination of uptake studies and autoradiography greatly increases our understanding of how metal transport kinetics and internal processing may influence the toxicity of essential and nonessential metals in the environment. © 2014 American Chemical Society
Central nervous system expression and PET imaging of the translocator protein in relapsing–remitting experimental autoimmune encephalomyelitis
(Society of Nuclear Medicine and Molecular Imaging, 2013-01-15) Mattner, F; Staykova, M; Berghofer, PJ; Wong, HJ; Fordham, S; Callaghan, PD; Jackson, TW; Pham, TQ; Grégoire, MC; Zahra, D; Rahardjo, GL; Linares, D; Katsifis, A
Glial neuroinflammation is associated with the development and progression of multiple sclerosis. PET imaging offers a unique opportunity to evaluate neuroinflammatory processes longitudinally in a noninvasive and clinically translational manner. (18)F-PBR111 is a newly developed PET radiopharmaceutical with high affinity and selectivity for the translocator protein (TSPO), expressed on activated glia. This study aimed to investigate neuroinflammation at different phases of relapsing-remitting (RR) experimental autoimmune encephalomyelitis (EAE) in the brains of SJL/J mice by postmortem histologic analysis and in vivo by PET imaging with (18)F-PBR111. METHODS: RR EAE was induced by immunization with PLP(139-151) peptide in complete Freund's adjuvant. Naive female SJL/J mice and mice immunized with saline-complete Freund's adjuvant were used as controls. The biodistribution of (18)F-PBR111 was measured in 13 areas of the central nervous system and compared with PET imaging results during different phases of RR EAE. The extents of TSPO expression and glial activation were assessed with immunohistochemistry, immunofluorescence, and a real-time polymerase chain reaction. RESULTS: There was significant TSPO expression in all of the central nervous system areas studied at the peak of the first clinical episode and, importantly, at the preclinical stage. In contrast, only a few TSPO-positive cells were observed at the second episode. At the third episode, there was again an increase in TSPO expression. TSPO expression was associated with microglial cells or macrophages without obvious astrocyte labeling. The dynamics of (18)F-PBR111 uptake in the brain, as measured by in vivo PET imaging and biodistribution, followed the pattern of TSPO expression during RR EAE. CONCLUSION: PET imaging with the TSPO ligand (18)F-PBR111 clearly reflected the dynamics of microglial activation in the SJL/J mouse model of RR EAE. The results are the first to highlight the discrepancy between the clinical symptoms of EAE and TSPO expression in the brain, as measured by PET imaging at the peaks of various EAE episodes. The results suggest a significant role for PET imaging investigations of neuroinflammation in multiple sclerosis and allow for in vivo follow-up of antiinflammatory treatment strategies. © 2013 Society of Nuclear Medicine and Molecular Imaging, Inc.
Characterisation of peripheral benzodiazepine receptors changes in early phase of epileptogenesis in the rat with PET and [18F]PBR111
(Society of Nuclear Medicine, 2009-05) Grégoire, MC; Dedeurwaerdere, S; Callaghan, PD; Loc'h, C; Pham, TQ; Katsifis, A
The current project aims at investigating the role of microglial activation in epileptogenesis by estimating PBR changes in the rat brain with a new and highly specific PBR ligand, [18F]PBR111, during the early phase, i.e. one week after status epilepticus induced by kainic acid (KA). Methods Four controls and 6 KA rats were scanned for 180 minutes with our small animal PET/CT under a triple-injection protocol. The results presented here cover only the first 60 minutes after injection of 0.06nmoles of [18F]PBR111. Arterial blood samples were withdrawn and metabolite corrected plasma time-activity curves were derived. Each CT and PET data were co-registered to an age and strain matched rat brain atlas containing 25 Regions-Of-Interest (ROIs). The Volume of Distribution (Vd) were calculated for each region. Whole-brain-normalised Vd (nVd) were also calculated to assess local variations. Results Compared to controls, KA-treated rats show a 2 to 3-fold increase of the Vd in all brain areas except the midbrain. No significant asymmetry was detected (< 9%), so the ROIs were grouped. Normalized Vd values (Table 1) show that Amygdala, Striata, Thalamus and Hippocampus are predominantly involved. No significant changes were detected in the midbrain and all cortical areas. Estimates of receptors densitiy (Bmax) and apparent affinity (KdVr) will be calculated from the full kinetics (three phases) and reported later. Conclusions This in vivo imaging study has identified significant microglial activation during early epileptogenesis in several brain regions which are known to play a key role in chronic epilepsy.
Comparative analysis of novel decynium-22 analogs to inhibit transport by the low-affinity, high-capacity monoamine transporters, organic cation transporters 2 and 3, and plasma membrane monoamine transporter
(Elsevier B. V., 2019-01) Fraser-Spears, R; Krause-Heuer, AM; Basiouny, M; Mayer, FP; Manishimwe, M; Wyatt, NA; Dobrowolski, JC; Roberts, MP; Greguric, ID; Kumar, N; Koek, W; Sitte, HH; Callaghan, PD; Fraser, BH; Daws, LC
Growing evidence supports involvement of low-affinity/high-capacity organic cation transporters (OCTs) and plasma membrane monoamine transporter (PMAT) in regulating clearance of monoamines. Currently decynium-22 (D22) is the best pharmacological tool to study these transporters, however it does not readily discriminate among them, underscoring a need to develop compounds with greater selectivity for each of these transporters. We developed seven D22 analogs, and previously reported that some have lower affinity for α1-adrenoceptors than D22 and showed antidepressant-like activity in mice. Here, we extend these findings to determine the affinity of these analogs for OCT2, OCT3 and PMAT, as well as serotonin, norepinephrine and dopamine transporters (SERT, NET and DAT) using a combination of uptake competition with [3H]methyl-4-phenylpyridinium acetate in overexpressed HEK cells and [3H]citalopram, [3H]nisoxetine and [3H]WIN 35428 displacement binding in mouse hippocampal and striatal preparations. Like D22, all analogs showed greater binding affinities for OCT3 than OCT2 and PMAT. However, unlike D22, some analogs also showed modest affinity for SERT and DAT. Dual OCT3/SERT and/or OCT3/DAT actions of certain analogs may help explain their ability to produce antidepressant-like effects in mice and help account for our previous findings that D22 lacks antidepressant-like effects unless SERT function is either genetically or pharmacologically compromised. Though these analogs are not superior than D22 in discriminating among OCTs/PMAT, our findings point to development of compounds with combined ability to inhibit both low-affinity/high-capacity transporters, such as OCT3, and high-affinity/low-capacity transporters, such as SERT, as therapeutics with potentially improved efficacy for treatment of psychiatric disorders. © 2021 Elsevier B.V.
Comparison of in vivo binding properties of the 18-kDa translocator protein (TSPO) ligands [18F]PBR102 and [18F]PBR111 in a model of excitotoxin-induced neuroinflammation
(Springer Link, 2015-01) Callaghan, PD; Wimberley, CA; Rahardjo, GL; Berghofer, PJ; Pham, TQ; Jackson, TW; Zahra, D; Bourdier, T; Wyatt, N; Greguric, ID; Howell, NR; Siegele, R; Pastuovic, Z; Mattner, F; Loc'h, C; Grégoire, MC; Katsifis, A
The in vivo binding parameters of the novel imidazopyridine TSPO ligand [18F]PBR102 were assessed and compared with those of [18F]PBR111 in a rodent model of neuroinflammation. The validity of the key assumptions of the simplified reference tissue model (SRTM) for estimation of binding potential (BP) was determined, with validation against a two-tissue compartment model (2TC). Methods Acute neuroinflammation was assessed 7 days after unilateral stereotaxic administration of (R,S)-α-amino-3-hydroxy-5-methyl-4-isoxazolopropionique (AMPA) in anaesthetized adult Wistar rats. Anaesthetized rats were implanted with a femoral arterial cannula then injected with a low mass of [18F]PBR102 or [18F]PBR111 and dynamic images were acquired over 60 min using an INVEON PET/CT camera. Another population of rats underwent the same PET protocol after pretreatment with a presaturating mass of the same unlabelled tracer (1 mg/kg) to assess the validity of the reference region for SRTM analysis. Arterial blood was sampled during imaging, allowing pharmacokinetic determination of radiotracer concentrations. Plasma activity concentration–time curves were corrected for unchanged tracer based on metabolic characterization experiments in a separate cohort of Wistar rats. The stability of neuroinflammation in both imaging cohorts was assessed by [125I] CLINDE TSPO quantitative autoradiography, OX42/GFAP immunohistochemistry, Fluoro-Jade C histology, and elemental mapping using microparticle-induced x-ray emission spectroscopy. The BP of each ligand were assessed in the two cohorts of lesioned animals using both SRTM and a 2TC with arterial parent compound concentration, coupled with the results from the presaturation cohort for comparison and validation of the SRTM. Results The BPs of [18F]PBR102 [18F]PBR111 were equivalent, with improved signal-to-noise ratio and sensitivity compared with [11C]PK11195. The presaturation study showed differences in the volume of distribution between the ipsilateral striatum and the striatum contralateral to the injury (0.7) indicating that an assumption of the SRTM was not met. The modelling indicated that the BPs were consistent for both ligands. Between the SRTM and 2TC model, the BPs were highly correlated, but there was a bias in BP. Conclusion [18F]PBR102 and [18F]PBR111 have equivalent binding properties in vivo, displaying significantly greater BPs with lower signal-to-noise ratio than [11C]PK11195. While an assumption of the SRTM was not met, this modelling approach was validated against 2TC modelling for both ligands, facilitating future use in longitudinal PET imaging of neuroinflammation.© 2014, Springer Nature
Differential activity of decynium-22 analogs: novel targets for probing low-affinity/high-capacity biogenic amine transporters
(Federation of American Societies for Experimental Biology (FASEB), 2015-04-01) Fraser, R; Owens, A; Wyatt, NA; Krause-Heuer, AM; Greguric, ID; Callaghan, PD; Fraser, BH; Daws, LC
We study neurotransmitter clearance by low-affinity, high-capacity uptake-2 transporters. This family includes plasma membrane monoamine transporter (PMAT) and three organic cation transporter isoforms (OCT1-3). We have shown uptake-2 transporters limit the effectiveness of the selective serotonin reuptake inhibitor (SSRI) fluvoxamine. Discerning the transporter type(s) involved is restricted by the lack of highly selective ligands. This project examines the pharmacological characteristics of novel uptake-2 compounds. Activity of ANSTO analogs, structurally based on the non-selective inhibitor decynium 22 (D22), was tested in human OCT3-HEK cells. Ligand competitions of [3H]MPP+ uptake were measured in whole, attached cells. Compared to D22, dose-responses of ANSTO compounds shifted 1- or 2 log-rightward, indicating reduced potency to inhibit OCT3 mediated [3H]MPP+ uptake. ANSTO analogs displayed similar potencies to corticosterone and may have higher selectivity at alternate uptake 2 subtypes. © 2015 Federation of American Societies for Experimental Biology (FASEB)
Differential behavioural and neurochemical outcomes from chronic paroxetine treatment in adolescent and adult rats: a model of adverse antidepressant effects in human adolescents?
(International Journal of Neuropsychopharmacology., 2011-05-01) Karanges, E; Li, KM; Motbey, CP; Callaghan, PD; Katsifis, A; McGregor, IS
Selective serotonin reuptake inhibitor use is associated with increased risk of suicidal ideation in adolescent humans, yet the neuropharmacological basis of this phenomenon is unknown. Consequently, we examined the behavioural and neurochemical effects of chronic paroxetine (PRX) treatment in adult and adolescent rats. Rats received PRX in their drinking water (target dose 10 mg/kg) for 22 d, during which time they were assessed for depression- and anxiety-like behaviours. Subsequent ex-vivo analyses examined serum PRX concentrations, striatal neurotransmitter content, and regional serotonin and dopamine transporter (SERT, DAT) binding density. After 11–12 d treatment, PRX-treated adolescent rats showed a significant inhibition of social interaction while adults were unaffected. After 19–20 d treatment, adolescents failed to show an antidepressant-like effect of PRX treatment on the forced swim test (FST), while PRX-treated adults showed a typical decrease in immobility and increase in swimming. Two PRX-treated adolescents died unexpectedly after the FST suggesting a compromised response to physical stress. Despite their greater apparent adverse reaction to the drug, adolescents had significantly lower plasma PRX than adults at day 22 of treatment. Chronic PRX treatment had similar effects in adults and adolescents on striatal 5-HT (unchanged relative to controls) and 5-HIAA levels (decreased), while markers of dopaminergic function (DOPAC, HVA, DA turnover) were increased in adults only. SERT density was up-regulated in the amygdala in PRX-treated adolescents only while DAT density in the nucleus accumbens was down-regulated only in PRX-treated adults. These data suggest that the immature rat brain responds differently to PRX and that this might be of use in modelling the atypical response of human adolescents to antidepressants. The age-specific PRX-induced changes in dopaminergic markers and SERT and DAT binding provide clues as to the neural mechanisms underlying adverse PRX effects in adolescent humans. © 2011, Cambridge University Press
The differential binding of antipsychotic drugs to the ABC transporter P-glycoprotein predicts cannabinoid–antipsychotic drug interactions
(Springer, 2017-03-08) Brzozowska, NI; de Tonnerre, EJ; Li, KM; Wang, XS; Boucher, AA; Callaghan, PD; Kuligowski, M; Wong, A; Arnold, JC
Cannabis use increases rates of psychotic relapse and treatment failure in schizophrenia patients. Clinical studies suggest that cannabis use reduces the efficacy of antipsychotic drugs, but there has been no direct demonstration of this in a controlled study. The present study demonstrates that exposure to the principal phytocannabinoid, Δ9-tetrahydrocannabinol (THC), reverses the neurobehavioral effects of the antipsychotic drug risperidone in mice. THC exposure did not influence D2 and 5-HT2A receptor binding, the major targets of antipsychotic action, but it lowered the brain concentrations of risperidone and its active metabolite, 9-hydroxy risperidone. As risperidone and its active metabolite are excellent substrates of the ABC transporter P-glycoprotein (P-gp), we hypothesized that THC might increase P-gp expression at the blood–brain barrier (BBB) and thus enhance efflux of risperidone and its metabolite from brain tissue. We confirmed that the brain disposition of risperidone and 9-hydroxy risperidone is strongly influenced by P-gp, as P-gp knockout mice displayed greater brain concentrations of these drugs than wild-type mice. Furthermore, we demonstrated that THC exposure increased P-gp expression in various brain regions important to risperidone’s antipsychotic action. We then showed that THC exposure did not influence the neurobehavioral effects of clozapine. Clozapine shares a very similar antipsychotic mode of action to risperidone, but unlike risperidone is not a P-gp substrate. Our results imply that clozapine or non-P-gp substrate antipsychotic drugs may be better first-line treatments for schizophrenia patients with a history of cannabis use. © 2017 American College of Neuropsychopharmacology, published by Springer Nature Limited.
Entactogen
(Springer-Verlag Berlin Heidelberg, 2010) Callaghan, PD; McGregor, IS; Thompson, MR
Entactogens are drugs, including MDMA (Ecstasy) and other MDxx structure compounds, that cause distinctive prosocial, emotional, and sensory effects in users. Most of them are substituted amphetamine compounds of the phenethylamine class. © 2010 Springer-Verlag Berlin Heidelberg
Evaluation of the antidepressant therapeutic potential of isocyanine and pseudoisocyanine analogues of the organic cation decynium-22
(Elsevier B. V., 2017-09-08) Krause-Heuer, AM; Fraser-Spears, R; Dobrowolski, JC; Ashford, ME; Wyatt, NA; Roberts, MP; Gould, GG; Cheah, WC; Ng, CKL; Bhadbhade, MM; Zhang, B; Greguric, ID; Wheate, NJ; Kumar, N; Koek, W; Callaghan, PD; Daws, LC; Fraser, BH
Antidepressant-like activity Herein we describe the synthesis and evaluation of antidepressant properties of seven analogues (1–7) of the low affinity/high capacity transporter blocker decynium-22 (D-22). All analogues (1–7) were synthesized via base promoted coupling reactions between N-alkylated-2-methylquinolinium iodides or N-alkylated-4-methylquinolinium iodides and electrophilic N-alkylated-2-iodoquinolinium iodides. All final compounds were purified by re-crystallization or preparative HPLC and initial evaluation studies included; 1) screening for in vitro α1-adrenoceptor activity (a property that can lead to unwanted side-effects), 2) measuring antidepressant-like activity in a mouse tail suspension test (TST), and 3) measuring effects upon mouse locomotion. The results showed some analogues have lower affinities at α1-adrenoceptors compared to D-22 and showed antidepressant-like activity without the need for co-administration of SSRIs. Additionally, many analogues did not affect mouse locomotion to the same extent as D-22. Plans for additional evaluations of these promising analogues, including measurement of antidepressant-like activity with co-administration of selective serotonin re-uptake inhibitors (SSRIs), are outlined. © 2017 Elsevier B.V.
Evaluation of the PBR ligand [123I]CLINDE in an animal model of experimental autoimmune encephalomyelitis
(Australasian Quaternary Association, 2008-05-01) Mattner, F; Linares, D; Staykova, M; Grégoire, MC; Pham, TQ; Bourdier, T; Quinlivan, M; Callaghan, PD; Willenborg, DO; Katsifis, A
Objectives: The aim of this study was to evaluate the Peripheral Benzodiazepine Receptor (PBR) radioligand [123I]CLINDE in the rat inflammatory disease model of Experimental Autoimmune Encephalomyelitis (EAE). Methods: EAE was induced with blast cells collected from spleen and lymph nodes of Lewis rats induced with myelin basic protein and complete Freund's adjuvant. Biodistribution with [123I]CLINDE was undertaken on EAE rats exhibiting different disease severity and compared to controls.The relationship between inflammatory lesions and tracer uptake was investigated using ex vivo autoradiography and immunohistochemistry. Results: Disease severity was confirmed by histopathology in spinal cord. Results indicate enhanced uptake of [123I]CLINDE in all animals induced with EAE compared to controls. This uptake reflected the ascending nature of the inflammatory lesions ie. uptake in the lumbar spinal cord > thoracic cord > cervical cord > medulla > cerebellum. Uptake of [123I]CLINDE in the lumbar and thoracic cord correlated with disease severity. A 2 and 3 fold enhancement in PBR expression was observed in the brain and spinal cord of animals with a clinical score of 3 compared to controls. Regional [123I]CLINDE uptake closely correlated with localisation of PBR, shown using autoradiography and immunohistochemisty. Conclusions: These results demonstrate the ability of [123I]CLINDE to measure in vivo changes of PBR density according to area of involvement and the severity of disease suggesting it as a potential SPECT tracer for the study of inflammation and multiple sclerosis. © 2022 Journal of Nuclear Medicine
Fluorine-18 radiolabelling and in vitro / in vivo metabolism of [18F]D4-PBR111
(John Wiley & Sons, Inc, 2019-05-26) Wyatt, NA; Safavi-Naeini, M; Wotherspoon, ATL; Arthur, A; Nguyen, AP; Parmar, A; Hamze, H; Day, CM; Zahra, D; Matesic, L; Davis, E; Rahardjo, GL; Yepuri, NR; Shepherd, R; Murphy, RB; Pham, TQ; Nguyen, VH; Callaghan, PD; Holden, PJ; Grégoire, MC; Darwish, TA; Fraser, BH
Objectives The purinergic receptor P2X ligand-gated ion channel type 7 (P2X7R) is an adenosine triphosphate (ATP)-gated ion-channel, and P2X7R is a key player in inflammation. P2X7R is an emerging therapeutic target in central nervous system (CNS) diseases including Alzheimer's disease (AD) and Parkinson's disease (PD), because P2X7R also plays a pivotal role in neuroinflammation. P2X7R represents a potential molecular imaging target for neuroinflammation via biomedical imaging technique positron emission tomography (PET), and several radioligands targeting P2X7R have been developed and evaluated in animals. In our previous work, we have developed and characterized [11C]GSK1482160 as a P2X7R radioligand for neuroinflammation,2 clinical evaluation of [11C]GSK1482160 in healthy controls and patients is currently underway, and the estimation of radiation dosimetry for [11C]GSK1482160 in normal human subjects has been reported.3 Since the half-life (t1/2) of radionuclide carbon-11 is only 20.4 min, it is attractive for us to develop derivatives of [11C]GSK1482160, which can be labeled with the radionuclide fluorine-18 (t1/2, 109.7 min), and a fluorine-18 ligand would be ideal for widespread use.4 To this end, a series of [18F]fluoroalkyl including [18F]fluoromethyl (FM), [18F]fluoroethyl (FE), and [18F]fluoropropyl (FP) derivatives of GSK1482160 have been prepared and examined as new potential P2X7R radioligands. © 2019 The Authors
From ultrasocial to antisocial: a role for oxytocin in the acute reinforcing effects and long‐term adverse consequences of drug use?
(The British Pharmacological Society, 2009-01-29) McGregor, IS; Callaghan, PD; Hunt, GE
Addictive drugs can profoundly affect social behaviour both acutely and in the long-term. Effects range from the artificial sociability imbued by various intoxicating agents to the depressed and socially withdrawn state frequently observed in chronic drug users. Understanding such effects is of great potential significance in addiction neurobiology. In this review we focus on the ‘social neuropeptide’ oxytocin and its possible role in acute and long-term effects of commonly used drugs. Oxytocin regulates social affiliation and social recognition in many species and modulates anxiety, mood and aggression. Recent evidence suggests that popular party drugs such as MDMA and gamma-hydroxybutyrate (GHB) may preferentially activate brain oxytocin systems to produce their characteristic prosocial and prosexual effects. Oxytocin interacts with the mesolimbic dopamine system to facilitate sexual and social behaviour, and this oxytocin-dopamine interaction may also influence the acquisition and expression of drug-seeking behaviour. An increasing body of evidence from animal models suggests that even brief exposure to drugs such as MDMA, cannabinoids, methamphetamine and phencyclidine can cause long lasting deficits in social behaviour. We discuss preliminary evidence that these adverse effects may reflect long-term neuroadaptations in brain oxytocin systems. Laboratory studies and preliminary clinical studies also indicate that raising brain oxytocin levels may ameliorate acute drug withdrawal symptoms. It is concluded that oxytocin may play an important, yet largely unexplored, role in drug addiction. Greater understanding of this role may ultimately lead to novel therapeutics for addiction that can improve mood and facilitate the recovery of persons with drug use disorders. © 2019 The British Pharmacological Society

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