Centre for Neuroscience - Research Publications
Now showing items 1-12 of 99
Combined antagonism of glutamate mGlu5 and adenosine A(2A) receptors interact to regulate alcohol-seeking in rats
(CAMBRIDGE UNIV PRESS, 2008-03-01)
Adenosine and glutamate have been implicated as mediators involved in the self-administration of alcohol. In the present study we sought to determine whether adenosine receptors could interact with metabotropic glutamate receptors to regulate operant responding for alcohol and also the integration of the salience of alcohol-paired cues. Alcohol-preferring (iP) rats were trained to self-administer alcohol under operant conditions. The availability of alcohol was paired with an olfactory cue plus a stimulus light. Rats were examined under fixed ratio responding and also following extinction under a cue-induced reinstatement paradigm. Administration of the selective adenosine A2A receptor antagonist, SCH 58261, reduced fixed ratio responding for alcohol in iP rats in a dose-related manner. Furthermore, the combination of a subthreshold dose of SCH 58261 with a subthreshold dose of the mGlu5 receptor antagonist MTEP also reduced alcohol self-administration and increased the latency to the first reinforced response, suggesting a pre-ingestive effect. Moreover, this combination of SCH 58261 and MTEP also prevented the conditioned reinstatement of alcohol-seeking elicited by the re-presentation of cues previously paired with alcohol availability. In contrast, combinations of the selective adenosine A1 receptor antagonist, DPCPX, with either SCH 58261 or MTEP had no effect on alcohol responding. Collectively, these data suggest a functional interaction between adenosine A2A and mGlu5 receptors in relation to alcohol-seeking and the integration of the drug-related cues.
Cocaine-mediated synaptic potentiation is absent in VTA neurons from mGlu5-deficient mice
(OXFORD UNIV PRESS, 2010-03-01)
Drugs of abuse have the ability to instantiate plastic adaptations within the central nervous system, and this property may relate to the development and persistence of addiction. In this context, a single exposure to cocaine in rodents may induce synaptic plasticity by increasing the AMPA/NMDA receptor excitatory post-synaptic current (EPSC) amplitude ratio in dopaminergic cells of the ventral tegmental area (VTA). Here, we examine the role of the metabotropic glutamate 5 (mGlu5) receptor in this regard using a genetic mouse model. The control AMPA/NMDA EPSC ratio is reduced in mGlu5-deficient mice compared to wild-types. Moreover, cocaine-induced enhancement of this EPSC ratio is also absent in mutant mice, which suggests that mGlu5 receptors are required for single-dose cocaine-induced plasticity onto VTA cells. While the temporal profile of hyperactivity to acute cocaine is altered in mGlu5-deficient mice; these mice still develop and express sensitized psychomotor responses to cocaine. These data suggest that the mGlu5 receptor is required for cocaine-induced plasticity in VTA dopaminergic cells. In contrast, the mGlu5 receptor may not be essential for psychostimulant behavioural sensitization; although it probably impacts other aspects drug addiction, such as motivation to self-administer.
Metabotropic glutamate 5 receptors regulate sensitivity to ethanol in mice
(CAMBRIDGE UNIV PRESS, 2008-09-01)
The metabotropic glutamate receptor 5 (mGlu5) has been implicated in ethanol- and drug-seeking behaviours in rodent studies. Here we examine a number of ethanol-related behavioural assays in mice lacking mGlu5 and wild-type littermates. In a two-bottle free-choice paradigm, mGlu5-deficient mice consumed less ethanol with a reduced preference compared to wild-type mice. Indeed, mGlu5-deficienct mice were ethanol-avoiding at both concentrations of ethanol proffered (5% and 10% v/v). However, there was no difference in the rate of hepatic ethanol and acetaldehyde metabolism between genotypes and consumption of saccharin was similar. In a conditioned place preference study, mGlu5-deficient mice displayed a place preference for ethanol when conditioned with a low dose (1g/kg) of ethanol. Thus, while mGlu5-deficient mice consume less ethanol (with a reduced preference) than wild-type mice, this is not apparently related to impaired hepatic metabolism or a lack of reward from ethanol. Rather, we provide evidence that deletion of the mGlu5 receptor increases sensitivity to centrally mediated effects of ethanol.
mGlu5 receptor functional interactions and addiction
(FRONTIERS MEDIA SA, 2012-01-01)
The idea of "receptor mosaics" is that proteins may form complex and dynamic networks with respect to time and composition. These have the potential to markedly expand the diversity and specificity of G protein-coupled receptors (GPCR) signaling, particularly in neural cells, where a few key receptors have been implicated in many neurological and psychiatric disorders, including addiction. Metabotropic glutamate type 5 receptors (mGlu5) can form complexes with other GPCRs, including adenosine A(2A) and dopamine D(2) receptors. mGlu5-containing complexes have been reported in the striatum, a brain region critical for mediating the rewarding and incentive motivational properties of drugs of abuse. mGlu5-containing complexes and/or downstream interactions between divergent receptors may play roles in addiction-relevant behaviors. Interactions between mGlu5 receptors and other GPCRs can regulate the rewarding and conditioned effects of drugs as well as drug-seeking behaviors. mGlu5 complexes may influence striatal function, including GABAergic output of striatopallidal neurons and glutamatergic input from corticostriatal afferents. Given their discrete localization, mGlu5-[non-mGlu5] receptor interactions and/or mGlu5-containing complexes may minimize off-target effects and thus provide a novel avenue for drug discovery. The therapeutic targeting of receptor-receptor functional interactions and/or receptor mosaics in a tissue specific or temporal manner (for example, a sub-population of receptors in a "pathological state") might reduce detrimental side effects that may otherwise impair vital brain functions.
Drugs of abuse and increased risk of psychosis development
(SAGE PUBLICATIONS LTD, 2012-12-01)
OBJECTIVE: There is considerable evidence to suggest that the abuse of illicit drugs, particularly cannabis and methamphetamine, has aetiological roles in the pathogenesis of psychosis and schizophrenia. Factors that may increase susceptibility to the propsychotic effects of these drugs include the age at which the abuse starts as well as family history of genetic polymorphisms relevant to the pathophysiology of this disorder. However, the neurobiological mechanisms involved in drug abuse-associated psychosis remain largely unclear. METHODS AND RESULTS: This paper presents an overview of the available evidence, including clinical, animal model, and molecular studies, with a focus on brain regions and neurotransmitters systems, such as dopamine and glutamate, previously implicated in psychosis. CONCLUSION: It is clear that further studies are urgently needed to provide a greater insight into the mechanisms that mediate the long-term and neurodevelopmental effects of cannabis and methamphetamine. A dialogue between basic science and clinical research may help to identify at-risk individuals and novel pathways for treatment and prevention.
The Effects of Terlipressin on Regional Hemodynamics and Kidney Function in Experimental Hyperdynamic Sepsis
(PUBLIC LIBRARY SCIENCE, 2012-02-15)
BACKGROUND AND AIMS: Although terlipressin (TP) may improve renal function in cirrhotic patients, its use in sepsis remains controversial due to concerns about regional ischemia. We investigated the effects of TP on regional hemodynamics and kidney function in experimental hyperdynamic sepsis. METHODS: We studied thirteen merino ewes in a university physiology laboratory using a randomized controlled cross over design. We implanted flow probes around the pulmonary, circumflex coronary, superior mesenteric, renal and iliac arteries. We injected live Escherichia coli and induced hyperdynamic sepsis. We treated animals with either bolus vehicle or a single dose of TP (sTP = 1 mg). In a second group, after 1 mg of TP, two additional bolus injections (mTP) of 0.5 mg were given at 2 hourly intervals. MAIN RESULTS: sTP (1 mg) significantly increased mean arterial pressure (MAP) (74 to 89 mmHg; P<0.0001) creatinine clearance (31 to 85 mL/min; P<0.0001) and urine output (24 to 307 mL/hr) (P<0.0001). However, it decreased CO (5.7 to 3.9 L/min; p<0.0001), coronary blood flow (CBF) (43 to 32 mL/min; p<0.0001) and mesenteric blood flow (MBF) (944 to 625 mL/min; p = 0.004) and increased blood lactate (2.1 to 4.0 mmol/L; p<0.0001). Extra doses of TP caused little additional effect. CONCLUSIONS: In hyperdynamic sepsis, bolus TP transiently improves MAP and renal function, but reduces CO, CBF and MBF, and increases blood lactate. Caution should be applied when prescribing bolus TP in septic patients at risk of coronary or mesenteric ischemia.
The benefit of hypothermia in experimental ischemic stroke is not affected by pethidine
BACKGROUND: Hypothermia is a promising experimental treatment for acute ischemic stroke. Human trials are still at an early stage, with the focus now on using hypothermia in awake patients. Pethidine (meperidine) is the principle agent used to control shivering in humans; however, whether it has any modulating effects on the neuroprotective efficacy of hypothermia is unknown. AIM: The aim of this study was to determine if pethidine influences the neuroprotective effect of hypothermia in experimental stroke. METHODS: Seventy-two male spontaneously hypertensive rats were anesthetized with isoflurane and randomly assigned to either normothermia (37. 4 °C rectal temperature); hypothermia (33 °C maintained for 130 mins); normothermia plus pethidine (2.5 mg/kg); or hypothermia plus pethidine. Temporary (90 mins) endovascular occlusion of the middle cerebral artery was induced blinded to treatment allocation and was confirmed with laser Doppler flowmetry. Pethidine and cooling were started immediately after vessel occlusion. Animals in the normothermia group had active temperature management using a heat lamp and fan. Assessments of outcome were carried out 24 after the induction of injury. RESULTS: Thirteen animals met our prespecified criteria for exclusion, and data for 59 rats were presented here. Hypothermia was associated with a 63% reduction in infarct size, and pethidine had no significant impact on the efficacy of hypothermia. No effects were observed in neurobehavioral outcome or edema volume across experimental groups. CONCLUSIONS: The effects of hypothermia in a model of focal ischemia are not affected by administration of pethidine.
Two lines of transgenic mice expressing cre-recombinase exhibit increased seizure susceptibility
(ELSEVIER SCIENCE BV, 2013-03-01)
Conditional mouse models based on the Cre-recombinase (Cre)-loxP method are a powerful tool for determining the spatial and temporal function of genes in neuroscience research. The Emx1-Cre conditional model is designed to drive Cre expression in a predominantly excitatory neuron specific manner and the Dlx5/6-Cre mouse expresses Cre predominantly in cortical inhibitory neurons. The mouse models expressing the Cre transgene are healthy, active and have no overt behavioural or brain histological phenotypes. Subcutaneous pentylenetetrazol (scPTZ) is a proconvulsant frequently used to probe neuronal network excitability. In both the Emx1-Cre and Dlx5/6-Cre conditional mouse models the latency to scPTZ-induced seizures was significantly shorter than for their wild-type littermates. This shows that mouse models carrying the Cre transgene alone can have significant behavioural phenotypes. This may act as a confound to the interpretation of data obtained from crosses with loxP-flanked targets especially in the context of epilepsy phenotypes. These data highlight that appropriate control experiments that compare wild-type mice to those that carry the cre-transgene but not the loxP-flanked target are essential when using this method.
A rare functional haplotype of the P2RX4 and P2RX7 genes leads to loss of innate phagocytosis and confers increased risk of age-related macular degeneration
(FEDERATION AMER SOC EXP BIOL, 2013-04-01)
Age-related macular degeneration (AMD) is a leading cause of blindness in Western countries and is diagnosed by the clinical appearance of yellow subretinal deposits called drusen. Genetic changes in immune components are clearly implicated in the pathology of this disease. We have previously shown that the purinergic receptor P2X7 can act as a scavenger receptor, mediating phagocytosis of apoptotic cells and insoluble debris. We performed a genetic association study of functional polymorphisms in the P2RX7 and P2RX4 genes in a cohort of 744 patients with AMD and 557 age-matched Caucasian control subjects. The P2X4 Tyr315Cys variant was 2-fold more frequent in patients with AMD compared to control subjects, with the minor allele predicting susceptibility to disease. Pairwise linkage disequilibrium was observed between Tyr315Cys in the P2RX4 gene and Gly150Arg in the P2RX7 gene, and these two minor alleles formed a rare haplotype that was overrepresented in patients with AMD (n=17) compared with control subjects (n=3) (odds ratio 4.05, P=0.026). Expression of P2X7 (wild type or variant 150Arg) in HEK293 cells conferred robust phagocytosis toward latex beads, whereas coexpression of the P2X7 150Arg with P2X4 315Cys variants almost completely inhibited phagocytic capacity. Fresh human monocytes harboring this heterozygous 150Arg-315Cys haplotype showed 40% reduction in bead phagocytosis. In the primate eye, immunohistochemistry indicated that P2X7 and P2X4 receptors were coexpressed on microglia and macrophages, but neither receptor was seen on retinal pigment epithelial cells. These results demonstrate that a haplotype including two rare variants in P2RX7 and P2RX4 confers a functional interaction between these two variant receptors that impairs the normal scavenger function of macrophages and microglia. Failure of this P2X7-mediated phagocytic pathway may impair removal of subretinal deposits and predispose individuals toward AMD.
Bed rest or mobilization after rt-PA? A case-crossover study of factors influencing clinical decision making in stroke services
(SAGE PUBLICATIONS LTD, 2013-04-01)
BACKGROUND: Acute stroke management is a dynamic field. Treatment with recombinant tissue plasminogen activator is standard care in Australia, but there are no evidence-based practice guidelines about first out of bed activity (mobilization) after recombinant tissue plasminogen activator. AIMS: To identify factors influencing clinicians' decisions to delay or allow mobilization. METHODS: Case-crossover design. Using hypothetical case vignettes, we explored the factors that clinicians consider when deciding to first mobilize a patient after recombinant tissue plasminogen activator. Acute stroke physicians and nurses from Australian hospitals known to treat with recombinant tissue plasminogen activator participated. Information about hospital recombinant tissue plasminogen activator protocols and perceived benefits and harms of mobilization after recombinant tissue plasminogen activator were also captured. RESULTS: Fifty-four clinicians, 52% senior nurses, and 48% senior physicians from all states of Australia participated. Of the factors influencing decisions about mobilization after recombinant tissue plasminogen activator, neurological decline (0.29; confidence interval 0.12, 0.46; P = 0.001), neurological decline with symptomatic intracerebral hemorrhage (0.41; confidence interval 0.24, 0.59; P < 0.0001), infection of uncertain cause (0.32; confidence interval 0.14, 0.50; P = 0.001), severe chest infection (0.35; confidence interval 0.16, 0.53; P = 0.0004), severe stroke (0.29; confidence interval 0.12, 0.46; P = 0.001), drowsiness (0.47; confidence interval 0.29, 0.63; P < 0.0001), and confusion (0.31; confidence interval 0.15, 0.47; P = 0.0001) significantly influenced decisions. Falls risk was a common concern (85%). CONCLUSION: Growing interest in development of clear protocols that guide first mobilization after recombinant tissue plasminogen activator prompted this study. We have identified factors that may influence decisions about when to allow patients to mobilize after recombinant tissue plasminogen activator. These, combined with emerging evidence of risks and benefits of early mobilization, should help protocol development in the future.