Anatomy and Neuroscience - Research Publications
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ItemCentral amygdala relaxin-3/relaxin family peptide receptor 3 signalling modulates alcohol seeking in rats(WILEY, 2017-10)BACKGROUND AND PURPOSE: Alcohol use disorders are a leading cause of preventable deaths worldwide, and stress is a major trigger of relapse. The neuropeptide relaxin-3 and its cognate receptor, relaxin family peptide receptor 3 (RXFP3), modulate stress-induced relapse to alcohol seeking in rats, and while the bed nucleus of the stria terminalis has been implicated in this regard, the central nucleus of the amygdala (CeA) also receives a relaxin-3 innervation and CeA neurons densely express RXFP3 mRNA. Moreover, the CeA is consistently implicated in both stress and addictive disorders. Yohimbine precipitates relapse-like behaviour in rodents, although exactly how yohimbine induces relapse is unknown, possibly by increasing stress levels and inducing heightened cue reactivity. EXPERIMENTAL APPROACH: In the current study, we examined the effects of yohimbine (1 mg·kg-1 , i.p.) on anxiety-like behaviour in alcohol-experienced rats. Furthermore, we assessed CeA neuronal activation following yohimbine-induced reinstatement of alcohol seeking and the role of the relaxin-3/RXFP3 signalling within the CeA in yohimbine-induced reinstatement to alcohol seeking. KEY RESULTS: Low-dose yohimbine was anxiogenic in rats with a history of alcohol use. Furthermore, yohimbine-induced reinstatement of alcohol seeking increased Fos activation in CeA corticotrophin-releasing factor, dynorphin and GABA neurons compared with naïve and vehicle controls. Bilateral intra-CeA injections of the selective RXFP3 antagonist, R3(B1-22)R, attenuated yohimbine-induced reinstatement of alcohol seeking. CONCLUSIONS: Collectively, these data suggest that the CeA is a node where yohimbine acts to induce reinstatement of alcohol seeking and implicate the relaxin-3/RXFP3 system within the CeA in this process.
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ItemToluene inhalation in adolescent rats reduces flexible behaviour in adulthood and alters glutamatergic and GABAergic signalling(WILEY-BLACKWELL, 2016-12)Toluene is a commonly abused inhalant that is easily accessible to adolescents. Despite the increasing incidence of use, our understanding of its long-term impact remains limited. Here, we used a range of techniques to examine the acute and chronic effects of toluene exposure on glutameteric and GABAergic function, and on indices of psychological function in adult rats after adolescent exposure. Metabolomics conducted on cortical tissue established that acute exposure to toluene produces alterations in cellular metabolism indicative of a glutamatergic and GABAergic profile. Similarly, in vitro electrophysiology in Xenopus oocytes found that acute toluene exposure reduced NMDA receptor signalling. Finally, in an adolescent rodent model of chronic intermittent exposure to toluene (10 000 ppm), we found that, while toluene exposure did not affect initial learning, it induced a deficit in updating that learning when response-outcome relationships were reversed or degraded in an instrumental conditioning paradigm. There were also group differences when more effort was required to obtain the reward; toluene-exposed animals were less sensitive to progressive ratio schedules and to delayed discounting. These behavioural deficits were accompanied by changes in subunit expression of both NMDA and GABA receptors in adulthood, up to 10 weeks after the final exposure to toluene in the hippocampus, prefrontal cortex and ventromedial striatum; regions with recognized roles in behavioural flexibility and decision-making. Collectively, our data suggest that exposure to toluene is sufficient to induce adaptive changes in glutamatergic and GABAergic systems and in adaptive behaviour that may underlie the deficits observed following adolescent inhalant abuse, including susceptibility to further drug-use.
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ItemNo Preview AvailableNucleus incertus corticotrophin-releasing factor 1 receptor signalling regulates alcohol seeking in rats(WILEY, 2017-11)Alcoholism is a chronic relapsing disorder, and stress is a key precipitant of relapse. The nucleus incertus (NI) is highly responsive to corticotrophin-releasing factor (CRF) and psychological stressors, receives a CRF innervation and expresses CRF1 and CRF2 receptor mRNA. Furthermore, the ascending NI relaxin-3 system is implicated in alcohol seeking in rats. Therefore, in alcohol-preferring rats, we examined the effect of bilateral injections into the NI of the CRF1 receptor antagonist, CP376395 or the CRF2 receptor antagonist, astressin-2B on yohimbine-induced reinstatement of alcohol seeking. Using quantitative PCR analysis of NI micropunches, we assessed the effects of chronic alcohol consumption on gene expression profiles for components of the relaxin-3 and CRF systems. Bilateral intra-NI injections of CP376395 (500 ng/0.25 µl) attenuated yohimbine-induced reinstatement of alcohol seeking. In contrast, intra-NI injections of astressin-2B (200 ng/0.25 µl) had no significant effect. In line with these data, CRF1 , but not CRF2 , receptor mRNA was upregulated in the NI following chronic ethanol intake. Relaxin family peptide 3 receptor mRNA was also increased in the NI following chronic ethanol. Our quantitative PCR analysis also identified CRF mRNA within the rat NI, and the existence of a newly identified population of CRF-containing neurons was subsequently confirmed by detection of CRF immunoreactivity in rat and mouse NI. These data suggest that NI neurons contribute to reinstatement of alcohol seeking, via an involvement of CRF1 signalling. Furthermore, chronic ethanol intake leads to neuroadaptive changes in CRF and relaxin-3 systems within rat NI.
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ItemThe effect of adolescent inhalant abuse on energy balance and growth(JOHN WILEY & SONS LTD, 2019-08)The abuse of volatile solvents such as toluene is a significant public health concern, predominantly affecting adolescents. To date, inhalant abuse research has primarily focused on the central nervous system; however, inhalants also exert effects on other organ systems and processes, including metabolic function and energy balance. Adolescent inhalant abuse is characterized by a negative energy balance phenotype, with the peak period of abuse overlapping with the adolescent growth spurt. There are multiple components within the central and peripheral regulation of energy balance that may be affected by adolescent inhalant abuse, such as impaired metabolic signaling, decreased food intake, altered dietary preferences, disrupted glucose tolerance and insulin release, reduced adiposity and skeletal density, and adrenal hypertrophy. These effects may persist into abstinence and adulthood, and the long-term consequences of inhalant-induced metabolic dysfunction are currently unknown. The signs and symptoms resulting from chronic adolescent inhalant abuse may result in a propensity for the development of adult-onset metabolic disorders such as type 2 diabetes, however, further research investigating the long-term effects of inhalant abuse upon energy balance and metabolism are needed. This review addresses several aspects of the short- and long-term effects of inhalant abuse relating to energy and metabolic processes, including energy balance, intake and expenditure; dietary preferences and glycemic control; and the dysfunction of metabolic homeostasis through altered adipose tissue, bone, and hypothalamic-pituitary-adrenal axis function.
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ItemExploring the Modulation of Hypoxia-Inducible Factor (HIF)-1α by Volatile Anesthetics as a Possible Mechanism Underlying Volatile Anesthetic-Induced CNS Injury(SPRINGER/PLENUM PUBLISHERS, 2014-09)This review summarizes recent research on the potential cognitive and behavioural abnormalities induced by exposure to volatile anesthetics and suggests a role of hypoxia-inducible factor (HIF)-1α in mediating these events. Volatile anesthetics are widely utilized in clinical and research settings, yet the long-term safety of exposure to these agents is under debate. Findings from various animal models suggest volatile anesthetics induce widespread apoptosis in the central nervous system (CNS) that correlates with lasting deficits in learning and memory. Longitudinal analysis of clinical data highlight an increased risk of developmental disorders later in life when children are exposed to volatile anesthetics, particularly when exposures occur over multiple sessions. However, the mechanisms underlying these events have yet to be established. Considering the extensive use of volatile anesthetics, it is crucial that these events are better understood. The possible role of HIF-1α in volatile anesthetic-induced CNS abnormalities will be suggested and areas requiring urgent attention will be outlined.
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ItemNo Preview AvailableAdolescent inhalant abuse leads to other drug use and impaired growth; implications for diagnosis(WILEY, 2017-02)OBJECTIVE: Abuse of inhalants containing the volatile solvent toluene is a significant public health issue, especially for adolescent and Indigenous communities. Adolescent inhalant abuse can lead to chronic health issues and may initiate a trajectory towards further drug use. Identification of at-risk individuals is difficult and diagnostic tools are limited primarily to measurement of serum toluene. Our objective was to identify the effects of adolescent inhalant abuse on subsequent drug use and growth parameters, and to test the predictive power of growth parameters as a diagnostic measure for inhalant abuse. METHODS: We retrospectively analysed drug use and growth data from 118 Indigenous males; 86 chronically sniffed petrol as adolescents. RESULTS: Petrol sniffing was the earliest drug used (mean 13 years) and increased the likelihood and earlier use of other drugs. Petrol sniffing significantly impaired height and weight and was associated with meeting 'failure to thrive' criteria; growth diagnostically out-performed serum toluene. CONCLUSIONS: Adolescent inhalant abuse increases the risk for subsequent and earlier drug use. It also impairs growth such that individuals meet 'failure to thrive' criteria, representing an improved diagnostic model for inhalant abuse. Implications for Public Health: Improved diagnosis of adolescent inhalant abuse may lead to earlier detection and enhanced health outcomes.
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ItemNo Preview AvailableInvolvement of central relaxin-3 signalling in sodium (salt) appetite(WILEY, 2015-09-01)What is the central question of this study? Sodium appetite is controlled by conserved neuronal transmitter-receptor systems. Here, we tested the contribution made by relaxin family peptide 3 receptor (RXFP3), the cognate G-protein-coupled receptor for the neuropeptide relaxin-3. What is the main finding and its importance? Intracerebroventricular infusion of an RXFP3 antagonist reduced in a dose-dependent manner the volume of 0.3 m NaCl consumed by sodium-depleted C57Bl/6J (wild-type) mice. This effect was absent in sodium-depleted Rxfp3 knockout mice, and RXFP3 antagonist infusion did not alter water consumption in wild-type mice subjected to multiple thirst tests, indicating both the pharmacological and the physiological specificity of observed effects. Our findings identify endogenous relaxin-3-RXFP3 signalling as a modulator of sodium appetite. Overconsumption of highly salted foods is common in Western diets and contributes significantly to metabolic disorders such as hypertension, renal dysfunction and diabetes. Sodium appetite, or the desire of terrestrial animals to seek and consume sodium-containing salts, is a behaviour mediated by a set of evolutionarily conserved neuronal systems. In these studies, we tested whether this instinctive behavioural drive is influenced by the G-protein-coupled relaxin family peptide 3 receptor (RXFP3), the cognate receptor for the neuropeptide relaxin-3, because relaxin-3-RXFP3 signalling can modulate arousal, motivation and ingestive behaviours. Intracerebroventricular (i.c.v.) infusion of the selective RXFP3 antagonist, R3(B1-22)R, reduced in a dose-dependent manner the volume of 0.3 m NaCl solution consumed when offered to sodium-depleted C57Bl/6J wild-type mice, relative to vehicle-treated control animals. Notably, i.c.v. R3(B1-22)R infusion did not alter 0.3 m NaCl consumption relative to vehicle in sodium-depleted Rxfp3 knockout mice, confirming the pharmacological specificity of this effect. Furthermore, i.c.v. R3(B1-22)R did not alter the volume of water consumed by wild-type mice in three tests where water drinking was the normal physiological response, suggesting that the ability of R3(B1-22)R to reduce activated salt appetite is specific and not due to a generalized reduction in drinking behaviour. These findings identify, for the first time, that endogenous relaxin-3-RXFP3 signalling is a powerful mediator of salt appetite in mice and further elucidate the functional role of the relaxin-3-RXFP3 system in the integrative control of motivated behaviours.
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ItemNo Preview AvailableChronic intermittent toluene inhalation in adolescent rats results in metabolic dysfunction with altered glucose homeostasis(WILEY, 2015-11)BACKGROUND AND PURPOSE: Abuse of toluene-containing inhalants is an increasing public health problem, especially among adolescents. Abuse during adolescence is associated with emaciation, while industrial exposure leads to altered glycaemic control suggesting metabolic instability. However, the relationship between adolescent inhalant abuse and metabolic dysfunction remains unknown. EXPERIMENTAL APPROACH: To model human abuse patterns, we exposed male adolescent Wistar rats [postnatal day (PND) 27] to chronic intermittent inhaled toluene (CIT, 10,000 ppm) or air (control) for 1 h·day(-1) , three times a week for 4 weeks. Feeding and body composition were monitored. After 4 weeks, circulating metabolic hormone concentrations and responses to a glucose tolerance test (GTT) were measured. Dietary preference was measured by giving animals access to either a 'western diet' plus standard chow (WC + SC) or standard chow alone during 4 weeks of abstinence. Metabolic hormones and GTT were subsequently measured. KEY RESULTS: Adolescent CIT exposure significantly retarded weight gain, altered body composition, circulating metabolic hormones and responses to a GTT. While reduced body weight persisted, responses to a GTT and circulating hormones appeared to normalize for animals on standard chow following abstinence. In CIT-exposed WC + SC rats, we observed impaired glucose tolerance associated with altered metabolic hormones. Analysis of hypothalamic genes revealed differential expression profiles in CIT-exposed rats following both the exposure period and abstinence, suggesting a central contribution to inhalant-induced metabolic dysfunction. CONCLUSION AND IMPLICATIONS: CIT exposure during adolescence has long-term effects on metabolic function, which may increase the risk of disorders related to energy balance and glycaemic control.
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ItemRelaxin-3 Receptor (RXFP3) Signalling Mediates Stress-Related Alcohol Preference in Mice(PUBLIC LIBRARY SCIENCE, 2015-04-07)Stressful life events are causally linked with alcohol use disorders (AUDs), providing support for a hypothesis that alcohol consumption is aimed at stress reduction. We have previously shown that expression of relaxin-3 mRNA in rat brain correlates with alcohol intake and that central antagonism of relaxin-3 receptors (RXFP3) prevents stress-induced reinstatement of alcohol-seeking. Therefore the objectives of these studies were to investigate the impact of Rxfp3 gene deletion in C57BL/6J mice on baseline and stress-related alcohol consumption. Male wild-type (WT) and Rxfp3 knockout (KO) (C57/B6JRXFP3TM1/DGen) littermate mice were tested for baseline saccharin and alcohol consumption and preference over water in a continuous access two-bottle free-choice paradigm. Another cohort of mice was subjected to repeated restraint followed by swim stress to examine stress-related alcohol preference. Hepatic alcohol and aldehyde dehydrogenase activity was assessed in mice following chronic alcohol intake and in naive controls. WT and Rxfp3 KO mice had similar baseline saccharin and alcohol preference, and hepatic alcohol processing. However, Rxfp3 KO mice displayed a stress-induced reduction in alcohol preference that was not observed in WT littermates. Notably, this phenotype, once established, persisted for at least six weeks after cessation of stress exposure. These findings suggest that in mice, relaxin-3/RXFP3 signalling is involved in maintaining high alcohol preference during and after stress, but does not appear to strongly regulate the primary reinforcing effects of alcohol.
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ItemKnockdown of CRF1 Receptors in the Ventral Tegmental Area Attenuates Cue- and Acute Food Deprivation Stress-Induced Cocaine Seeking in Mice(SOC NEUROSCIENCE, 2014-08-27)Corticotrophin-releasing factor (CRF) modulates the influence of stress on cocaine reward and reward seeking acting at multiple sites, including the ventral tegmental area (VTA). There is controversy, however, concerning the contribution of CRF receptor type 1 (CRFR1) to this effect and whether CRF within the VTA is involved in other aspects of reward seeking independent of acute stress. Here we examine the role of CRFR1 within the VTA in relation to cocaine and natural reward using viral delivery of short hairpin RNAs (lenti-shCRFR1) and investigate the effect on operant self-administration and motivation to self-administer, as well as stress- and cue-induced reward seeking in mice. While knockdown of CRFR1 in the VTA had no effect on self-administration behavior for either cocaine or sucrose, it effectively blocked acute food deprivation stress-induced reinstatement of cocaine seeking. We also observed reduced cue-induced cocaine seeking assessed in a single extinction session after extended abstinence, but cue-induced sucrose seeking was unaffected, suggesting dissociation between the contribution of CRFR1 in the VTA in cocaine reward and sucrose and cocaine seeking. Further, our data indicate a role for VTA CRFR1 signaling in cocaine seeking associated with, and independent of, stress potentially involving conditioning and/or salience attribution of cocaine reward-related cues. CRFR1 signaling in the VTA therefore presents a target for convergent effects of both cue- and stress-induced cocaine-seeking pathways.