The effect of COVID19 pandemic restrictions on an urban rodent population.

Shortly after the enactment of restrictions aimed at limiting the spread of COVID-19, various local government and public health authorities around the world reported an increased sighting of rats. Such reports have yet to be empirically validated. Here we combined data from multi-catch rodent stations (providing data on rodent captures), rodent bait stations (providing data on rodent activity) and residents' complaints to explore the effects of a six week lockdown period on rodent populations within the City of Sydney, Australia. The sampling interval encompassed October 2019 to July 2020 with lockdown defined as the interval from April 1st to May 15th, 2020. Rodent captures and activity (visits to bait stations) were stable prior to lockdown. Captures showed a rapid increase and then decline during the lockdown, while rodent visits to bait stations declined throughout this period. There were no changes in the frequency of complaints during lockdown relative to before and after lockdown. There was a non-directional change in the geographical distribution of indices of rodent abundance suggesting that rodents redistributed in response to resource scarcity. We hypothesize that lockdown measures initially resulted in increased rodent captures due to sudden shortage of human-derived food resources. Rodent visits to bait stations might not show this pattern due to the nature of the binary data collected, namely the presence or absence of a visit. Relocation of bait stations driven by pest management goals may also have affected the detection of any directional spatial effect. We conclude that the onset of COVID-19 may have disrupted commensal rodent populations, with possible implications for the future management of these ubiquitous urban indicator species

The oxytocin analogue carbetocin prevents emotional impairment and stress-induced reinstatement of opioid-seeking in morphine-abstinent mice.

The main challenge in treating opioid addicts is to maintain abstinence due to the affective consequences associated with withdrawal which may trigger relapse. Emerging evidence suggests a role of the neurohypophysial peptide oxytocin (OT) in the modulation of mood disorders as well as drug addiction. However, its involvement in the emotional consequences of drug abstinence remains unclear. We investigated the effect of 7-day opioid abstinence on the oxytocinergic system and assessed the effect of the OT analogue carbetocin (CBT) on the emotional consequences of opioid abstinence, as well as relapse. Male C57BL/6J mice were treated with a chronic escalating-dose morphine regimen (20-100 mg/kg/day, i.p.). Seven days withdrawal from this administration paradigm induced a decrease of hypothalamic OT levels and a concomitant increase of oxytocin receptor (OTR) binding in the lateral septum and amygdala. Although no physical withdrawal symptoms or alterations in the plasma corticosterone levels were observed after 7 days of abstinence, mice exhibited increased anxiety-like and depressive-like behaviors and impaired sociability. CBT (6.4 mg/kg, i.p.) attenuated the observed negative emotional consequences of opioid withdrawal. Furthermore, in the conditioned place preference paradigm with 10 mg/kg morphine conditioning, CBT (6.4 mg/kg, i.p.) was able to prevent the stress-induced reinstatement to morphine-seeking following extinction. Overall, our results suggest that alterations of the oxytocinergic system contribute to the mechanisms underlying anxiety, depression, and social deficits observed during opioid abstinence. This study also highlights the oxytocinergic system as a target for developing pharmacotherapy for the treatment of emotional impairment associated with abstinence and thereby prevention of relapse

Differential behavioural and neurochemical outcomes from chronic paroxetine treatment in adolescent and adult rats: a model of adverse antidepressant effects in human adolescents?

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 Pres

CB1 Cannabinoid Receptor Activation Dose-Dependently Modulates Neuronal Activity within Caudal but not Rostral Song Control Regions of Adult Zebra Finch Telencephalon

CB1 cannabinoid receptors are distinctly expressed at high density within several regions of zebra finch telencephalon including those known to be involved in song learning (lMAN and Area X) and production (HVC and RA). Because: (1) exposure to cannabinoid agonists during developmental periods of auditory and sensory-motor song learning alters song patterns produced later in adulthood and; (2) densities of song region expression of CB1 waxes-and-wanes during song learning, it is becoming clear that CB1 receptor-mediated signaling is important to normal processes of vocal development. To better understand mechanisms involved in cannabinoid modulation of vocal behavior we have investigated the dose-response relationship between systemic cannabinoid exposure and changes in neuronal activity (as indicated by expression of the transcription factor, c- Fos) within telencephalic brain regions with established involvement in song learning and/or control. In adults we have found that low doses (0.1 mg/kg) of the cannabinoid agonist WIN-55212-2 decrease neuronal activity (as indicated by densities of c-fos-expressing nuclei) within vocal motor regions of caudal telencephalon (HVC and RA) while higher doses (3 mg/kg) stimulate activity. Both effects were reversed by pretreatment with the CB1-selective antagonist rimonabant. Interestingly, no effects of cannabinoid treatment were observed within the rostral song regions lMAN and Area X, despite distinct and dense CB1 receptor expression within these areas. Overall, our results demonstrate that, depending on dosage, CB1 agonism can both inhibit and stimulate neuronal activity within brain regions controlling adult vocal motor output, implicating involvement of multiple CB1-sensitive neuronal circuits. Originally published Psychopharmacology, Vol. 199, No. 2, Aug 200

Pharmacotherapy, alternative and adjunctive therapies for eating disorders: findings from a rapid review.

BACKGROUND: The current review broadly summarises the evidence base for pharmacotherapies and adjunctive and alternative therapies in the treatment of eating disorders and disordered eating. METHODS: This paper forms part of a Rapid Review series examining the evidence base in the field of eating disorders. This was conducted to inform the Australian National Eating Disorder Research and Translation Strategy 2021-2030. ScienceDirect, PubMed and Ovid/Medline were searched for included studies published between 2009 and 2021 in English. High-level evidence such as meta-analyses, large population studies and randomised control trials were prioritised, and grey literature excluded. Data from included studies relating to pharmacotherapy, and to adjunctive and alternative therapies in eating disorders, were synthesised and disseminated in the current review. RESULTS: A total of 121 studies were identified, relating to pharmacotherapy (n = 90), adjunctive therapies (n = 21) and alternative therapies (n = 22). Some of the identified studies involved combinations of the above (e.g. adjunctive pharmacotherapy). Evidence of efficacy of interventions across all three categories was very limited with few relevant high quality clinical trials. There was a particular scarcity of evidence around effective treatments for anorexia nervosa (AN). With treatment of bulimia nervosa (BN), fluoxetine has exhibited some efficacy leading to regulatory approval in some countries. With binge eating disorder (BED), recent evidence supports the use of lisdexamfetamine. Neurostimulation interventions show some emerging efficacy in the treatment of AN, BN and BED but some, such as deep brain stimulation can be highly invasive. CONCLUSION: Despite widespread use of medications, this Rapid Review has identified a lack of effective medications and adjunctive and alternative therapies in the treatment of EDs. An intensification of high-quality clinical trial activity and drug discovery innovation are required to better assist patients suffering from EDs

Mephedrone in adolescent rats: residual memory impairment and acute but not lasting 5-HT depletion

Mephedrone (4-methylmethcathinone, MMC) is a popular recreational drug, yet its potential harms are yet to be fully established. The current study examined the impact of single or repeated MMC exposure on various neurochemical and behavioral measures in rats. In Experiment 1 male adolescent Wistar rats received single or repeated (once a day for 10 days) injections of MMC (30 mg/kg) or the comparator drug methamphetamine (METH, 2.5 mg/kg). Both MMC and METH caused robust hyperactivity in the 1 h following injection although this effect did not tend to sensitize with repeated treatment. Striatal dopamine (DA) levels were increased 1 h following either METH or MMC while striatal and hippocampal serotonin (5-HT) levels were decreased 1 h following MMC but not METH. MMC caused greater increases in 5-HT metabolism and greater reductions in DA metabolism in rats that had been previously exposed to MMC. Autoradiographic analysis showed no signs of neuroinflammation ([125I]CLINDE ligand used as a marker for translocator protein (TSPO) expression) with repeated exposure to either MMC or METH. In Experiment 2, rats received repeated MMC (7.5, 15 or 30 mg/kg once a day for 10 days) and were examined for residual behavioral effects following treatment. Repeated high (30 mg/kg) dose MMC produced impaired novel object recognition 5 weeks after drug treatment. However, no residual changes in 5-HT or DA tissue levels were observed at 7 weeks post-treatment. Overall these results show that MMC causes acute but not lasting changes in DA and 5-HT tissue concentrations. MMC can also cause long-term memory impairment. Future studies of cognitive function in MMC users are clearly warranted. © 2012 PLoS On

Contribution of limbic norepinephrine to cannabinoid-induced aversion

RATIONALE: The cannabinoid system has risen to the forefront in the development of novel treatments for a number of pathophysiological processes. However, significant side effects have been observed in clinical trials raising concerns regarding the potential clinical utility of cannabinoid-based agents. Understanding the neural circuits and neurochemical substrates impacted by cannabinoids will provide a better means of gaging their actions within the central nervous system that may contribute to the expression of unwanted side effects. OBJECTIVES: In the present study, we investigated whether norepinephrine (NE) in the limbic forebrain is a critical determinant of cannabinoid receptor agonist-induced aversion and anxiety in rats. METHODS: An immunotoxin lesion approach was combined with behavioral analysis using a place conditioning paradigm and the elevated zero maze. RESULTS: Our results show that the non-selective CB1/CB2 receptor agonist, WIN 55,212-2, produced a significant place aversion in rats. Further, NE in the nucleus accumbens was critical for WIN 55,212-2-induced aversion but did not affect anxiety-like behaviors. Depletion of NE from the bed nucleus of the stria terminalis was ineffective in altering WIN 55,212-2-induced aversion and anxiety. CONCLUSIONS: These results indicate that limbic, specifically accumbal, NE is required for cannabinoid-induced aversion but is not essential to cannabinoid-induced anxiety.This works was supported by PHS grant DA 020129. Ana Franky Carvalho was supported by the Portuguese Foundation for Science and Technology (SFRH/BD/33236/2007)

The Acute Effects of Non-concussive Head Impacts on Brain Microstructure, Chemistry and Function in Male Soccer Players: A Pilot Randomised Controlled Trial

Background: Head impacts, particularly, non-concussive impacts, are common in sport. Yet, their effects on the brain remain poorly understood. Here, we investigated the acute effects of non-concussive impacts on brain microstructure, chemistry, and function using magnetic resonance imaging (MRI) and other techniques. Results: Fifteen healthy male soccer players participated in a randomised, controlled, crossover pilot trial. The intervention was a non-concussive soccer heading task (‘Heading’) and the control was an equivalent ‘Kicking’ task. Participants underwent MRI scans ~ 45 min post-task which took ~60 min to complete. Blood was also sampled, and cognitive function assessed, pre-, post-, 2.5 h post-, and 24 h post-task. Brain chemistry: Heading increased total N-acetylaspartate (p = 0.012; g = 0.66) and total creatine (p = 0.010; g = 0.77) levels in the primary motor cortex (but not the dorsolateral prefrontal cortex) as assessed via proton magnetic resonance spectroscopy. Glutamate-glutamine, myoinositol, and total choline levels were not significantly altered in either region. Brain structure: Heading had no significant effects on diffusion weighted imaging metrics. However, two blood biomarkers expressed in brain microstructures, glial fibrillary acidic protein and neurofilament light, were elevated 24 h (p = 0.014; g = 0.64) and ~ 7-days (p = 0.046; g = 1.19) post-Heading (vs. Kicking), respectively. Brain Function: Heading decreased tissue conductivity in 11 clusters located in the white matter of the frontal, occipital, temporal and parietal lobes, and cerebellum (p’s < 0.001) as assessed via electrical properties tomography. However, no significant differences were identified in: (1) connectivity within major brain networks as assessed via resting-state functional MRI; (2) cerebral blood flow as assessed via pseudo continuous arterial spin labelling; (3) activity within electroencephalography frequencies (infra-slow [0.03–0.06 Hz], theta [4–8 Hz], alpha [9–12 Hz], or beta [13–25 Hz]); or (4) cognitive (memory) function. Conclusions: This study identified chemical, microstructural and functional brain alterations in response to an acute non-concussive soccer heading task. These alterations appear to be subtle, with some only detected in specific regions, and no corresponding cognitive deficits observed. Nevertheless, our findings suggest that individuals should exercise caution when performing repeated non-concussive head impacts in sport. Trial registration ACTRN12621001355864. Date of registration: 7/10/2021. URL: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=382590&isReview=true

Effects of anandamide in migraine: data from an animal model

Systemic nitroglycerin (NTG) produces spontaneous-like migraine attacks in migraine sufferers and induces a condition of hyperalgesia in the rat 4 h after its administration. Endocannabinoid system seems to be involved in the modulation of NTG-induced hyperalgesia, and probably, in the pathophysiological mechanisms of migraine. In this study, the analgesic effect of anandamide (AEA) was evaluated by means of the formalin test, performed in baseline conditions and following NTG-induced hyperalgesia in male Sprague–Dawley rats. AEA was administered 30 min before the formalin injection. In addition, the effect of AEA (administered 30 min before NTG injection) was investigated on NTG-induced Fos expression and evaluated 4 h following NTG injection. AEA induced a significant decrease in the nociceptive behavior during both phases of the formalin test in the animals treated with vehicle, while it abolished NTG-induced hyperalgesia during the phase II. Pre-treatment with AEA significantly reduced the NTG-induced neuronal activation in nucleus trigeminalis caudalis, confirming the results obtained in our previous study, and in area postrema, while the same treatment induced an increase of Fos expression in paraventricular and supraoptic nuclei of the hypothalamus, parabrachial nucleus, and periaqueductal grey. The study confirms that a dysfunction of the endocannabinoid system may contribute to the development of migraine attacks and that a pharmacological modulation of CB receptors can be useful for the treatment of migraine pain

A Conserved Developmental Patterning Network Produces Quantitatively Different Output in Multiple Species of Drosophila

Differences in the level, timing, or location of gene expression can contribute to alternative phenotypes at the molecular and organismal level. Understanding the origins of expression differences is complicated by the fact that organismal morphology and gene regulatory networks could potentially vary even between closely related species. To assess the scope of such changes, we used high-resolution imaging methods to measure mRNA expression in blastoderm embryos of Drosophila yakuba and Drosophila pseudoobscura and assembled these data into cellular resolution atlases, where expression levels for 13 genes in the segmentation network are averaged into species-specific, cellular resolution morphological frameworks. We demonstrate that the blastoderm embryos of these species differ in their morphology in terms of size, shape, and number of nuclei. We present an approach to compare cellular gene expression patterns between species, while accounting for varying embryo morphology, and apply it to our data and an equivalent dataset for Drosophila melanogaster. Our analysis reveals that all individual genes differ quantitatively in their spatio-temporal expression patterns between these species, primarily in terms of their relative position and dynamics. Despite many small quantitative differences, cellular gene expression profiles for the whole set of genes examined are largely similar. This suggests that cell types at this stage of development are conserved, though they can differ in their relative position by up to 3–4 cell widths and in their relative proportion between species by as much as 5-fold. Quantitative differences in the dynamics and relative level of a subset of genes between corresponding cell types may reflect altered regulatory functions between species. Our results emphasize that transcriptional networks can diverge over short evolutionary timescales and that even small changes can lead to distinct output in terms of the placement and number of equivalent cells