Morphine-Induced Hyperactivity is Attenuated by Intra-Accumbens Administration of the Highly-Selective Dopamine D3 Receptor Antagonist VK4-40

Opioids exert their abuse-related effects by enhancing dopamine (DA) neurotransmission within the brain’s mesolimbic reward system, a neural projection involving DA neurons in the ventral tegmental area (VTA) that project to medium spiny neurons within the nucleus accumbens (NAc). Mu (MOR) are expressed by several populations of GABAergic neurons that tonically inhibit VTA DA neurons. By inhibiting these GABAergic neurons in a MOR-dependent manner, opioids indirectly enhance DA neurotransmission via disinhibition of DAergic neurons. Accumulating evidence indicates that selective pharmacological antagonism of the dopamine D3 receptor (D3R) attenuates the abuse-related effects of several opioids, but the neurobiological mechanisms mediating this phenomenon remains unclear. This project sought to determine whether the NAc may represent one site of action within the mesolimbic DA system where D3R antagonists exert their anti-opioid behavioral effects. To address this question, we assessed whether intra-NAc microinfusion of a highly-selective D3R antagonist, VK4-40, alters morphine-induced hyperactivity in mice, a behavioral marker of increased DA neurotransmission within the mesolimbic VTA-NAc projection. Adult male and female C57Bl/6 mice (n=8) were surgically implanted with bilateral guide cannulae targeting the NAc. Mice were then tested weekly for the impact of VK4-40 administration (0, 100, 1000 ng/side) on hyperactivity induced by morphine (18 mg/kg, i.p.). Our preliminary data suggests that intra-NAc administration of VK4-40 attenuated morphine-induced hyperactivity at the highest concentration tested (1000 ng/side). These early results suggest that the NAc may be one brain region in which D3R antagonists act to reduce the abuse-related effects of opioids. Next phases of this ongoing research project include 1) determining whether intra-NAc VK4-40 administration perturbs basal locomotor activity, 2) studying the effects of VK4-40 infusion in other nodes of the mesolimbic DA system, and 3) examining whether VK4-40 disrupts opioid-induced increases in the activity of VTA DA neurons and/or opioid-induced increases in NAc DA levels. Collectively, these studies are poised to reveal the neurobiological mechanisms by which selective D3R antagonism disrupts the abuse-related effects of opioids

Abdominal aortic aneurysm rupture presenting with focal weakness and altered mental status: a case report.

BACKGROUND: Abdominal aortic aneurysms (AAA) can present asymptomatically and may be found through routine screening or seen incidentally on imaging. Rupture due to weaking of the aortic wall is the main complication of an AAA and leads to approximately 200,000 deaths annually worldwide. Clinically, AAA rupture most frequently presents with abdominal and/or back pain, pulsatile abdominal mass, and hypotension. Here, we present an unusual presentation of embolic cerebrovascular accident associated with an AAA rupture. CASE PRESENTATION: A 58-year-old African American man transported to the emergency department via ambulance presents with altered mental status and unilateral extremity weakness. The initial presentation was concerning for acute cerebrovascular accident, acute kidney injury, severe sepsis, and urinary tract infection. Several hours after the initial presentation, the patient\u27s abdomen began to appear distended and he became hypotensive. An abdominal CT was ordered which showed a large AAA rupture with a retroperitoneal bleed. The patient was transferred to a higher-level medical center for surgical repair. CONCLUSION: Abdominal aortic aneurysm rupture can rarely present due to an acute cerebrovascular accident with altered mental status and focal neurologic deficits

The Dopamine D3 Receptor Antagonist VK4-40 Attenuates Morphine-Induced Hyperactivity But Not Cocaine-Induced Hyperactivity in Mice

In light of the increasing rates of opioid abuse in the US, the search for viable medications to treat opioid abuse disorder (OUD) has become ever more urgent. Opioids exert their abuse-related effects in part by indirectly increasing dopamine (DA) neurotransmission in the mesolimbic system, a dopaminergic projection arising in the ventral tegmental area and terminating in the nucleus accumbens. The DA D3 receptor (D3R), which belongs to the D2 family of dopamine receptors (D2, D3 , D4 receptor subtypes), is highly expressed in these brain regions and has shown strong potential as a pharmacotherapeutic target for the treatment of OUD. More specifically, D3R antagonists have been shown by us and others to attenuate the abuse-related behavioral effects of opioids without producing adverse side effects associated with nonselective D2-like receptor antagonists. We previously examined the effects of the selective D3R antagonist PG01037 (133-fold selectivity for D3R vs. D2R) using drug-induced hyperactivity as a behavioral proxy for DA release within the nucleus accumbens. Interestingly, we found that PG01037 enhances cocaine-induced hyperlocomotion while it attenuates morphine-induced hyperlocomotion in mice. The potentiation of psychostimulant effects could confound the potential use of D3R antagonists for the treatment of OUD, since many opioid users co-abuse stimulants such as cocaine. However, recent studies with more selective D3R antagonists found that they do not enhance certain effects of cocaine while still reducing opioid effects. It is currently unknown what impact these highly-selective D3R antagonists will have on cocaine-induced hyperactivity and/or dopamine neurotransmission. The purpose of this study was to examine the impact of pretreatment with the novel and highly selective D3R antagonist VK4-40 (250-fold selectivity for D3R vs. D2R) on cocaine- and morphine-induced hyperlocomotion in mice

Presynchronizing PGF2α and GnRH injections before timed artificial insemination CO-Synch + CIDR program

Fixed-time artificial insemination is an effective management tool that reduces the labor associated with more conventional artificial insemination programs requiring detection of estrus. The 7-day CO-Synch + controlled internal drug release (CIDR) insert protocol has been shown to effectively initiate estrus and ovulation in cycling and non-cycling suckled beef cows, producing pregnancy rates at or greater than 50% in beef cows. The gonadotropin-releasing hormone (GnRH) injection that begins the CO-Synch + CIDR program initiates ovulation in a large proportion of cows, particularly anestrous cows. The CIDR, which releases progesterone intravaginally, prevents short estrous cycles that usually follow the first postpartum ovulation in beef cows. Our hypothesis was that inducing estrus with a prostaglandin injection followed 3 days later with a GnRH injection, 7 days before applying the 7-day CO-Synch + CIDR protocol, might increase the percentage of cycling cows that would exhibit synchronous follicular waves after the onset of the CO-Synch + CIDR protocol. We also hypothesized that the additional GnRH injection would increase the percentage of anestrous cows that would ovulate, thereby increasing pregnancy outcomes

The dynamics of sediment-associated contaminants over a transition from drought to multiple flood events in a lowland UK catchment

Fine sediment in suspended form, recently deposited overbank and in temporary storage on or in channel beds, was collected in the Nene basin during a period of drought through to a period of four high flows. The sediment was analysed for arsenic, copper, lead, phosphorus and zinc concentrations with the aim of investigating their sources, movement, temporary storage and potential for environmental harm. Copper, lead and zinc probably originated from urban street dusts, phosphorus (originally in dissolved form) from sewage effluent and arsenic from natural soils developed over ironstone. There was little difference in the metal or arsenic concentrations in the sediment under different flow conditions; instead, proximity to pollutant sources appeared to control their concentrations. Phosphorus in tributary sub-catchments probably adsorbed to sediment during periods of low flow but these sediments were flushed away during high flows and replaced by sediment with lower concentrations. However, concentrations of all pollutants in overbank sediments along the Nene's main channel were not reduced in successive flood events, suggesting no first flush effect. Only phosphorus accumulated on sediment at concentrations exceeding those of its catchment-based sources (e.g. street dusts, channel banks and catchment soils). This scavenging of aqueous phosphate by sediment explained the difference in behaviour between phosphorus, arsenic and heavy metals. The surface area and organic matter content were shown to have a small effect on contaminant concentrations. Street dust contaminants only exceeded predicted effect levels in close proximity to urban areas, suggesting a small potential for harm to the aquatic environment. Arsenic concentrations exceeded predicted effect levels in most sediment samples. However, it has been shown to be largely non-bioavailable in previously published research on the Nene, limiting its potential for significant environmental harm. Phosphorus concentrations in river sediments are high in comparison to the soils in the catchment and in comparison with sediment–P concentrations in other published lowland catchment studies, indicating a large potential for eutrophication should the Phosphorus be, or become, bioavailable

Fos Expression in Lateral Hypothalamus/Perifornical Area is Correlated with Psychosocial Stress-Induced Cocaine-Seeking Behavior in a Sex-Specific Manner

Cocaine Use Disorder persists as a significant public health concern in the United States. Recent epidemiological data indicate that rates of cocaine-involved overdose deaths are rising, and treatment of Cocaine Use Disorder is challenging due to a lack of FDA-approved medications to help patients achieve abstinence and avoid relapse. Stress can precipitate cocaine craving and trigger relapse episodes, however the underlying neural circuitry by which stressors drive cocaine seeking is not completely understood. Our laboratory has recently identified the potential involvement of the rostrolateral aspect of the periaqueductal gray (rlPAG) in psychosocial stress-induced cocaine-seeking behavior using a rodent model of cocaine relapse. Neuroanatomical evidence points to a dense monosynaptic input from the lateral hypothalamus (LH) to the rlPAG, yet whether activity within the LH is also associated specifically with psychosocial-stress induced cocaine seeking has not been previously explored. In this study, adult male and female Long-Evans rats were allowed to self-administer cocaine (0.5 mg/kg/inf, IV) in 2-h daily sessions for 20 sessions. During sessions 11, 14, 17, and 20, a tactile cue (perforated polycarbonate enclosure) was placed within the operant chamber, and these sessions were immediately followed by either social defeat stress (SDS, n=16; 8M, 8F) or a no-stress empty-cage control condition (EC, n=12; 6M, 6F). Beginning on day 21, animals underwent extinction training during which lever-presses were not reinforced. Once responding was extinguished, rats were re-exposed to the tactile cue that signaled their assigned stress/no-stress stimulus, and reinstatement of cocaine-seeking was measured for 2 h under extinction conditions. Immediately after the reinstatement test, animals were sacrificed, and brains collected and processed via immunohistochemistry for expression of the immediate early gene c-Fos and the neuropeptide orexin within the LH and neighboring Perifornical Area (PfA). Despite no significant difference between groups in the number of Fos+ or orexin+ cells in the LH/PfA, there was a significant positive correlation between Fos expression in non-orexinergic LH/PfA cells and stress-induced cocaine-seeking magnitude specifically within males. Additionally, Fos expression in these cells was also significantly and positively correlated with Fos expression in the rostrolateral periaqueductal gray. Collectively, these findings suggest that a LH --\u3e rlPAG projection may be selectively engaged during psychosocial stress-induced cocaine seeking behavior in male rats

The soil organic carbon: Clay ratio in North Devon, UK: Implications for marketing soil carbon as an asset class

Building up stocks of agricultural soil organic carbon (SOC) can improve soil conditions as well as contribute to climate change mitigation. As a metric, the ratio of SOC to clay offers a better predictor of soil condition than SOC alone, potentially providing a benchmark for ecosystem service payments. We determined SOC:clay ratios for 50 fields in the North Devon UNESCO World Biosphere Reserve using 30 cm soil cores (divided into 0-10 cm and 10-30 cm depth samples), with soil bulk density, soil moisture and land-use history recorded for each field. All the arable soils exceeded the minimum desirable SOC:clay ratio threshold, and the ley grassland soils generally exceeded it but were inconsistent at 10-30 cm. Land use was the primary factor driving SOC:clay ratios at 0-10 cm, with permanent pasture fields having the highest ratios followed by ley grass and then arable fields. Approximately half of the fields sampled had potential for building up SOC stock at 10-30 cm. However, at this depth, the effect of land use is significantly reduced. Within-field variability in SOC and clay was low (coefficient of variation was similar to 10%) at both 0-10 cm and 10-30 cm, suggesting that SOC:clay ratios precisely characterized the fields. Due to the high SOC:clay ratios found, we conclude that there is limited opportunity to market additional carbon sequestration as an asset class in the North Devon Biosphere or similar areas. Instead, preserving existing SOC stocks would be a more suitable ecosystem service payment basis

The Waiting And Mating Game: Condition Dependent Mate Sampling In Female Gray Treefrogs (Hyla Versicolor)

Strong sexual selection by receivers can lead to the evolution of elaborate courtship behaviors in signalers. However the process by which receivers sample signalers and execute mate choice under complex signaling conditions—and thus the realized strength of sexual section—is poorly understood. Moreover, receivers can vary in condition, which can further influence mate sampling strategies. Using wild female frogs we tested two hypotheses at the intersection of these important problems: that some of the individual variation in mate sampling is explained by (1) the reproductive urgency hypothesis, which predicts that receivers in a more urgent reproductive state will sample mates less and/or (2) the reproductive investment hypothesis, which predicts that receivers that have invested less in the current reproductive effort will sample mates less. Eastern gray treefrogs, Hyla versicolor, were collected in amplexus and repeatedly tested for phonotaxis behavior using a dynamic playback assay. To evaluate if hormonal mechanisms explained variation in the mate sampling, three steroid hormones, estradiol, progesterone, and corticosterone, were collected using a noninvasive water-borne hormone assay, validated for this species in the present study. Finally, we measured clutch size (investment) and the duration of time required for each female to oviposit after being reunited with their male mate (urgency). We found repeatability in many of the behaviors, including mate sampling. We found that females with higher concentrations estradiol and corticosterone made quicker choices, and that females with higher progesterone sampled mates more. We also found that female frogs in a more urgent reproductive state had lower concentrations of progesterone and estradiol, thereby providing the first evidence of a relationship between gonadal hormones and reproductive urgency. Collectively we found some support for the reproductive urgency but not the investment hypothesis. Thus, even though a female frog\u27s reproductive readiness is a highly transient life history stage, fine scale variation in her reproductive timeline could mitigate the strength of directional selection

Neuronal Activity Within the Ventral Tegmental Area Is Correlated with Cocaine-Seeking Behavior in Male, But Not Female, Rats

The objective of this study was to begin to determine the neurobiological underpinnings of psychosocial stress-induced cocaine seeking. Social defeat stress, achieved using the well-established resident-intruder procedure, is an ecologically-valid psychosocial stressor in rodents that may more closely recapitulate those psychosocial experiences that elicit cocaine craving and relapse in human cocaine users. Our laboratory has developed a model of psychosocial stress-induced relapse in rats in which extinguished cocaine seeking is reinstated by re-exposure to a discrete cue that signals impending social defeat stress. We previously reported that an individual rat’s predilection towards the display of active coping behaviors during prior social defeat stress exposures was positively correlated with levels of psychosocial stress-induced cocaine seeking. The current study’s goal was to expand upon these initial findings by assessing and comparing patterns of neural activation within the ventral tegmental area (VTA) during stress-induced cocaine seeking triggered by psychosocial stress-predictive or foot shock stress-predictive cues. The VTA was selected for investigation in the present study because of its known role in the manifestation of stress-induced reinstatement of cocaine seeking. We postulated that neural activation in this brain region would be associated with the magnitude of observed psychosocial stress-induced cocaine seeking, thus providing important insights into the neurobiological underpinnings of this phenomenon

Does cattle and sheep grazing under best management significantly elevate sediment losses? Evidence from the North Wyke Farm Platform, UK

Purpose: Intensive livestock grazing has been associated with an increased risk of soil erosion and concomitant negative impacts on the ecological status of watercourses. Whilst various mitigation options are promoted for reducing livestock impacts, there is a paucity of data on the relationship between stocking rates and quantified sediment losses. This evidence gap means there is uncertainty regarding the cost–benefit of policy preferred best management. Methods: Sediment yields from 15 hydrologically-isolated field scale catchments on a heavily instrumented ruminant livestock farm in the south west UK were investigated over ~26 months spread across six years. Sediment yields were compared to cattle and sheep stocking rates on long-term, winter (November–April) and monthly time scales. The impacts of livestock on soil vegetation cover and bulk density were also examined. Cattle were tracked using GPS collars to determine how grazing related to soil damage. Results: No observable impact of livestock stocking rates of 0.15 – 1.00 UK livestock units (LU) ha-1 for sheep and 0 - 0.77 LU ha-1 for cattle on sediment yields was observed at any of the three timescales. Cattle preferentially spent time close to specific fences where soils were visually damaged. However, there was no indication that livestock have a significant effect on soil bulk density on a field-scale. Livestock were housed indoors during winters when most rainfall occurs and best management practices were used which when combined with low erodibility clayey soils likely limited sediment losses. Conclusion: A combination of clayey soils and soil trampling in only a small proportion of the field areas lead to little impact from grazing livestock. Within similar landscapes with best practice livestock grazing management, additional targeted measures to reduce erosion are unlikely to yield a significant cost-benefit