bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interactions between Delta and Mu Opioid Agonists in Assays of Pain‐Depressed Operant Responding and Schedule‐Controlled Rate Suppression
Authors: Lanpher Janell , Kinens Abby , Richard Philomena , Rice Kenner C , Bilsky Edward J , Stevenson Glenn W 
Published: November 2023

Interactions between delta and mu opioid agonists in rodents vary as a function of behavioral endpoint. Previous literature includes assessment of interactions across therapeutic (eg: antinociceptive) and side effect (eg: sedation, respiratory depression) endpoints. The present study is the first to characterize these receptor interactions using a mult‐cycle operant assay of pain‐depressed behavior as the antinociceptive measure. The selective delta agonist SNC80 (ED50 = 4.11mg/kg) and the selective mu agonist methadone (ED50 = 0.35mg/kg) both produced dose‐dependent restoration of lactic acid pain‐depressed operant responding. SNC80 (ED50 = 56.0mg/kg) and methadone (ED50 = 1.55mg/kg) also produced a dose‐dependent suppression of response rates in the operant assay in the absence of the pain‐like stimulus. Based on relative potencies in the nociceptive assay, fixed‐ratio mixtures of SNC80 and methadone (35.1:1, 11.7:1, 3.9:1) are currently being characterized in both assays. Preliminary data indicate that the 11.7:1 mixture produced additive effects in the antinociceptive assay and sub‐additive effects in the rate suppression assay, thus yielding a higher therapeutic index (TI or dose ratio) for the mixture relative to the TI of either drug alone. These results provide further evidence that delta/mu interactions depend on experimental endpoint and that assessment of these interactions utilizing an assay of pain‐depressed behavior is possible.Support or Funding InformationAR0554975‐02A1 (NIAMS) to G.W.S.
Identification of a major QTL influencing oxycodone behavioral sensitivity and dependence in C57BL/6 substrains
Authors: Bryant Camron D , Goldberg Lisa R , Kirkpatrick Stacey L , Yazdani Neema , Wu Jiayi , Jenkins David F , Luong Alex , Luttik Kimberly P , Johnson William E , Mulligan Megan K 
Published: November 2023

Opioid addiction is heritable, yet its genetic basis remains poorly understood. Mice are valuable for identifying novel genes that contribute to variation in addiction‐associated phenotypes, including acute psychomotor stimulation and conditioned reward. The closely related C57BL/6J and C57BL/6NJ substrains exhibit limited genetic diversity, yet frequently show strain differences in addiction‐associated traits, including oxycodone‐induced (OXY) locomotor activity and naloxone conditioned place aversion. Quantitative trait locus (QTL) mapping in closely related substrains drastically reduces the number of segregating genetic variants from millions to thousands, accelerating the identification of the causal genetic factors. We conducted QTL mapping for oxycodone (OXY)‐induced conditioned place preference (CPP, N=212), and naloxone (NAL)‐induced conditioned place aversion (CPA, N=209), and concomitant behaviors along with saline‐treated mice as controls (SAL, N=213). We utilized a 9 day (D) CPP/CPA protocol. Mice received drug (1.25 mg/kg OXY, 4 mg/kg NAL, or SAL, i.p.,) on D2 and D4, and SAL on D3 and D5. Mice were assessed for drug‐free CPP/CPA (D8) and drug state‐dependent CPP/CPA (D9). Mice were genotyped at 96 informative markers and QTL mapping was performed in R/qtl (scanone, 1000 permutations). We identified a major genome‐wide significant QTL for OXY‐induced locomotor activity (Chr. 1, 72.43 cM, LOD = 9.79) that co‐mapped to the same region as a QTL for anxiety‐like OXY withdrawal behavior in the elevated plus maze (chr. 1 77.33 cM; LOD = 5.33). We are currently conducting fine mapping with interval‐specific congenics and striatal transcriptome analysis via RNA‐seq to facilitate identification of genes and neurobiological mechanisms.Support or Funding InformationR00DA029635 (NIDA; C.D.B.), R03DA038287 (C.D.B), R21DA038738 (C.D.B.), Transformative Training Program in Addiction Science (Burroughs Wellcome 9550300872; N.Y. and J.W.), and T32GM00854118
Blockade of a Novel Neuropeptide Receptor System, BigLEN‐GPR171, Reduces Adverse Effects of Prolonged Morphine Administration
Authors: Bobeck Erin N , Pena Darlene , Gomes Ivone , Fakira Amanda , Devi Lakshmi 
Published: November 2023

ProSAAS derived peptides, such as BigLEN, are abundantly expressed throughout the brain. We recently identified BigLEN as the endogenous peptide for the orphan receptor GPR171. Immunohistochemical analysis shows that both BigLEN and GPR171 are highly expressed in areas of the brain involved in opioid function, such as nucleus accumbens (NAc), medial prefrontal cortex (mPFC), and basolateral amygdala (BLA). C57bl/6 mice showed an increase in GPR171 mRNA expression in NAc and BLA following conditioned place preference to morphine. Whereas there was no change in GPR171 expression under these conditions in the mPFC, but there was a reduction in BigLEN expression and enhanced cAMP signaling. Next we examined the role of GPR171 in the BLA of mice using lentiviral‐mediated local knockdown and found that this leads to a reduction in conditioned place preference to morphine. We have recently identified MS21570 as a selective antagonist of GPR171 by in silico screening of a library of small molecules using a homology model of GPR171. Pretreatment with MS21570 (5 mg/kg, i.p. in 6% DMSO) prior to 4 morphine (10 mg/kg, s.c.) pairings, reduced conditioned place preference to morphine. In addition, mice were made tolerant by twice daily morphine injections for 5 days. We found that MS21570 pretreatment reduced the development of morphine tolerance and withdrawal. Together, these data support the idea that the BigLEN‐GPR171 system plays an important role in the regulation of some of the adverse effects associated with prolonged opioid exposure.Support or Funding InformationSupported by NIH grants, DA019521 and NS026880 (to LAD) and NIDA postdoctoral training grant DA007135 (to ENB).
Examining the capacity of nAChR antagonists to block the effects of nicotine in nicotine‐tolerant C57BL/6J mice
Authors: de Moura Fernando Barreto , McMahon Lance Richard 
Published: November 2023

The clinical effectiveness of some nAChR‐based smoking cessation aids is proposed to be due to antagonism of the effects of nicotine. However, it is unclear whether nicotine antagonism varies as a function of repeated nicotine exposure. In the current stidy, nicotine, mecamylamine (nonselective nAChR antagonist), and dihydro‐β‐erythroidine (DHβE; α4β2* nAChR antagonist) were studied in male C57BL/6J mice responding under an FR20 schedule of food delivery before, during, and after discontinuation of daily nicotine treatment consisting of 1.78 mg/kg nicotine administered three times per day. Before daily nicotine treatment, nicotine decreased response rate and rectal temperature with ED50 values of 0.44 and 0.82 mg/kg, respectively. DHβE significantly antagonized the rate‐decreasing and hypothermic effects of nicotine, evidenced by 2.9‐ and 3.2‐ fold rightward shifts of the nicotine dose‐response functions, respectively. Daily nicotine treatment produced tolerance, as evidenced by 3.6‐ and 4.8‐fold rightward shifts in the nicotine dose‐response functions for rate‐decreasing and hypothermic effects, respectively. During daily nicotine treatment, mecamylamine and DHβE no longer antagonized the rate‐decreasing effects of nicotine, whereas both antagonists continued to block the hypothermic effects of nicotine. After discontinuation of daily nicotine treatment, there was a time‐related loss of tolerance to nicotine; under these conditions, mecamylamine and DHβE retained their capacity to antagonize the rate‐decreasing and hypothermic effects of nicotine. These data suggest that nicotine produces rate‐decreasing and hypothermic effects through different receptor types, and further suggest that nicotine can act at non‐nAChRs in nicotine‐tolerant animals. A potential loss of nicotine antagonist activity in cigarette smokers could underscore a potential limitation in the effectiveness of some nAChR‐based smoking cessation aids.Support or Funding InformationFunding: USPHS DA25267
Methamphetamine‐Induced Changes to Serotonergic Markers in the Frontal Cortex
Authors: Cordie Rebecca , Livermont Tamee , Johansen Andrew , McFadden Lisa M 
Published: November 2023

Methamphetamine use is associated with a variety of negative health outcomes including psychosis. Alternations in the frontal cortex including changes in serotonin (5HT) 2A receptors are thought to contribute to psychosis‐like behaviors. Previously we have reported that methamphetamine self‐administration changes serotonin in the frontal cortex of rats. The purpose of this study was to investigate changes in serotonergic markers in the frontal cortex following methamphetamine self‐administration and how these changes relate to hallucination‐like behavior. Male and female rats were allowed to self‐administer either methamphetamine or saline and were sacrificed either one hour after the last self‐administration session or following extinction training. Serotonin transporters (SERT) and 5HT2A receptors were assessed in the frontal cortex via autoradiography. No changes in SERT autoradiography was observed in the orbitofrontal, prelimbic, or infralimbic cortices one hour after self‐administration or after extinction training. However, preliminary findings suggest time dependent changes in 5HT2A receptors in the frontal cortex. One hour after the last self‐administration session 5HT2A receptors were increased in the orbitofrontal cortex. Further, there was a trend towards an increase in prelimbic 5HT2A receptors in rats that self‐administered methamphetamine. However, no changes were found in male rats following extinction training. To assess the functioning of the 5HT2A receptors, the 5HT2A/2C agonist, DOI, was administered in a separate group of animals following extinction training. Preliminary results suggest that rats with a history of METH self‐administration have reduced hyperthermia following the administration of DOI. Efforts are underway to quantify DOI‐induced head twitches which are thought to reflect 5HT2A receptor function in the brain and hallucination‐like behavior. Overall, results of the current study suggest that methamphetamine self‐administration causes time dependent changes in 5HT2A receptors but not SERT in the frontal cortex. Ongoing studies will examine how methamphetamine‐induced changes in the frontal cortex may result in changes in behaviors associated with psychosis such as hallucinations.Support or Funding InformationFunding for this study was provided the NIH grant DA036012.
Dose Effects of Synthetic Cathinone Mephedrone on Cocaine Reinstatement in Rats
Authors: Saber Iman A , Ward Sara J , Rawls Scott , Walker Ellen A 
Published: November 2023

Mephedrone is a recreational synthetic cathinone and a major component of psychoactive ‘bath salts.’ In previous in vitro studies, mephedrone increases dopamine (DA) and serotonin (5‐HT) release and inhibits DA and 5‐HT synaptosomal uptake similar to other abused stimulants.The purpose of this study was to determine the capacity of mephedrone to reestablish on cocaine self‐administration when a history of cocaine is already established in rats. We predict that rats will readily engage in cocaine‐seeking behavior after the extinction of cocaine self‐administration, when presented with a mephedrone‐induced prime injection. If mephedrone activates the mesolimbic DA system and produces a rewarding effect through DA mechanisms, then mephedrone will reinstate the extinguished cocaine‐seeking behavior in a pattern comparable to cocaine. Male Sprague‐Dawley rats were allowed to self‐administer 0.375 mg/kg/inf of cocaine for two hours for a total of 10–14 days. Following 8–20 days of extinction, rats were reinstated with either i.p. injection of 10 mg/kg cocaine, 1, 5, or 10 mg/kg mephedrone.After acquisition and extinction, a high dose of 10.0 mg/kg cocaine produced reinstatement of cocaine‐responding. A moderate dose of 5.0 mg/kg mephedrone decreased amount of infusions administered during reinstatement. However, a low and high dose of 1.0 and 10.0 mg/kg mephedrone produced an increased amount of infusions, but not higher than cocaine. In addition, only 4 rats failed to reinstate cocaine responding after cocaine‐prime but 10 rats failed to reinstate after any dose of mephedrone‐prime. These preliminary results suggest that after a history of cocaine self‐administration, cocaine reinstates cocaine responding more fully than mephedrone. This may be due to mephedrone's dual dopaminergic and serotonergic mechanism.
A role for GPR83, a newly deorphanized G protein‐coupled receptor, in stress‐induced neuroimmune modulation
Authors: Lueptow Lindsay Mariah , Gomes Ivone , Fakira Amanda , Devi Lakshmi A 
Published: November 2023

GPR83 is a recently deorphanized G‐protein coupled receptor (GPCR) found to be widely expressed throughout the brain and immune system of mice. Analysis of expression reveals high levels in discrete brain regions, such as nucleus accumbens, hypothalamus, amygdala and hippocampus, regions known to be involved in stress modulation, anxiety, depression, and memory. Previous studies have reported that GPR83 is regulated by the stress hormone corticosterone and that GPR83 knockout mice are resistant to stress‐induced anxiety, despite having similar increases in plasma corticosterone as wild type mice. Because stress is known to have a profound effect on immune function, we have recently begun to explore a role for GPR83 in neuroimmune interactions during stress. Using flow cytometry, we have identified the immune cell types that express GPR83. We find GPR83 expression on CD4+ and CD8+ T‐cell populations, as well as a small portion of B cells and natural killer cells. To explore the neuronal pathway that activates GPR83 in these cells, we sought to map the projections from the brain to the spleen and thymus. For this, we injected attenuated pseudorabies virus tagged with GFP into the spleen and thymus and examined viral expression following 72 hrs of retrograde transport. Expression was observed in portions of the reticular formation (notably gigantocellular reticular nucleus), nucleus raphe magnus, dorsal raphe nucleus, and periaqueductal grey. There was strong expression in the paraventricular hypothalamus and in the gray matter cells of the subthalamus, known as the zona incerta. Most interestingly, projections to the central amygdala and anterior insular cortex were also observed. Since many of these brain regions are involved in somatic regulation, fear learning and response to stress, as well as pain modulation, these results are consistent with a role for the GPR83‐PEN receptor system as a mediator of neuroimmune interactions.Support or Funding InformationFunding: NS026880 and DA019521 to L.A.D and T32 grant DA007135 to L.M.L.
AMPA receptor RNA editing may alleviate the long‐term effects of prenatal stress.
Authors: Bristow Greg , Sodhi Monsheel 
Published: November 2023

BackgroundA post‐transcriptional process known as RNA editing regulates the trafficking and function of α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid glutamate receptors (AMPARs), which are critical for synaptic plasticity, learning and memory. These processes are impaired in psychiatric disorders that are exacerbated by stress, such as schizophrenia. RNA editing of AMPARs has been associated with several neurological disorders, including epilepsy and schizophrenia.MethodsWe exposed mice to environmental stress during gestation i.e. prenatal stress (PRS). In adulthood, mice were treated with haloperidol (1mg/kg), clozapine (5mg/kg) or saline twice daily for 5 days. 16hrs after the final injection, mice were assessed for social interaction behavior and locomotor activity. The hippocampus of each mouse was analyzed for the expression of the RNA editing enzymes (ADARs 1–3) in addition to tagged next‐generation sequencing analysis of the RNA editing levels of 24 genes, including the AMPA glutamate receptor subunits.ResultsPRS mice exhibited reduced social interaction behavior. This abnormal behavior was associated with reduced hippocampal RNA editing of several ADAR targets, including the AMPAR subunits GluA2‐4, the potassium channel Kv1.1, and the serotonin2C receptor (5‐HT2CR). Treatment of the PRS mice with clozapine, but not haloperidol, eliminated abnormal social interaction, along with elimination of abnormal GluA2 RNA editing. Measurement of the RNA editing enzymes revealed increased ADAR3 expression in the clozapine‐treated PRS mice, indicating that PRS and clozapine both alter transcriptional pathways associated with RNA editing in the hippocampus.ConclusionsOur data show that PRS produces long‐term changes in behavior that may be due to abnormal development of the hippocampus. Social interaction behavior was correlated with the hippocampal RNA editing of several ADAR targets. Only GluA2 RNA editing appeared to be ‘normalized’ by clozapine treatment, along with the elimination of abnormal social interaction in PRS mice. Therefore the long‐term behavioral effects of prenatal stress may be alleviated by clozapine through a molecular pathway involving GluA2 RNA editing.Support or Funding InformationFunded by a Hans W. Vahlteich Scholar Award (MS), the Chicago Biomedical Consortium and a University of Illinois Centre for Drug Discovery seed grant (MS). Work completed in collaboration with Dr. Erbo Dong, Dr. Alessandro Guidotti (UIC), Dr. Evelyn Nwabuisi‐Heath and Michelle Vierra.
GENDER DIFFERENCES IN THE INTERACTION OF CATHINONE WITH CAFFEINE ON LOCOMOTOR ACTIVITY IN THE RAT
Authors: Docherty Jim , Alsufyani Hadeel A. 
Published: November 2023

Leaves of Khat (Catha edulis Forsk) contain the β‐keto‐amphetamine cathinone that has MDMA‐like actions (Kalix, 1990). The actions of cathinone are largely indirect by release of monoamines to act both centrally and peripherally (Alsufyani & Docherty, 2015). Gender differences occur in the use and effects of stimulants, including Khat, in humans, but in basic research, female animal models have been rarely studied. We have investigated gender differences in the effects of cathinone (the major stimulant from Khat) and the interaction with caffeine on locomotor activity in Wistar rats. Indeed, Khat users often combine coffee with the stimulant. Animals were implanted with telemetry probes under isoflurane anaesthesia, and 7 days later, locomotor activity was recorded in conscious unrestrained animals. Following an equilibration period, sampling was commenced and at 5 min, caffeine (10 mg/kg) or vehicle, and 30 min later, cathinone (5 mg/kg) or vehicle were injected subcutaneously in male and female rats. Recording continued for a further 240 min. Time course of effects was investigated at 5 min intervals. Caffeine alone produced only small increases in total locomotor activity, but even these small effects were significantly greater in female rats (one way Anova of total activity over the whole sampling period, P<0.05). Cathinone produced significant and marked increases in locomotor activity, beginning soon after injection, and the response to cathinone was significantly greater in female animals (two way Anova of time course of effect, P<0.05). The combination of caffeine and cathinone causes a transient potentiation, followed by a prolonged inhibition, of the locomotor response to cathinone. Hence, the peak response to injection of cathinone was significantly increased, but for much of the next 120 min, the response to cathinone was significantly reduced by the presence of caffeine, especially in female rats. In conclusion, cathinone causes greater increases in locomotor activity in female than in male rats, but although the acute effects of cathinone are potentiated by caffeine, the maintained effects of cathinone on locomotor activity are, perhaps surprisingly, reduced by caffeine in both male and female rats. These differences highlight the need to carry out gender studies of the actions and interactions of stimulants in basic studies.Alsufyani HA, Docherty JR (2015). Eur J Pharmacol 758: 142–146 Kalix P (1990) Pharmacol Ther, 48:397–416.Support or Funding InformationHAA is funded by a scholarship from the Saudi Government Ministry of Higher Education, KAU.
The role of estradiol on social stress induced depressive‐like behavior and neuroinflammation in females
Authors: Finnell Julie E , Lombard Calliandra M , Moffitt Casey M , Padi Akhila R , Wood Christopher S , Wilson Marlene A , Wood Susan K 
Published: November 2023

It has long been established that repeated exposure to social stress can lead to the development of psychosocial disorders, such as depression. Strikingly, women are more sensitive to stress‐related disorders, such as depression compared to men. This enhanced stress sensitivity in females begins at the onset of puberty and ends during menopause, suggesting that ovarian hormones could be a large contributing factor to this phenomenon. However, the mechanism by which ovarian hormones could be driving this enhanced stress sensitivity is unknown. Using a modified social defeat paradigm which consists of a rat bearing witness to an aggressive social defeat encounter, we have previously shown that witness stress produces depressive‐like anhedonia and enhanced pressor and tachycardic responses selectively in intact cycling females while females that are ovariectomized (OVX) are resistant, making this an ideal model to study mechanisms of stress susceptibility in females. We recently demonstrated that neuroinflammation is crucial in the development of depressive‐like anhedonia in socially stressed males. The purpose of this study was to determine the effects of estradiol on social stress‐induced neuroinflammation within the central amygdala (CeA) and locus coeruleus (LC) of witness stressed females. Study 1 determined the differential neuroinflammatory consequences of witness stress in intact cycling vs. OVX females. Much like our behavioral data suggests, intact cycling females show enhanced neuroinflammation in the CeA compared to OVX females. Interestingly, neuroinflammation was not elevated in the LC in response to witness stress, but rather OVX females demonstrated stress‐induced reductions of IL‐1β within the LC vs. controls. In order to determine the discrete role of estradiol in these neuroinflammatory responses to stress, study 2 determined cytokine levels in OVX females that received estradiol or placebo replacement. While estradiol replacement did not result in the emergence of stress‐induced depressive‐like anhedonia, it did promote anxiety‐like behavior as evidenced by increased burying during witness stress exposure. Based on this enhanced anxiety‐like response, we predict concomitant increases in neuroinflammation within the CeA, a brain region known to contribute to behavioral stress responses. Therefore, the current study suggests that ovarian hormones, potentially estrogen, may mediate enhanced stress sensitivity in females by promoting stress‐induced inflammation in critical brain regions involved in the behavioral stress response, providing novel therapeutic targets to study female stress resiliency and susceptibility.Support or Funding InformationASPIRE18080‐16‐41861, 15SDG22430017, and P20GM103641