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Effects of the selective dopamine D3 receptor antagonist PG01037 on morphine-induced hyperactivity and antinociception in mice
Christian A.Botz-ZappaStephanie L.FosteraDesta M.PulleybBrianaHempelcGuo-HuaBicZheng-XiongXicAmy HauckNewmancDavidWeinshenkeraDaniel F.Manvichab1
doi : 10.1016/j.bbr.2021.113506
Volume 415, 11 October 2021, 113506
Recent preclinical studies have reported that pretreatment with the novel and highly-selective dopamine D3 receptor (D3R) antagonists R-VK4-40 or VK4-116 attenuates the abuse-related behavioral effects of oxycodone while enhancing its analgesic properties. However, whether these observed effects are generalizable to the broad class of D3R antagonists and/or extend to opioids other than oxycodone has not been extensively explored. The present study sought to assess the impact of pretreatment with another selective D3R antagonist, PG01037, on several behavioral effects of morphine in mice. C57Bl/6?J mice were pretreated with PG01037 (0–10?mg/kg) and tested for 1) hyperlocomotion induced by acute morphine (5.6–56?mg/kg), 2) locomotor sensitization following repeated morphine (56?mg/kg), 3) antinociception following acute morphine (18?mg/kg), and 4) catalepsy following administration of PG01037 alone or in combination with morphine (56?mg/kg). PG01037 dose-dependently attenuated morphine-induced hyperlocomotion and morphine-induced antinociception at doses that did not alter basal locomotion or nociception alone, but did not prevent the induction of locomotor sensitization following repeated morphine administration. Moreover, PG01037 did not induce catalepsy either alone or in combination with morphine. These results suggest that attenuation of acute opioid-induced hyperactivity may be a behavioral effect shared among D3R-selective antagonists, thus supporting continued investigations into their use as potential treatments for opioid use disorder. However, PG01037 is unlike newer, highly-selective D3R antagonists in its capacity to reduce opioid-induced antinociception, indicating that modulation of opioid analgesia may vary across different D3R antagonists.
Behavioural and cardiovascular effects of orexin-A infused into the central amygdala under basal and fear conditions in rats
NickOlsena1Teri M.Furlongab1PascalCarrivea
doi : 10.1016/j.bbr.2021.113515
Volume 415, 11 October 2021, 113515
The neuropeptide orexin-A (OX-A) has diverse functions, including maintaining arousal, autonomic control, motor activity and stress responses. These functions are regulated at different terminal regions where OX-A is released. The current study examined the physiological and behavioural effects of OX-A microinjections into the central amygdala (CeA) under basal and stressed conditions in rats. When OX-A was microinjected into the CeA and the animals returned to the home-cage, heart rate and mean arterial pressure were increased compared to vehicle-injected controls. General activity of the animal was also increased, indicating that OX-A activity in CeA contributes to increased arousal. This outcome is similar to the effects of central intracerebroventricular infusions of OX-A, as well as the cardiovascular effects previously demonstrated at many of OX’s efferent hypothalamic and brainstem structures. In a second study, animals were fear-conditioned to a context by delivery of electric footshocks and then animals were re-exposed to the conditioned context at test. When OX-A was microinjected at test, freezing behaviour was reduced and there was a corresponding increase in the animal’s activity but no impact on the pressor and cardiac responses (i.e, blood pressure and heart rate were unchanged). This reduction in freezing suggests that OX-A activates amygdala neurons that inhibit freezing, which is similar to the actions of other neuropeptides in the CeA that modulate the appropriate defence response to fearful stimuli. Overall, these data indicate that the CeA is an important site of OX-A modulation of cardiovascular and motor activity, as well as conditioned freezing responses.
Apolipoprotein E e4 is associated with worse self-reported neurobehavioral symptoms following uncomplicated mild traumatic brain injury in U.S. military service members
Rael T.LangeabcdilVictoria C.MerrittefTracey A.BrickellabcgilClifton L.DalgardgjAnthony R.SoltiskmJamieHershawabciSara M.LippabcJessicaGillhLouis M.Frenchabcg
doi : 10.1016/j.bbr.2021.113491
Volume 415, 11 October 2021, 113491
Past research has found a relationship between the apolipoprotein E (APOE) e4 allele and worse neurobehavioral functioning following mild traumatic brain injury (MTBI) in civilian populations. The purpose of this study was to examine this relationship in service members and veterans (SMVs) following MTBI. Participants were 151 SMVs (103 uncomplicated MTBI; 48 Injured Controls [IC]) prospectively enrolled in the DVBIC-TBICoE 15-Year Longitudinal TBI Study. Participants completed a battery of self-reported neurobehavioral symptom measures on average 76.2 months post-injury (SD = 31.8). APOE genotyping was undertaken using non-fasting blood samples. Participants were classified into four subgroups based on injury (MTBI vs. IC) and APOE e4 allele status (e4 present/absent). In the IC group, there were no significant differences across APOE e4 status subgroups for all measures. In the MTBI group, participants with the APOE e4 allele had significantly worse scores on measures of depression, pain, anxiety, grief, positive well-being, social participation, and resilience compared to those without the e4 allele (d = .44 to d = .69). When comparing the number of ‘clinically elevated’ neurobehavioral measures simultaneously, the MTBI/e4 present subgroup consistently had a higher number of elevated measures compared to the MTBI/e4 absent, IC/e4 present, and IC/e4 absent subgroups. The APOE e4 allele was associated with poorer neurobehavioral outcome in SMVs in the chronic phase of recovery following MTBI. APOE e4 could be incorporated into screening tools to predict SMVs at risk for poor long-term neurobehavioral outcome in an effort to provide early intervention to improve long-term clinical outcome.
Quantitative Proteomics Analysis of Susceptibility and Resilience to Stress in a Rat model of PTSD
JiaoDuanb1WenjunLic1WeiyanLidQingzhenLiudMiTiandChunlongChendLidongZhangdMinhaoZhanga
doi : 10.1016/j.bbr.2021.113509
Volume 415, 11 October 2021, 113509
Posttraumatic stress disorder (PTSD) is a prevalent psychiatric disorder and sometimes deadly consequence of exposure to severe psychological trauma. However, there has been little known about the definitive molecular changes involved in determining vulnerability to PTSD. In the current study, we used proteomics to quantify protein changes in the hippocampus of foot shocks rats. A total of 6151 proteins were quantified and 97 proteins were significantly differentially expressed. The protein-protein interaction (PPI) analysis showed that oxidation-reduction process and glutathione homeostasis may be the potential key progress of being vulnerable to PTSD. The Gene Ontology analysis revealed enriched GO terms in the protein groups of Susceptible group vs Control group rats for glutathione binding,oligopeptide binding,modified amino acid binding,and glutathione transferase activity for their molecular functions (MF) and in the process of cellular response to toxic substance,xenobiotic metabolic process, urea metabolic process, and response to drug for the biological process (BP).SIGNIFICANCE:In recent years, there has been a growing interest in mental illness associated with trauma exposure. We found that stress susceptibility was associated with increased expression of arginase 1 indicated as a potential treatment target. Our results also proposed that carbonic anhydrases 3 could be a biomarker for the development of PTSD. This research helps to explain the potential molecular mechanism in PTSD and supply a new method for ameliorating PTSD.
Adolescent exposure to delta-9-tetrahydrocannabinol and ethanol heightens sensitivity to fear stimuli
Cora E.SmileyHeyam K.SalehKatherine E.NimchukConstanzaGarcia-KellerJustin T.Gass
doi : 10.1016/j.bbr.2021.113517
Volume 415, 11 October 2021, 113517
Cannabis use disorder (CUD) has doubled in prevalence over the past decade as a nation-wide trend toward legalization allows for increased drug accessibility. As a result, marijuana has become the most commonly used illicit drug in the United States particularly among the adolescent population. This is especially concerning since there is greater risk for the harmful side effects of drug use during this developmental period due to ongoing brain maturation. Increasing evidence indicates that CUD often occurs along with other debilitating conditions including both alcohol use disorder (AUD) and anxiety disorders such post-traumatic stress disorder (PTSD). Additionally, exposure to cannabis, alcohol, and stress can induce alterations in glutamate regulation and homeostasis in the prefrontal cortex (PFC) that may lead to impairments in neuronal functioning and cognition. Therefore, in order to study the relationship between drug exposure and the development of PTSD, these studies utilized rodent models to determine the impact of adolescent exposure to delta-9-tetrahydrocannabinol (THC) and ethanol on responses to fear stimuli during fear conditioning and used calcium imaging to measure glutamate activity in the prelimbic cortex during this behavioral paradigm. The results from these experiments indicate that adolescent exposure to THC and ethanol leads to enhanced sensitivity to fear stimuli both behaviorally and neuronally. Additionally, these effects were attenuated when animals were treated with the glutamatergic modulator N-acetylcysteine (NAC). In summary, these studies support the hypothesis that adolescent exposure to THC and ethanol leads to alterations in fear stimuli processing through glutamatergic reliant modifications in PFC signaling.
Examining the impact of neuroimmune dysregulation on social behavior of male and female juvenile rats
AlexandraTuranoElizabeth M.McAuleyMegan C.MuenchJaclyn M.Schwarz
doi : 10.1016/j.bbr.2021.113449
Volume 415, 11 October 2021, 113449
Many individuals diagnosed with neuropsychiatric disorders, such as autism, attention-deficit/hyperactivity disorder, schizophrenia, and social anxiety disorder, all share a common dimension of aberrant social behavior. Epidemiological data indicate that adverse environmental factors contribute to the risk for neurodevelopmental disorders, including those associated with aberrant social behavior. Early-life exposure to infectious pathogens is one of those adverse environmental factors, suggesting that activation of the immune system during early development may contribute to disease pathology associated with altered social behavior. In the current project, we examined the impact of neonatal infection, with or without juvenile immune activation, on the expression of juvenile social behavior and on the expression of inflammatory cytokines and microglial signaling molecules in the juvenile rat brain. The outcomes of these experiments revealed that neonatal infection significantly decreased juvenile social interaction, but significantly increased juvenile play behavior in male and female rats. Moreover, neonatal infection alone, juvenile immune activation alone, and neonatal infection plus juvenile immune activation all significantly impaired social recognition in juvenile male rats. Juvenile female rats (including controls) did not demonstrate social recognition as measured in our three-chamber social recognition test. Taken together, the behavioral and molecular data presented here support the sensitivity of the developing brain to immune activation, particularly in the expression of age-appropriate social behaviors. These data warrant the design of additional studies to examine the mechanistic relationship between early-life immune activation and aberrant social behavior to develop novel as well as modify existing therapeutic targets and preventative measures to help those who display aberrant social behavior.
Perinatal exposure to high fat diet alters expression of MeCP2 in the hypothalamus
JessicaFrayre1PriscilaFrayre1IdaWongAnushaMithaniStephanieBishopChelsyManiKarenPonce-RubioRuvaidVirkMichael J.MorrisElisa S.Na
doi : 10.1016/j.bbr.2021.113518
Volume 415, 11 October 2021, 113518
Obesity is a complex disease that is the result of a number of different factors including genetic, environmental, and endocrine abnormalities. Given that monogenic forms of obesity are rare, it is important to identify other mechanisms that contribute to its etiology. Methyl-Cp-G binding protein 2 (MeCP2) is a neuroepigenetic factor that binds to methylated regions of DNA to influence transcription. Past studies demonstrate that disruption in MeCP2 function produces obesity in mice. Using a diet-induced obesity mouse model, we show that perinatal exposure to high fat diet significantly decreases MeCP2 protein expression in the hypothalamus of female mice, effects not seen when high fat diet is given to mice during adulthood. Moreover, these effects are seen specifically in a subregion of the hypothalamus known as the arcuate nucleus with females having decreased MeCP2 expression in rostral areas and males having decreased MeCP2 expression in intermediate regions of the arcuate nucleus. Interestingly, mice gain more weight when exposed to high fat diet during adulthood relative to mice exposed to high fat diet perinatally, suggesting that perhaps high fat diet exposure during adulthood may be affecting mechanisms independent of MeCP2 function. Collectively, our data demonstrate that there are developmentally sensitive periods in which MeCP2 expression is influenced by high fat diet exposure and this occurs in a sexually dimorphic manner.
Paternal and infanticidal behavior in the Mongolian gerbil (Meriones unguiculatus): An approach to neuroendocrine regulation
LuisRomero-MoralesaBrendaGarcía-SaucedoaMartínMartínez-TorresaRenéCárdenas-VázquezbCarmenÁlvarez-RodríguezaAgustínCarmonacJuanaLuisa
doi : 10.1016/j.bbr.2021.113520
Volume 415, 11 October 2021, 113520
This study aimed to provide evidence on estrogen and androgen pathways regulating the Mongolian gerbil's paternal and infanticidal behaviors (Meriones unguiculatus). We analyzed estrogen receptor alpha (ER?) and androgen receptor (AR) distribution in the medial preoptic area (mPOA), the bed nucleus of stria terminalis (BNST), as well as the anterior hypothalamic nucleus (AHN), the ventromedial hypothalamus nucleus (VMH), and the periaqueductal gray area (PAG) nuclei activated when males interact paternally or aggressively with the pups, respectively. Twenty aggressive males towards the pups and 10 paternal were selected through a screen paternal behavior test. Three groups of 10 males each were formed: paternal males (PAT), males with testosterone (T)-induced paternal behavior (T-PAT), and aggressive males (AGG). Male gerbils could interact with a pup for a few minutes, and their brains were removed and dissected for ER? and AR immunoreactivity (ir). The results showed that in T-PAT and PAT males, the number of ER?-ir and AR-ir cells in the mPOA/BNST was significantly higher than in AGG males. In AGG males, the number of ER?-ir and AR-ir cells in the AHN/VMH/PAG was significantly higher than PAT and T-PAT males. This difference in the presence of ER? and AR in nuclei activated in paternal interactions in the Mongolian gerbil supports the idea that these receptors participate in regulating paternal behavior. Also, these results suggest, for the first time, that they could be involved in the infanticidal behavior in this rodent.
Involvement of the dopamine system in paternal behavior induced by repeated pup exposure in virgin male ICR mice
WenqiCaiHuanMaYufengXunWenjuanHouLiminWangXueniZhangYufengRanWeiYuanQianqianGuoJingZhangLaifuLiYangYangYitongLiZijianLvZhixiongHeRuiJiaFadaoTai
doi : 10.1016/j.bbr.2021.113519
Volume 415, 11 October 2021, 113519
Like mothers, fathers play a vital role in the development of the brain and behavior of offspring in mammals with biparental care. Unlike mothers, fathers do not experience the physiological processes of pregnancy, parturition, or lactation before their first contact with offspring. Whether pup exposure can induce the onset of paternal behavior and the underlying neural mechanisms remains unclear. By using Slc:ICR male mice exhibiting maternal-like parental care, the present study found that repeated exposure to pups for six days significantly increased the total duration of paternal behavior and shortened the latency to retrieve and care for pups. Repeated pup exposure increased c-Fos-positive neurons and the levels of dopamine- and TH-positive neurons in the nucleus accumbens (NAc). In addition, inhibition of dopamine projections from the ventral tegmental area to the NAc using chemogenetic methods reduced paternal care induced by repeated pup exposure. In conclusion, paternal behavior in virgin male ICR mice can be initiated by repeated pup exposure via sensitization, and the dopamine system may be involved in this process.
Engagement of lateral habenula in the extinction of the appetitive conditioned responses
Dong-HeeKimBo-RyoungChoiYong-JaeJeonYoon-SunJangJung-SooHan
doi : 10.1016/j.bbr.2021.113516
Volume 415, 11 October 2021, 113516
Following the association of a neutral stimulus (conditioned stimulus, CS) with a biologically significant stimulus (unconditioned stimulus, US), CS-alone presentations generate extinction: a decline in the conditioned response. Many studies have revealed the neural substrates of fear extinction; however, a few have identified the brain regions responsible for appetitive extinction. Midbrain dopamine neurons are activated by presenting a reward or predictable reward cue, whereas the cue signaling the absence of reward activates the lateral habenula (LHb) neurons. We examined the engagement of the LHb in appetitive extinction. In the first phase, rats first received pairings of a CS (light) with US delivery (food pellets). In the second phase, rats in the CS-alone group underwent four CS-alone presentations, whereas those in the paired group received four pairings of light with food pellets. We also included a comparison group for CS-alone presentations: rats were placed in the training box without CS or US exposures in the first phase and received four CS-alone presentations in the second phase. Thirty minutes after the second phase, c-Fos levels in the ventral tegmental area (VTA), substantia nigra pars compacta (SNc), and LHb in these groups were measured. c-Fos levels in the LHb were higher in the paired-CS-alone group than in the paired-paired and comparison groups, while those in the VTA and SNc were significantly higher in the paired-paired group than in the other groups. On examination of LHb neurotoxic lesion effects on the decline of conditioned food-cup responses when a CS was repeatedly presented with no US, LHb lesions decelerated the decline in conditioned food-cup responses, suggesting a crucial role of LHb in appetitive extinction.
The primary motor cortex electrical and chemical stimulation attenuates the chronic neuropathic pain by activation of the periaqueductal grey matter: The role of NMDA receptors
Sylmara EstherNegrini-FerrariabPriscilaMedeirosabRafael BraghettoMalvestioabMarianade Oliveira SilvaabAna CarolinaMedeirosabNorberto CysneCoimbraabdHelio RubensMachadoaeRenato Leonardode Freitasabcd
doi : 10.1016/j.bbr.2021.113522
Volume 415, 11 October 2021, 113522
Motor cortex stimulation (MCS) is proper as a non-pharmacological therapy for patients with chronic and neuropathic pain (NP).
Blocking serotonin 2A (5-HT2A) receptors attenuates the acquisition of methamphetamine-induced conditioned place preference in adult female rats
John T.MaddenaNicole C.ReynaaEmerald V.GoransonaTiffany A.GonzalezbArturo R.ZavalabNathan S.Pentkowskia
doi : 10.1016/j.bbr.2021.113521
Volume 415, 11 October 2021, 113521
Methamphetamine withdrawal can induce intense cravings leading to relapse. Contexts/cues paired with chronic methamphetamine use develop incentive motivational properties, promoting future drug-seeking and taking behavior. Research has shown that, in adult male rats, the selective 5-HT2A receptor antagonist M100907 attenuates the acquisition of methamphetamine-induced conditioned place preference (CPP), a measure that examines conditioned associations between the rewarding properties of drugs and contexts. However, these findings have not been extended to adult female rats. The present study investigated the effects of M100907 on the acquisition of methamphetamine-CPP in adult female rats. During conditioning, rats were administered M100907 (0, 0.025, 0.25 mg/kg, i.p.) 15 min before methamphetamine (1 mg/kg, i.p.) and then placed into their initially non-preferred chamber for 30 min, or administered saline and placed into their initially preferred chamber for 30 min. Conditioning sessions were separated by four hours. Following four days of conditioning, the effects of M100907 on the acquisition of methamphetamine-CPP were assessed during a 15 min drug-free test trial. Pretreatment with M100907 dose-dependently attenuated the acquisition of methamphetamine-induced CPP. Blocking 5-HT2A receptors with a low dose of the selective antagonist M100907 attenuated the rewarding effects of methamphetamine in adult female rats. These data provide further evidence that the 5-HT2A receptor subtype is involved in the behavioral effects of methamphetamine.
