Novel RXFP3 negative allosteric modulator RLX-33 reduces alcohol self-administration in rats.

There is much interest in identifying novel pharmacotherapeutic targets that improve clinical outcomes for the treatment of alcohol use disorder (AUD). One promising target for therapeutic intervention is the relaxin family peptide 3 (RXFP3) receptor, a cognate receptor for neuropeptide relaxin-3, which has previously been implicated in regulating alcohol drinking behavior. Recently, we developed the first small-molecule RXFP3-selective negative allosteric modulator (NAM) RLX-33.

Toll-like receptor 3 neuroimmune signaling and behavior change: A strain comparison between Lewis and Wistar rats.

There are many unanswered questions about the interaction between the immune system and behavior change, including the contributions of individual differences. The present study modeled individual differences in the immune system by comparing inbred Lewis rats, which have dysregulated stress and immune systems, to their genetically diverse parent strain, Wistar rats. The objective was to examine the consequences of an immune challenge on behavior and neuroimmune signaling in both strains.

The Toll-like receptor 7 agonist imiquimod increases ethanol self-administration and induces expression of Toll-like receptor related genes.

There is growing evidence that immune signalling may be involved in both the causes and consequences of alcohol abuse. Toll-like receptor (TLR) expression is increased by alcohol consumption and is implicated in AUD, and specifically TLR7 may play an important role in ethanol consumption. We administered the TLR7-specific agonist imiquimod in male and female Long-Evans rats to determine (1) gene expression changes in brain regions involved in alcohol reinforcement, the nucleus accumbens core and anterior insular cortex, in rats with and without an alcohol history, and (2) whether TLR7 activation could modulate operant alcohol self-administration.

Increased alcohol self-administration following repeated Toll-like receptor 3 agonist treatment in male and female rats.

Toll-like receptor (TLR) signaling may play an important role in the neuroimmune system's involvement in the development and maintenance of alcohol use disorder (AUD). In the present study we administered the TLR3 agonist poly(I:C) in male and female Long-Evans rats to determine whether TLR3 agonism can increase alcohol consumption on a daily 15% alcohol operant self-administration paradigm. We found few effects when poly(I:C) was given every-other-day at 0.

RTICBM-74 Is a Brain-Penetrant Cannabinoid Receptor Subtype 1 Allosteric Modulator that Reduces Alcohol Intake in Rats.

The endocannabinoid system is implicated in the neuronal mechanisms of alcohol use disorder (AUD), with the cannabinoid receptor subtype 1 (CB) representing a promising target for AUD therapeutic interventions. We have previously shown negative allosteric modulators (NAMs) of the CB receptor attenuated the reinstatement of other drugs of abuse including cocaine and methamphetamine in rats; however, their effects on alcohol-related behaviors have not been investigated. Here, we tested the pharmacokinetic properties of one such CB NAM, RTICBM-74, and its effects on alcohol self-administration in rats.

Interoception and alcohol: Mechanisms, networks, and implications.

Interoception refers to the perception of the internal state of the body and is increasingly being recognized as an important factor in mental health disorders. Drugs of abuse produce powerful interoceptive states that are upstream of behaviors that drive and influence drug intake, and addiction pathology is impacted by interoceptive processes. The goal of the present review is to discuss interoceptive processes related to alcohol.

Low-dose alcohol: Interoceptive and molecular effects and the role of dentate gyrus in rats.

Alcohol abuse and dependence are world-wide health problems. Most research on alcohol use focuses on the consequences of moderate to high levels of alcohol. However, even at low concentrations, alcohol is capable of producing effects in the brain that can ultimately affect behavior.

Exposure to the predator odor TMT induces early and late differential gene expression related to stress and excitatory synaptic function throughout the brain in male rats.

Persistent changes in brain stress and glutamatergic function are associated with post-traumatic stress disorder (PTSD). Rodent exposure to the predator odor trimethylthiazoline (TMT) is an innate stressor that produces lasting behavioral consequences relevant to PTSD. As such, the goal of the present study was to assess early (6 hours and 2 days-Experiment 1) and late (4 weeks-Experiment 2) changes to gene expression (RT-PCR) related to stress and excitatory function following TMT exposure in male, Long-Evans rats.

Acute stress imposed during adolescence has minimal effects on hypothalamic-pituitary-adrenal (HPA) axis sensitivity in adulthood in female Sprague Dawley rats.

Adolescence is a developmental epoch marked by maturation of stress-responsive systems including the Hypothalamic-Pituitary-Adrenal (HPA) axis. Emerging evidence has found sex-specificity in the long term behavioral and neural effects of stressors experienced during this sensitive period, though most studies have utilized chronic stress exposures that span much of the adolescent period. Using Sprague-Dawley rats, we examined how a single exposure to inescapable footshock (80 shocks, 5 s, 1.

Acute stress imposed during adolescence yields heightened anxiety in Sprague Dawley rats that persists into adulthood: Sex differences and potential involvement of the Medial Amygdala.

Stressors experienced during adolescence have been demonstrated to have a long-lasting influence on affective behavior in adulthood. Notably, most studies to date have found these outcomes after chronic stress during adolescence. In the present study we tested how exposure to a single episode of acute footshock during early adolescence would modify subsequent adult anxiety- and depressive-like behaviors in male and female Sprague-Dawley rats.

Neuroendocrine and neuroimmune adaptation to Chronic Escalating Distress (CED): A novel model of chronic stress.

Acute and chronic stress challenges have a profound influence on the development and expression of subsequent affective disorders, alcohol use disorders, and natural aging processes. These experiments examined adaptation in neuroimmune and neuroendocrine responses that occurred as a result of exposure to a novel model of chronic stress, termed chronic escalating distress (CED). This model involves exposure to highly predictable daily stress challenges involving a systematic escalation in both the intensity and length of daily stress challenges, and has recently been shown to profoundly alter alcohol sensitivity.

Late aging alters behavioral sensitivity to ethanol in a sex-specific manner in Fischer 344 rats.

Responsiveness to ethanol (EtOH) differs as a function of age. Adolescent rodents are less sensitive than adults to the sedative effects of EtOH, whereas they show enhanced sensitivity to EtOH-induced social facilitation. Late aging is associated with a natural decline in social behavior and aging-related peculiarities in sensitivity to EtOH have been largely unexplored.

Assessment of social behavior directed toward sick partners and its relation to central cytokine expression in rats.

Acute illness not only reduces the expression of social behavior by sick rodents, but can also lead to avoidance responses when detected by healthy, would-be social partners. When healthy animals interact with a sick partner, an intriguing question arises: does exposure to a sick conspecific elicit an anticipatory immune response that would facilitate defense against future infection? To address this question, healthy adult male Sprague-Dawley rats (N=64) were given a brief social interaction (30min) with a partner that was either sick (250μg/kg injection with lipopolysaccharide [LPS] 3h prior to test) or healthy (sterile saline injection). During this exposure, social behavior directed toward the healthy or sick conspecific was measured.

A multispecies approach for understanding neuroimmune mechanisms of stress.

The relationship between stress challenges and adverse health outcomes, particularly for the development of affective disorders, is now well established. The highly conserved neuroimmune mechanisms through which responses to stressors are transcribed into effects on males and females have recently garnered much attention from researchers and clinicians alike. The use of animal models, from mice to guinea pigs to primates, has greatly increased our understanding of these mechanisms on the molecular, cellular, and behavioral levels, and research in humans has identified particular brain regions and connections of interest, as well as associations between stress-induced inflammation and psychiatric disorders.

Accelerated maternal responding following intra-VTA pertussis toxin treatment.

Prior studies have supported a role for mesolimbic dopaminergic mechanisms in the regulation of maternal behavior. Accordingly, the ventral tegmental area (VTA) and its dopaminergic projections to the nucleus accumbens (NAc) and medial prefrontal cortex (mPFC) have been implicated in both the onset and maintenance of normal maternal behavior. To date, studies of direct manipulation of VTA neurochemistry at the onset of maternal behavior have been limited.

Enhanced maternal aggression and associated changes in neuropeptide gene expression in multiparous rats.

Although it has often been speculated that prior reproductive experience improves subsequent maternal care, few studies have examined specific changes in behavior during a 1st versus 2nd lactation. During lactation, mothers display heightened aggression toward male intruders, purportedly to protect vulnerable young. In the current study, maternal aggression was examined in primiparous and age-matched multiparous females on postpartum days 5 (PPD5) and PPD15.

The progesterone receptor and parental behavior in juvenile rats.

Juvenile rats exhibit enhanced parental behavior responses to foster pups from 18 to 25 days of age, compared to virgin adults. Previous studies in adult rats and mice suggest that progesterone can inhibit the display of parental care towards offspring. The present study investigated the role of progesterone in juvenile rat parental behavior.