Biology subjects

Van Voorhies, K.

Publications and source records attributed to Van Voorhies, K..

7 recordsLinked to original sources

bioRxiv2022

Predator odor (TMT) exposure potentiates interoceptive sensitivity to alcohol and increases GABAergic gene expression in the anterior insular cortex and nucleus accumbens in male rats

Post-traumatic stress disorder (PTSD) confers enhanced vulnerability to develop comorbid alcohol use disorder (AUD). Exposure to the scent of a predator, such as the fox odor TMT, has been used to model a traumatic stressor with relevance to PTSD symptomatology. Alcohol produces distinct interoceptive (subjective) effects that may influence vulnerability to problem drinking and AUD. As such, understanding the lasting impact of stressor on sensitivity to the interoceptive effects of alcohol is clinically relevant. The present study used a 2-lever, operant drug discrimination procedure to train male, Long-Evans rats to discriminate the interoceptive effects of alcohol (2 g/kg, i.g.) from water. Upon stable performance, rats underwent a 15-min exposure to TMT. Two weeks later, an alcohol dose-response curve was conducted to evaluate the lasting effects of the TMT stressor on the interoceptive effects of alcohol. The TMT group showed a leftward shift in ED50 of the dose response curve compared to controls, reflecting potentiated interoceptive sensitivity to alcohol. TMT exposure did not affect response rate. GABAergic signaling in both the anterior insular cortex (aIC) and the nucleus accumbens (Acb) is involved in the interoceptive effects of alcohol and stressor-induced adaptations. As such, follow-up experiments in alcohol-naive rats examined neuronal activation (as measured by c-Fos immunoreactivity) following TMT and showed that TMT exposure increased c-Fos expression in the aIC and the nucleus accumbens core (AcbC). 2 weeks after TMT exposure, Gad-1 gene expression was elevated in the aIC and Gat-1 was increased in the Acb compared to controls. Lastly, the alcohol discrimination and alcohol-naive groups displayed dramatic differences in stress reactive behaviors during the TMT exposure, suggesting that alcohol exposure may alter the behavioral response to predator odor. Together, these data suggest that predator odor stressor results in potentiated sensitivity to alcohol possibly through GABAergic adaptations in the aIC and Acb, which may be relevant to understanding PTSD-AUD comorbidity.

neuroscience↗

bioRxiv2021

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 systems involvement in the development and maintenance of alcohol use disorder. In the present study we administered TLR3 agonist poly(I:C) in male and female Long-Evans rats to determine whether TLR3 agonism can increase alcohol consumption in a daily 15% alcohol operant self-administration paradigm. We found few effects when poly(I:C) was given every-other-day at 0.3 or 1.0 mg/kg, however when instead 1.0 mg/kg was given on consecutive days alcohol intake increased in the days following injections specifically in females. Furthermore, in a second experiment we found that this effect only emerged when rats had a history of multiple poly(I:C) injections. In the final experiment the dose was increased to 3.0 mg/kg on consecutive days which resulted in significant reductions on injection days in females that were not accompanied by subsequent increases. The dose was increased to 9 mg/kg for one final pair of injections which led to reductions in intake in both males and females but only increased subsequent alcohol consumption in males. Overall, poly(I:C) was able to increase subsequent alcohol consumption in both sexes, with females being sensitive to lower doses than males both in terms of changes in alcohol consumption and general locomotor reduction. These findings show that TLR3 agonism may be involved in driving increased alcohol consumption and add to the body of work identifying the neuroimmune system as a potential therapeutic target for AUD.

neuroscience↗

bioRxiv2021

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

BackgroundThere is growing evidence that immune signaling 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. MethodsWe 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. ResultsInterferon regulatory factor 7 (IRF7) was dramatically increased in both sexes at both 2 and 24 h post-injection regardless of alcohol history, while TLR3 and 7 gene expression changes were region- and sex-specific. The pro-inflammatory cytokine TNF was increased 24h post-injection in rats with an alcohol self-administration history but this effect did not persist after four injections, suggesting molecular tolerance. In both males and females, ethanol consumption was increased 24 h after imiquimod injections with sex-specific differences: in females this effect emerged following the first injection but in males this increase did not occur until the third injection, suggesting sex differences in adaptation to repeated TLR7 activation. Notably, imiquimod reliably induced weight loss, indicating that sickness behavior persisted across repeated injections. ConclusionThese findings show that TLR7 activation can modulate alcohol drinking in an operant self-administration paradigm, and suggest that TLR7 and IRF7 signaling pathways may be a viable druggable target for treatment of AUD.

neuroscience↗

bioRxiv2021

RTICBM-74 is a Brain-Penetrant CB1 Receptor 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 (CB1) representing a promising target for AUD therapeutic interventions. We have previously shown negative allosteric modulators (NAMs) of the CB1 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 CB1 NAM, RTICBM-74, and its effects on alcohol self-administration in rats. RTICBM-74 showed low aqueous solubility and high protein binding but had excellent half-life and low clearance against rat liver microsomes and hepatocytes, and excellent brain penetrance in rats. RTICBM-74 pretreatment specifically reduced alcohol intake across a range of doses in male or female Wistar or Long-Evans rats that were trained to self-administer alcohol. These effects were similar to the CB1 antagonist/inverse agonist rimonabant which was tested as a positive control. Importantly, RTICBM-74 was effective at reducing alcohol intake at doses that did not affect locomotion or sucrose self-administration. Our findings suggest that CB1 NAMs such as RTICBM-74 have promising therapeutic potential in treatment of AUD. SIGNIFICANCE STATEMENTThe present work shows that a metabolically stable and brain penetrant CB1 receptor negative allosteric modulator (NAM) reduces alcohol self-administration in rats without affecting locomotion or sucrose self-administration, suggesting potential therapeutic relevance for the treatment of AUD.

neuroscience↗

bioRxiv2021

The Role of the Nucleus Reuniens in Regulating Contextual Conditioning with the Predator Odor TMT

RationaleExperiencing intrusive distressing memories of a traumatic event(s) is a prominent symptom profile for post-traumatic stress disorder (PTSD). Understanding the neurobiological mechanisms associated with this symptom profile can be invaluable for effective treatment for PTSD. ObjectivesHere, we investigated the functional role of the nucleus reuniens (RE), a midline thalamic in modulating stressor-related memory. MethodsFemale Long Evans rats were implanted with a cannula aimed at the RE. The RE was pharmacologically inactivated via muscimol (0.5 mM) prior to exposure to the predator odor stressor trimethylthiazoline (TMT; synthetically derived fox feces component) or water (controls) in a distinct context with bedding material (Experiment 1) or no bedding (Experiment 2). To measure context reactivity, the index of the contextual memory, 2 weeks following exposure to TMT, rats were re-exposed to the TMT-paired context (in the absence of TMT). ResultsIn Experiment 1, during context re-exposure (with bedding), inactivation of the RE had no effect on context reactivity. In Experiment 2, during context re-exposure (no bedding), rats previous exposed to TMT showed decreased immobility compared to controls, indicating reactivity to the context and likely related to increased exploration of the environment. Rats in the TMT group that received RE inactivation showed increased immobility relative to rats that received aCSF, suggesting that muscimol pre-treatment blunted context reactivity. ConclusionIn conclusion, recruitment of the RE in stressor-related contextual memory appears to be dependent on the contextual environment and whether the animal is able to engage in different stress coping strategies.

neuroscience↗

bioRxiv2020

Central amygdala mineralocorticoid receptors modulate alcohol self-administration.

The mineralocorticoid receptor (MR) is an emerging target in the field of alcohol research. The MR is a steroid receptor in the same family as the glucocorticoid receptor, with which it shares the ligand corticosterone in addition to the MR selective ligand aldosterone. Recent studies have shown correlations between central amygdala (CeA) MR expression and alcohol drinking in rats and macaques, as well as correlations between aldosterone and alcohol craving in individuals with alcohol use disorder (AUD). Additionally, our previous work demonstrated that systemic treatment with the MR antagonist spironolactone reduced alcohol self-administration and response persistence in both male and female rats. This study examined if reductions in self-administration following MR antagonist treatment were related to dysregulation of MR-mediated corticosterone negative feedback. Female rats treated with spironolactone (50 mg/kg; IP) showed increased plasma corticosterone following self-administration which correlated with reduced alcohol self-administration. Next, local microinjection of the MR-selective antagonist eplerenone was used to identify the brain-regional locus of MR action on alcohol self-administration. Eplerenone infusion produced dose-dependent reductions in alcohol self-administration in the CeA, but had no effect in the dorsal hippocampus. Finally, to assay the functional role of CeA MR expression in alcohol self-administration, CeA MR was knocked down by antisense oligonucleotide (ASO) infusion prior to alcohol self-administration. Rats showed a transient reduction in alcohol self-administration 1 day after ASO infusion. Together these studies demonstrate a functional role of CeA MR in modulating alcohol self-administration and make a case for studying MR antagonists as a novel treatment for AUD.

neuroscience↗

bioRxiv2020

The synthetically produced predator odor 2,5-dihydro-2,4,5-trimethylthiazoline increases alcohol self-administration and alters basolateral amygdala response to alcohol in rats.

Post-traumatic stress disorder (PTSD) is a psychiatric illness that can increase the risk for developing an alcohol use disorder (AUD). While clinical data has been useful in identifying similarities in the neurobiological bases of these disorders, preclinical models are essential for understanding the mechanism(s) by which PTSD increases the risk of developing AUD. The purpose of these studies was to examine if exposure of male Long-Evans rats to the synthetically produced predator odor 2,5-dihydro-2,4,5-trimethylthiazoline (TMT) would increase alcohol self-administration, potentially by facilitating transfer of salience towards cues, and alter neuronal response to alcohol as measured by the immediate early gene c-Fos. In Experiment 1 rats exposed to repeated (4x) TMT showed reductions in goal-tracking behavior in Pavlovian conditioned approach, and increases in alcohol self-administration. In Experiment 2 rats exposed to repeated TMT showed blunted basolateral amygdala c-Fos response to alcohol, and increased correlation between medial prefrontal cortex and amygdala subregions. In Experiment 3 rats exposed to single, but not repeated TMT showed increases in alcohol self-administration, and no change in anxiety-like behavior or hyperarousal. In Experiment 4, rats showed no habituation of corticosterone response after 4 TMT exposures. In summary, exposure of male rats to TMT can cause escalations in alcohol self-administration, reductions in goal-tracking behavior, and reduction in BLA response to alcohol. These studies outline and utilize a novel preclinical model that can be used to further neurobiological understanding of the relationship between PTSD and AUD.

neuroscience↗