Biology subjects

Tyler, R. E.

Publications and source records attributed to Tyler, R. E..

7 recordsLinked to original sources

bioRxiv2024

The persistent effects of predator odor stressor enhance interoceptive sensitivity to alcohol through GABA-A receptor adaptations in the prelimbic cortex in male, but not female rats

BackgroundTraumatic stress is associated with high rates of problematic alcohol use, but how the persistent effects of trauma impact sensitivity to alcohol remain unknown. This study examined the persistent effects of traumatic stress exposure on sensitivity to alcohol and underlying neurobiological mechanisms in rats. MethodsMale (N=98) and female (N=98) Long-Evans rats were exposed to the predator odor TMT, and two weeks later, molecular, neuronal, and behavioral sensitivity to alcohol were assessed. Next, rats were trained to discriminate alcohol from water (male N=70; female N=56), and the impact of TMT on interoceptive sensitivity to alcohol and the alcohol-like effects of systemic GABAA receptor activation were evaluated. Lastly, functional involvement of GABAA and NMDA receptors in the prelimbic cortex (PrL) and the anterior insular cortex (aIC) was investigated. ResultsTMT exposure sex-dependently altered PrL Gabra1, and elevated aIC Grin2b and Grin2c in males. TMT increased PrL c-Fos in males, which was attenuated by alcohol administration. Alcohol-induced locomotor and startle response effects were attenuated in the TMT group in both sexes. TMT exposure potentiated interoceptive sensitivity to alcohol in males but not in females, and this effect was driven by GABAA receptors in the PrL. Greater stress reactivity during TMT exposure was associated with higher interoceptive sensitivity to alcohol, and alcohol exposure history was linked to a heightened stress response to TMT in males. ConclusionsTraumatic stress increased interoceptive sensitivity to alcohol in males, but not females, through PrL GABAA receptor adaptations, potentially enhancing the stimulatory, and by extension the rewarding, effects of alcohol.

neuroscience↗

bioRxiv2024

β-arrestin-biased Allosteric Modulator of Neurotensin Receptor 1 Reduces Ethanol Drinking and Responses to Ethanol Administration in Rodents

Alcohol use disorders (AUDs) impose an enormous societal and financial burden, and world-wide, alcohol misuse is the 7th leading cause of premature death1. Despite this, there are currently only 3 FDA approved pharmacological treatments for the treatment of AUDs in the United States. The neurotensin (Nts) system has long been implicated in modulating behaviors associated with alcohol misuse. Recently, a novel compound, SBI-553, that biases the action of Nts receptor 1 (NTSR1) activation, has shown promise in preclinical models of psychostimulant misuse. Here we investigate the efficacy of this compound to alter ethanol-mediated behaviors in a comprehensive battery of experiments assessing ethanol consumption, behavioral responses to ethanol, sensitivity to ethanol, and ethanol metabolism. Additionally, we investigated behavior in avoidance and cognitive assays to monitor potential side effects of SBI-553. We find that SBI-553 reduces binge-like ethanol consumption in mice without altering avoidance behavior or novel object recognition. We also observe sex-dependent differences in physiological responses to sequential ethanol injections in mice. In rats, we show that SBI-553 attenuates sensitivity to the interoceptive effects of ethanol (using a Pavlovian drug discrimination task). Our data suggest that targeting NTSR1 signaling may be promising to attenuate alcohol misuse, and adds to a body of literature that suggests NTSR1 may be a common downstream target involved in the psychoactive effects of multiple reinforcing substances.

neuroscience↗

bioRxiv2022

mGlu2 and mGlu3 receptor negative allosteric modulators affect the discriminative stimulus effects of alcohol

RationaleThe subjective effects of alcohol are associated with alcohol use disorder (AUD) vulnerability and treatment outcomes. The interoceptive effects of alcohol are part of these subjective effects and can be measured in animal models using drug discrimination procedures. The newly developed mGlu2 and mGlu3 negative allosteric modulators (NAMs) are potential therapeutics for AUD and may alter interoceptive sensitivity to alcohol. ObjectivesTo determine the effects of mGlu2 and mGlu3 NAMs on the interoceptive effects of alcohol in rats. MethodsLong-Evans rats were trained to discriminate the interoceptive stimulus effects of alcohol (2.0 g/kg, i.g.) from water using both operant (males only) and Pavlovian (male and female) drug discrimination techniques. Following acquisition training, an alcohol dose-response (0, 0.5, 1.0, 2.0 g/kg) experiment was conducted to confirm stimulus control over behavior. Next, to test the involvement of mGlu2 and mGlu3, rats were pretreated with the mGlu2-NAM (VU6001966; 0, 3, 6, 12 mg/kg, i.p.) or the mGlu3-NAM (VU6010572; 0, 3, 6, 12 mg/kg, i.p.) before alcohol administration (2.0 g/kg, i.g.). ResultsIn Pavlovian discrimination, male rats showed greater interoceptive sensitivity to 1.0 and 2.0 g/kg alcohol compared to female rats. Both mGlu2-NAM and mGlu3-NAM attenuated the interoceptive effects of alcohol in male and female rats using Pavlovian and operant discrimination. There may be a potential sex difference in response to the mGlu2-NAM at the highest dose tested. ConclusionsMale rats may be more sensitive to the interoceptive effects of 2.0 g/kg alcohol training dose compared to female rats. Both mGlu2 and mGlu3 NAM attenuate the interoceptive effects of alcohol in male and female rats. Sex differences in mGlu2-NAM sensitivity were observed. These drugs may have potential for treatment of AUD in part by blunting the subjective effects of alcohol.

neuroscience↗

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

The effects of predator odor (TMT) exposure and mGlu3 NAM pretreatment on lasting behavioral and molecular adaptations in the insular cortex and BNST

A stressor can trigger adaptations that contribute to neuropsychiatric disorders. Predator odor (TMT) exposure is an innate stressor that produces lasting adaptations. TMT exposure may activate metabotropic glutamate receptor 3 (mGlu3), triggering excitatory corticolimbic adaptations that underlie behavioral changes. To evaluate functional involvement, the mGlu3 negative allosteric modulator (NAM, VU6010572; 3 mg/kg, i.p.) was administered before TMT exposure in male, Long Evans rats. Two weeks after stressor, rats underwent behavioral testing (context re-exposure, zero maze and acoustic startle response) followed by RT-PCR gene expression in the insular cortex and BNST. During the TMT exposure, rats displayed stress-reactive behaviors that were not affected by the VU6010572. During the context re-exposure, prior TMT exposure and VU6010572 pretreatment both produced a hyperactive response. TMT exposure did not affect zero maze or ASR measures, but VU6010572 increased time spent in the open arms and habituation to ASR, indicating anxiolytic-like effects. In the insular cortex, TMT exposure resulted in excitatory adaptations as shown by increased expression of mGlu (Grm3, Grm5), NMDA (GriN2A, GriN2B, GriN2C, GriN3A, GriN3B) and AMPA (GriA3) receptor transcripts. Interestingly, mGlu3 signaling during stressor mediated GriN3B upregulation. Stress reactivity during TMT exposure was associated with Grm5, GriN2A, GriN2C, and GriA3 upregulation in the insular cortex and context re-exposure reactivity in the TMT/vehicle, but not the TMT/mGlu3 NAM group. In the BNST, GriN2A, GriN2B and GriN3B were increased by VU6010572, but TMT prevented these effects. These data demonstrate that mGlu3 signaling contributes to the lasting behavioral and molecular adaptations of predator odor stressor.

neuroscience↗

bioRxiv2020

Increased alcohol self-administration following exposure to the predator odor TMT in high stress-reactive female rats

Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are highly comorbid. Additionally, individual differences in response to stress suggest resilient and susceptible populations. The current study exposed male and female Long Evans rats to the synthetically produced predator odor 2,5-dihydro-2,4,5-trimethylthiazoline (TMT) to examine individual differences in stress-reactive behaviors (digging and immobility) and whether these differences could predict lasting consequences of TMT and increases in alcohol drinking. Male and female Long Evans rats were trained on operant alcohol self-administration. After 9 sessions, rats underwent exposure to TMT or water (Control) in a distinct context. 6 days after TMT exposure, rats underwent re-exposure to the TMT-paired context (without TMT), and a series of behavioral assessments (acoustic startle, zero maze, light/dark box), after which rats resumed alcohol self-administration. Rats were divided into two TMT-subgroups using a ratio of digging and immobility behavior during TMT exposure: TMT-subgroup 1 (low digging/immobility ratio) and TMT-subgroup 2 (high digging/immobility ratio). Digging/immobility ratio scores predicted elevated corticosterone levels during TMT exposure and reactivity during context re-exposure in males and females (TMT-subgroup 2), as well as elevated corticosterone levels after context re-exposure and hyperarousal behavior in females (TMT-subgroup 1). Furthermore, TMT stress reactivity predicted increases in alcohol self-administration, specifically in females. These data show that stress-reactivity can predict lasting behavioral changes which may lead to a better understanding of increases in alcohol drinking following stress in females and that individual differences in stress-reactive behaviors using TMT may be helpful to understand resilience/susceptibility to the lasting consequences of stress. HighlightsO_LIExposure to the predator odor TMT produces distinct behavioral phenotypes in male and female rats C_LIO_LIMale and female high stress reactive rats show enhanced reactivity to the TMT-paired context C_LIO_LIStress-reactivity during TMT predicts increases in alcohol self-administration, in females C_LIO_LIStress-reactivity may help to understand resilience/susceptibility and impact on alcohol drinking C_LI

animal behavior and cognition↗

bioRxiv2020

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) and late (4 weeks) changes to gene expression (RT-PCR) related to stress and excitatory function following TMT exposure in male, Long-Evans rats. During TMT exposure, rats engaged in stress reactive behaviors, including digging and immobility. Further, the TMT group displayed enhanced exploration and mobility in the TMT-paired context one week after exposure, suggesting a lasting contextual reactivity. Gene expression analyses revealed upregulated FKBP5 6 hours post-TMT in the hypothalamus and dorsal hippocampus. Two days after TMT, GRM3 was downregulated in the prelimbic cortex and dorsal hippocampus, but upregulated in the nucleus accumbens. This may reflect an early stress response (FKBP5) that resulted in later glutamatergic adaptation (GRM3). Finally, four weeks after TMT exposure, several differentially expressed genes known to mediate excitatory tripartite synaptic function were observed. Specifically in the prelimbic cortex (GRM5, DLG4 and SLC1A3 upregulated), infralimbic cortex (GRM2 downregulated, Homer1 upregulated), nucleus accumbens (GRM7 and SLC1A3 downregulated), dorsal hippocampus (FKBP5 and NR3C2 upregulated, SHANK3 downregulated) and ventral hippocampus (CNR1, GRM7, GRM5, SHANK3, and Homer1 downregulated). These data demonstrate that TMT exposure stress induces early and late stress and excitatory molecular adaptations, which may help us understand the persistent glutamatergic dysfunction observed in PTSD.

neuroscience↗