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

Abstract

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-2,4,5trimethylthiazoline (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.

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

“…We initially hypothesized that TMT exposure would blunt interoceptive sensitivity to alcohol [43]. This hypothesis was supported by previous experiments showing blunted interoceptive sensitivity to alcohol following 7-day exposure to corticosterone in the rats’ drinking water [47–49].…”

“…The analyses were conducted with Image-Pro Premier image analysis software (Media Cybernetics, Rockville, MD). Bilateral immunoreactivity data (c-Fos-positive cells/mm 2 ; [43, 54]) were taken from a minimum of 2 sections/brain region/animal (e.g., 4 data points per animal), conducted by an experimenter blind to animal groups. These data were then averaged to obtain one value for each subject as in [43, 48, 54].…”

“…Bilateral immunoreactivity data (c-Fos-positive cells/mm 2 ; [43, 54]) were taken from a minimum of 2 sections/brain region/animal (e.g., 4 data points per animal), conducted by an experimenter blind to animal groups. These data were then averaged to obtain one value for each subject as in [43, 48, 54]. The regions examined were the anterior insular cortex (aIC, bregma +0.84 to +2.28) and the nucleus accumbens core (AcbC, bregma +1.62 to +2.52).…”

“…The predator odor 2,5-dihydro-2,4,5-trimethylthiazoline (TMT) is a synthetic component of fox feces that has been shown to produce freezing, avoidance and defensive digging behaviors as well as molecular and physiological adaptations in the brain [34,35,[39][40][41][42]. Additionally, several studies have reported increased alcohol drinking following predator odor exposure [40,[43][44][45][46], which may be influenced by a change to the interoceptive effects of alcohol. Indeed, prior work has shown that 7-day exposure to the stress-related hormone corticosterone blunts sensitivity to the interoceptive effects of alcohol [47][48][49].…”

Artificial Intelligence Identified Resilient and Vulnerable Female Rats After Traumatic Stress and Ethanol Exposure: Investigation of Neuropeptide Y Pathway Regulation

“…The present study revealed that the phenotype after SPS that was most predictive of high ethanol drinking in females was anxiety scores on the elevated plus maze and open field test. Some studies, although not all, indicate that anxiety is predictive of ethanol consumption also in male rodents ( Izídio and Ramos, 2007 ; Bahi, 2013 ; Barchiesi et al, 2021 ; Makhijani et al, 2021 ). Other work has shown that female rats are more likely to drink during social isolation which is anxiogenic and males are more likely to drink in groups, demonstrating anxiety is a more important driver for female ethanol consumption than for males ( Varlinskaya et al, 2015 ).…”