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

Abstract

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.

The effects of predator odor (TMT) exposure and mGlu3NAM pretreatment on lasting behavioral and molecular adaptations in the insular cortex and BNST

“…Consistent with previous findings, the TMT exposure produced engagement in stress-reactive behaviors (immobility, digging, avoidance, and decreased grooming, distance traveled and midline crossings), indicating that TMT exposure is an acute stressor [56, 58]. Pretreatment with the mGlu 3 NAM (VU6010572) did not affect any of these behaviors, suggesting that mGlu 3 -signaling during the stressor does not contribute to the engagement of acute stress-reactive behaviors.…”

“…Understanding individual differences in response to stressor may prove valuable in understanding vulnerability to stress-related disorders [61] and behavioral outcomes in rodents [42, 56]. Therefore, correlational analyses were conducted between stress-reactive behaviors during the TMT exposure (Fig.…”

“…Immobility was operationally defined as the absence of movement other than respiration for longer than 2 seconds, and also captures freezing behavior during the TMT exposure [58]. Time spent digging in the bedding (see [56, 58]) and time spent grooming were quantified manually by an experimenter blind to experimental conditions. For the context re-exposure, two rats were removed from analysis due to a camera recording error.…”

“…and returned to the home cage for 45 mins prior to TMT-exposure testing. TMT exposure test chambers and experimental set-up were identical to those used in [56, 58]. Rats were transported from the vivarium in the home cage to a separate, well□ventilated room that contained the test chambers in which rats were exposed to TMT (45.72□×□17.78□×□21.59□cm; UNC Instrument Shop, Chapel Hill, NC).…”

“…Animal models have used exposure to the scent of a predator as a stressor that produces lasting behavioral consequences with relevance to stress-related neuropsychiatric disorders [42-55]. For example, exposure to the synthetically derived fox odor 2,5□dihydro□2,4,5□trimethylthiazoline (TMT) produces avoidance and freezing behaviors, indicative of a fear□like response and increased serum corticosterone, reflecting a stress response [47, 50, 56, 57]. Other studies have showed lasting anxiety□like and hyperarousal behavior, as well as avoidance of a TMT□paired context or cue [43, 51].…”