Stress history increases alcohol intake in relapse: relation to phosphodiesterase 10A

Abstract

Stressful experiences can result in elevated alcohol drinking, as exemplified in many individuals with post-traumatic stress disorder. However, how stress history, rather than acute stressors, influences alcohol intake remains uncertain. To model the protracted effects of past stress, male Wistar rats were subjected to light-cued footshock (stress history) or light cues alone (control) prior to acquisition of alcohol self-administration (1-hour sessions, fixed ratio 1-3, 100 µl of 10% v/v alcohol as reinforcer). Stress history did not alter mean alcohol intake during acquisition of self-administration, but it increased preference for the alcohol-paired lever over the inactive lever. Following an extinction period, rats with a history of stress exposure and low baseline alcohol intake showed a twofold elevation in alcohol self-administration, as compared with low-drinking rats with no stress history. Similar effects were not seen in rats self-administering 0.1% sucrose. Analysis of mRNA levels of phosphodiesterase 10A (PDE10A), a dual-specificity cyclic adenosine monophosphate and cyclic guanosine monophosphate hydrolyzing enzyme, showed that stress history increased Pde10a mRNA levels in the basolateral amygdala and, in low-drinking rats, the prelimbic prefrontal cortex (plPFC). Pde10a mRNA levels in the plPFC correlated directly with greater alcohol self-administration during the relapse-like phase, and greater BLA Pde10a mRNA levels correlated with increased ethanol preference after acquisition. The data demonstrate that stress history sensitizes otherwise low alcohol drinkers to consume more alcohol in a relapse-like situation and identify stress-induced neuroadaptations in amygdala and prefrontal cortical Pde10a expression as changes that may drive heightened alcohol intake and preference in susceptible individuals.

Figure 1

Rapid acquisition model allows for stress exposure prior to operant alcohol training. Rats received 48-h home cage access to 10% EtOH (v/v) and water. The following day, rats received 1-h 2-bottle access time-matched to future operant schedule. 1-h 2-bottle sessions continued for the next 5 days, excluding the day on which rats were trained for active/inactive lever discrimination in a single 12-h session with 0.1 ml water delivered for each active lever press. Once all rats had completed the water training session, they received 3 days of 30-min cued footshock or cue only exposure. After a day of rest, operant alcohol training commenced for 5 sessions at FR1, 8 sessions at FR3, 15 sessions of extinction and 9 sessions of renewed alcohol access (relapse-like reacquisition training) at FR3.

Figure 2

A history of stress increases relapse-like self-administration in previously Low Drinking rats. Rats were trained in 1-h operant self-administration sessions with 0.1 ml 10% alcohol (v/v) delivered after 1 (FR1) or 3 (FR3) depressions of the active lever, as indicated. Low (A, C, E) and High (B, D, F) Drinkers were subdivided by a median split of pre-extinction baseline (FR3) self-administration (0.5 g/kg intake). (A, B) Number of presses on the active lever and (C, D) body weight-normalized alcohol intake (g/kg) are shown across all sessions, spanning the acquisition (FR1 and FR3), extinction, and reacquisition (FR3 “RELAPSE”) phases of operant training. (E, F) Alcohol intake during relapse-like sessions controlled for baseline FR3 alcohol self-administration via ANCOVA analysis. Data are expressed as M (A–D) or LSMeans (E–F, covarying for baseline self-administration) ± SEM. *p<0.05, **p<0.01 vs. Control, n=10–14 per group.

Figure 3

Stress history does not significantly alter sucrose self-administration, regardless of pre-extinction baseline. Rats were trained in 1-h operant self-administration sessions with 0.1 ml of 0.1 % sucrose (w/v) delivered after 1 (FR1) or 3 (FR3) depressions of the active lever, as indicated. Low (A, C, E) and High (B, D, F) Drinkers were subdivided by a median split of pre-extinction baseline (FR3) self-administration (7 ml/kg intake). (A, B) Number of presses on the active lever and (C, D) body weight-normalized alcohol intake (ml/kg) are shown across all sessions, spanning the acquisition (FR1 and FR3), extinction, and reacquisition (FR3 “RELAPSE”) phases of operant training. (E, F) Sucrose intake during relapse-like sessions controlled for FR3 baseline self-administration via ANCOVA analysis. Data are expressed as M (A–D) or LSMeans (E–F, covarying for baseline self-administration) ± SEM. n=10–14 per group.

Figure 4

A history of stress exposure reduces inactive lever pressing during the acquisition phase of operant alcohol self-administration. Average inactive lever presses by training phase for alcohol (A,B) and sucrose (C, D) self-administration, separated by low (A, C) and high (B, D) baseline levels of self-administration. Data are expressed as 5-day M ± SEM. **p<0.01 vs. Control, n=10–14 per group.

Figure 5

Differential modulation of Pde10a expression by stress and alcohol drinking history in the basolateral (BLA) and central (CeA) nuclei of the amygdala. At the conclusion of relapse-like alcohol self-administration, Stress History rats showed increased Pde10a in the BLA (A) but not CeA (B) or MeA (C). Drinking status was also related to differences in Pde10a expression, with significant direct correlations between BLA Pde10a and baseline alcohol lever preference in High Drinkers (E), but not Low Drinkers (D). CeA Pde10a showed a trend towards positive correlation with baseline FR3 alcohol intake in Low Drinkers (F) but not High Drinkers (G). Data are expressed as LSMeans ± SEM for Pde10a, controlled for Cyp covariate effects following z-score transformation of gene expression data (A–C) or as partial regression plots of the normalized active lever preference (D, E) or operant alcohol intake (F, G) during the pre-extinction FR3 baseline period versus amygdala Pde10a expression, controlling for Cyp levels (D–G). n = 23–24 per group (A–C), or 20–24 (D–F). *p < 0.05, #p<0.07 (vs. Control where applicable).

Figure 6

Pde10a in the medial prefrontal cortex correlates with relapse-like alcohol intake. plPFC Pde10a expression shows a strong positive correlation with relapse-like alcohol intake in Low Drinkers (A) but not High Drinkers (B). Conversely, ilPFC Pde10a showed a significant positive relationship to relapse-like alcohol intake for High Drinkers (D) but not Low Drinkers (C). Data are presented as partial regression plots of the normalized 9-day mean relapse-like operant alcohol intake versus mPFC Pde10a expression, controlling for Cyp levels. n = 18–23. *p<0.05, **p<0.01.