Differential effects of acute and prolonged morphine withdrawal on motivational and goal-directed control over reward-seeking behaviour

Abstract

Opioid addiction is a relapsing disorder marked by uncontrolled drug use and reduced interest in normally rewarding activities. The current study investigated the impact of spontaneous withdrawal from chronic morphine exposure on emotional, motivational and cognitive processes involved in regulating the pursuit and consumption of food rewards in male rats. In Experiment 1, rats experiencing acute morphine withdrawal lost weight and displayed somatic signs of drug dependence. However, hedonically driven sucrose consumption was significantly elevated, suggesting intact and potentially heightened reward processing. In Experiment 2, rats undergoing acute morphine withdrawal displayed reduced motivation when performing an effortful response for palatable food reward. Subsequent reward devaluation testing revealed that acute withdrawal disrupted their ability to exert flexible goal-directed control over reward seeking. Specifically, morphine-withdrawn rats were impaired in using current reward value to select actions both when relying on prior action-outcome learning and when given direct feedback about the consequences of their actions. In Experiment 3, rats tested after prolonged morphine withdrawal displayed heightened rather than diminished motivation for food rewards and retained their ability to engage in flexible goal-directed action selection. However, brief re-exposure to morphine was sufficient to impair motivation and disrupt goal-directed action selection, though in this case, rats were only impaired in using reward value to select actions in the presence of morphine-paired context cues and in the absence of response-contingent feedback. We suggest that these opioid-withdrawal induced deficits in motivation and goal-directed control may contribute to addiction by interfering with the pursuit of adaptive alternatives to drug use.

Keywords: goal‐directed; habit; incentive; opiate; reward; sensitization; withdrawal.

FIGURE 1

Effects of morphine exposure on somatic withdrawal signs and hedonic feeding in rats (Experiment 1). (A) Schematic representation of behavioural testing during withdrawal from morphine (n = 5) or saline (n = 8) exposure in rats. Rats were tested for somatic signs and sucrose intake during withdrawal days (WDs) 1 and 2. (B) Schematic diagram illustrating context conditioning in rats from the morphine or saline groups. (C) Initial sucrose intake increases across a range of concentrations (conc.; ^##main effect of concentration, p < 0.001) during pretesting (i.e., before morphine exposure) but does not differ with planned exposure groups. (D) Locomotor activity is differently altered by morphine and saline treatments exposures in paired or unpaired contexts. It is initially reduced by morphine exposure (paired context; day X group **p = 0.002). However, activity in the unpaired context is similar following morphine and saline exposure. (E) Morphine exposure induces significant weight loss that persists during withdrawal (group X day ***p < 0.001). Horizontal green mark shows morphine exposure days. (F) Discontinuation of morphine exposure elicits further weight loss, which is apparent on WD2 (% of last exposure day for WD1 and WD2; group X day **p = .002). (G) Graded and checked withdrawal signs and their corresponding weighing factors for withdrawal scoring. (H) Morphine exposure induces significant somatic withdrawal signs on WDs 1 and 2 (group ***p < 0.001). (I) Sucrose intake is significantly elevated in WD1 (**p = 0.007). On WD2, there is no effect of drug exposure or test context

FIGURE 2

Early morphine withdrawal impairs motivation and goal‐directed control over instrumental behaviour in rats (Experiment 2). (A) Schematic representation of behavioural testing during early morphine withdrawal (n = 9) or following saline exposure (n = 10). Rats were assessed for motivation vigour during instrumental retraining on withdrawal day (WD) 1. On WD2, rats were given a reward devaluation test in either paired or unpaired contexts to assess their capacity for goal‐directed control. (B) Schematic representation of instrumental training contingencies. (C) Baseline press rates during initial instrumental training did not differ between groups or planned devaluation treatment. (D) As in Experiment 1, locomotor activity is differently altered during morphine and saline exposures in paired or unpaired contexts. For paired context sessions, morphine‐exposed rats displayed a suppression of activity that was less apparent over days (day X group **p = 0.001). The groups did not differ and showed similar rates of habituation of locomotor activity during unpaired context sessions. (E) Instrumental performance is reduced in morphine‐exposed rats during instrumental retraining on WD1. Left, press rates are separated by group and by planned devaluation conditions, showing an overall decrease in press rate (group **p = 0.006) but not as a function of planned devaluation treatment. Right, press rates were averaged across actions and plotted as a proportion of baseline performance (**p = 0.004). (F) Schematic of the outcome‐specific reward devaluation test. (G) Food intake during the prefeeding period (specific‐satiety induction) was slightly reduced in morphine exposed rats (p = 0.067). (H) Morphine‐exposed rats show impaired sensitivity to reward devaluation in the extinction (left; group X devaluation *p = 0.046) and reinforced (right; group X devaluation *p = 0.033) phases of the test. During the reinforced phase, press rates were significantly lower in the morphine group (*p = 0.025). Press rates during the test session are separated by devaluation (dev or non), group (morphine or saline), test phase (extinction and reinforced) and context (paired or unpaired). See the main text for detailed statistical analysis. Dev, devalued; Non, nondevalued; R, retraining; SCM, sweetened condensed milk; T, test. *p < 0.05; **p < 0.01

FIGURE 3

Prolonged morphine withdrawal spares motivation and goal‐directed control in rats (Experiment 3). (A) Schematic of behavioural testing during prolonged morphine withdrawal (n = 13) or following saline exposure (n = 13). Rats were assessed for motivation vigour during instrumental retraining on withdrawal days (WDs) 19–23. On WDs 22 and 24, rats were given a reward devaluation test in either paired or unpaired contexts to assess their capacity for goal‐directed control. Rats were retested during early withdrawal following morphine re‐exposure (see Figure 4). (B) Baseline press rates during initial instrumental training did not differ between groups. (C) Locomotor activity during morphine and saline exposures in paired or unpaired contexts. Morphine exposure influences locomotor activity, which varies across exposure days. For paired context sessions, morphine injections initially suppress locomotor activity (day X group ***p < 0.001). Saline and morphine groups show a similar decline in activity over days in the unpaired context. (D) Instrumental performance during instrumental retraining on WDs 19–21 and 23. Left, press rates in rats separated by group and by planned devaluation conditions do not differ. Right, press rates averaged across actions and plotted as a proportion of baseline performance show a slight elevation in responding in the morphine group (p = 0.077). (E) Food intake during the prefeeding period (specific‐satiety induction) does not differ between groups. (F) Morphine‐exposed rats show intact sensitivity to reward devaluation and elevated press rates during the reinforced phase of the test (*p = 0.041). See THE main text for detailed statistical analysis. Press rates during the test session are separated by devaluation (dev or non), group (morphine or saline), test phase (extinction and reinforced) and context (paired or unpaired). Dev, devalued; non, nondevalued; R, retraining; T, test

FIGURE 4

Early withdrawal following morphine re‐exposure impairs motivation and goal‐directed control in rats (Experiment 3). (A) Schematic of behavioural testing following morphine (n = 11) or saline re‐exposure (n = 13). (B) Locomotor activity during morphine and saline re‐exposure. Saline or morphine exposures were given in the original paired or unpaired contexts. Morphine increased locomotor activity in an experience‐dependent manner, which was more apparent in paired (day X group ***p = 0.003) than in unpaired sessions (day X group *p = 0.048). (C) Instrumental performance was depressed in morphine‐exposed rats during instrumental retraining on WD1 following morphine re‐exposure. Left, press rates in rats are separated by group and by planned devaluation conditions. General suppression of lever press rate (group effect *p = 0.032) is not dependent on planned devaluation conditions. Right, press rates were averaged across actions and plotted as a proportion of baseline performance showing a marginal suppression after morphine reexposure (p = 0.06). (D) Food intake during the prefeeding period (specific‐satiety induction) is reduced in the morphine group (*p = 0.016). (E) Morphine‐exposed rats show a deficit in sensitivity to reward devaluation that was specific to the extinction phase of the test that was conducted in the paired context (devaluation X group *p = 0.032 and devaluation X group X context p = 0.059). See the main text for detailed statistical analysis. Press rates during the test session are separated by devaluation (dev or non), group (morphine or saline), test phase (extinction and reinforced) and context (paired or unpaired). Dev, devalued; non, nondevalued; R, retraining; T, test. *p < 0.05

FIGURE 5

Individual differences in reward devaluation sensitivity do not vary with response rate or prefeeding levels. Data are combined from early withdrawal tests in Experiments 2 and 3 (see text for details). (A) Devaluation sensitivity is significantly impaired in the morphine group (***p < 0.001). (B) Overall press rates during the extinction phase of the devaluation test do not significantly differ between morphine and saline groups. (C) Food intake during the prefeeding (specific satiety) period is significantly lower in the morphine group (**p < 0.01). (D) Devaluation sensitivity does not correlate with response rate at test. (E) Devaluation sensitivity does not correlate with pre‐test food intake. Dev, devalued; non, nondevalued