Compound stimulus presentation and the norepinephrine reuptake inhibitor atomoxetine enhance long-term extinction of cocaine-seeking behavior

Abstract

Drug abstinence is frequently compromised when addicted individuals are re-exposed to environmental stimuli previously associated with drug use. Research with human addicts and in animal models has demonstrated that extinction learning (non-reinforced cue-exposure) can reduce the capacity of such stimuli to induce relapse, yet extinction therapies have limited long-term success under real-world conditions (Bouton, 2002; O'Brien, 2008). We hypothesized that enhancing extinction would reduce the later ability of drug-predictive cues to precipitate drug-seeking behavior. We, therefore, tested whether compound stimulus presentation and pharmacological treatments that augment noradrenergic activity (atomoxetine; norepinephrine reuptake inhibitor) during extinction training would facilitate the extinction of drug-seeking behaviors, thus reducing relapse. Rats were trained that the presentation of a discrete cue signaled that a lever press response would result in cocaine reinforcement. Rats were subsequently extinguished and spontaneous recovery of drug-seeking behavior following presentation of previously drug-predictive cues was tested 4 weeks later. We find that compound stimulus presentations or pharmacologically increasing noradrenergic activity during extinction training results in less future recovery of responding, whereas propranolol treatment reduced the benefit seen with compound stimulus presentation. These data may have important implications for understanding the biological basis of extinction learning, as well as for improving the outcome of extinction-based therapies.

Figure 1

Experimental design. (a) Timeline of the experiments. (b) Summary of the discriminative stimulus procedure. Presentations of the discriminative stimuli (30 s light, white noise and clicker presented in pseudorandom order separated by an inter-trial interval averaging 270 s) signaled the availability of cocaine reward if the lever-press response was performed. At the end of training responding was reinforced according to a random ratio 4 schedule; ie on average, every fourth response during the stimulus-period resulted in cocaine (i.v.; 0.8 mg/kg/2 s infusion). Lever presses in the absence of the stimuli had no programmed consequences.

Figure 2

Extinction of a stimulus compound reduces spontaneous recovery of cocaine seeking relative to extinction of a single stimulus. (a) Summary of the within-subjects experimental design. All rats were trained that performance of the lever-press response in the presence of any of the three stimuli resulted in cocaine delivery. Responding during all three stimuli was extinguished before trials in which the stimuli were presented either alone or as part of a compound. Finally, spontaneous recovery of responding in the presence of the stimuli that had been extinguished either alone or as part of a compound was assessed 4 weeks later. (b) Mean lever presses performed per 30 s stimulus or in the pre-stimulus interval of equal length (30 s) on the final day of acquisition. Stimulus identity (ie, ‘to-be compound' or ‘to-be single') refers to the treatment that would be given in the third extinction session (noise or clicker; counterbalanced). ^*Responding during the stimuli was significantly greater than during the pre-stimulus interval; ^responding during the to-be single and to-be compound stimuli was not different. (c) Mean lever presses per stimulus for the initial extinction sessions (days 1 and 2) and the single stimulus trials in the first half of day 3. ^*Responding was significantly reduced from the first extinction session and ^responding to the different stimuli did not differ. (d) Mean lever presses per stimulus during the last half of the final extinction session, in which two of the three stimuli were presented in compound and the remaining stimulus continued to be presented alone, and in the test conducted 4 weeks later. Presentation of a stimulus compound increased responding during extinction; however, when the element of that compound was tested alone 4 weeks later, animals responded less to the stimulus that was extinguished in compound than to the stimulus extinguished alone. No cocaine was delivered during extinction or test. ^*Indicates a significant difference in number of lever presses; p<0.05; ^**p<0.01; N=10.

Figure 3

Atomoxetine treatment enhances extinction of cocaine seeking. (a) Summary of the experimental design. (b) Mean lever presses performed per 30 s stimulus or in the 30 s pre-stimulus interval on the final acquisition day for rats in the saline or atomoxetine groups; note that atomoxetine was given 45 min prior to the third extinction session. ^*Responding during the stimuli was significantly greater than during the pre-stimulus interval and ^responding during the stimuli was not different between groups. (c) Mean lever presses per stimulus for the initial extinction sessions; atomoxetine was given 45 min before the third extinction session. ^*Responding was significantly lower than on day 1. ^Responding did not differ between groups. (d) Mean lever presses per stimulus during the final extinction session following atomoxetine treatment and during the test session conducted drug-free 4 weeks later. Rats treated with atomoxetine showed reduced responding at test compared with rats treated with saline. ^**Indicates a significant difference in the number of lever presses; p<0.01. N=11 for the atomoxetine group and 10 for the saline group.

Figure 4

Propranolol treatment blocks the benefit to extinction produced by extinction of a stimulus compound. (a) Summary of the experimental design. (b) Mean lever presses performed per 30 s stimulus or in the 30 s pre-stimulus interval on the final acquisition day for rats in the saline and propranolol groups; note that propranolol treatments were given 30 min before the third extinction session. ^*Responding during the stimuli was significantly greater than during the pre-stimulus interval and ^responding during the stimuli was not different between groups. (c) Mean lever presses per stimulus for the initial extinction sessions. ^*Responding was significantly lower than on day 1. ^Responding did not differ between groups. (d) Mean lever presses per stimulus during the final extinction session, in which two of the three stimuli were presented in compound, and during the test session, in which the stimuli were presented alone, conducted drug-free 4 weeks later. In saline treated animals, compound stimulus presentation produced robust responding in extinction and reduced responding when the element was tested 4 weeks later. In contrast, although compound stimulus presentation still produced robust responding in extinction, the group treated with 5.0 mg/kg of propranolol showed greater responding when the element of the compound subsequently tested drug-free. ^*p<0.05, N=10 per group.