Effect of naltrexone during extinction of alcohol-reinforced responding and during repeated cue-conditioned reinstatement sessions in a cue exposure style treatment

Abstract

The ability of alcohol-related cues to promote craving can be attenuated independently by giving the opioid antagonist naltrexone (NTX) or by subjecting alcohol-dependent patients to a cue exposure treatment. The effects of cue exposure treatment may be enhanced if conducted in the presence of NTX. The purpose of these experiments was to determine if NTX given during extinction of responding for alcohol in rats would alter cue-conditioned reinstatement of responding and to determine if NTX, paired with repeated cue-conditioned reinstatement, would reduce subsequent cue-conditioned reinstatement or reacquisition of self-administration in the absence of NTX. Rats lever pressed for alcohol in the presence of an olfactory cue. Visual and auditory stimuli were presented during alcohol delivery. In the first experiment, rats were injected with saline or 3mg/kg NTX prior to extinction sessions followed by cue-conditioned reinstatement tests. In the second experiment, extinction was followed by cue-conditioned reinstatement sessions presented twice per week. The rats received saline or NTX (3 and 10mg/kg) prior to several sessions. All rats received reinstatement tests with and without a pretreatment of NTX followed by reacquisition of alcohol self-administration. NTX had no effect on responding during extinction or on subsequent cue-conditioned reinstatement. Only 10mg/kg NTX reduced responding during the twice weekly reinstatement sessions. The twice weekly NTX treatment had no effect on subsequent cue-conditioned reinstatement in the absence of NTX. Reacquisition of responding for alcohol was reduced in the group receiving saline during repeated reinstatement sessions, whereas this effect was blocked in the NTX group. These findings support the notion that NTX given during a brief abstinence period (i.e., extinction) has minimal effects on future sensitivity to alcohol cues and alcohol consumption. NTX given during the repeated alcohol cue exposure does not alter the subsequent incentive value of alcohol cues in the absence of NTX or enhance the beneficial effects of cue exposure treatment.

Fig. 1

Diagrams illustrating conditions and parameters for each operant session: a) self-administration, b) extinction, c) S+/CS+ cue-conditioned reinstatement, and d) S−/CS− cue-conditioned reinstatement.

Fig. 2

Diagrams illustrating the timeline of experimental manipulations during Experiment 1 and Experiment 2.

Fig. 3

Average number of responses is shown during the last 7 days of ethanol self-administration baseline, during 5 days of extinction with pretreatment injections of 3 mg/kg NTX or saline, and the average number of responses during the 2 days of reinstatement tests under the S+/CS+ (ethanol) condition and the 2 days of S−/CS− (quinine) stimulus conditions for the groups of rats in Experiment 1. Data for both groups (n=6) are shown as means ± SEM. *Indicates p<0.05 compared to average of the last 3 days of extinction for both groups combined. #Indicates p<0.05 compared to the average of the S−/CS− days for both groups combined.

Fig. 4

Average number of responses for each session is shown during the 8 cue exposure sessions (S+/CS+) with rats receiving intraperitoneal pretreatment injections of either 3 mg/kg NTX or saline in Experiment 2. The average number of responses across all 8 sessions is depicted for the NTX Group (solid bars) and the Saline Group (lined bars). Similar data is shown for the subsequent treatment with 10 mg/kg NTX. *Indicates p<0.05 for between-groups comparison for average responding across the 8 sessions.

Fig. 5

Average number of responses is shown for the last 7 days of the original ethanol baseline, last 3 days of extinction, as well as the average number of responses on a single S+/CS+ session, a single S−/CS− session, and an S+/CS+ session with a pretreatment injection of 10 mg/kg NTX. *Indicates p<0.05 for comparison to extinction baseline. #Indicates p<0.05 for comparison to S−/CS− session and S+/CS+ session with a pretreatment injection of 10 mg/kg NTX.

Fig. 6

Average number of responses is shown for the last 7 days of the original ethanol baseline and the last 7 days of reacquisition of ethanol self-administration. *Indicates p<0.05 for within-group comparison to original ethanol baseline. ^&Indicates p<0.05 for between-groups comparison of responding during reacquisition.