Roles of opioid receptor subtypes in mediating alcohol-seeking induced by discrete cues and context

Abstract

The aim of this study was to assess the effects of selective blockade of the delta (DOP) or mu (MOP) opioid receptors on alcohol-seeking induced by discrete cues and context. In Experiment 1, rats were trained to self-administer alcohol in an environment with distinct sensory properties. After extinction in a different context with separate sensory properties, rats were tested for context-induced renewal in the original context following treatment with the DOP receptor antagonist naltrindole (0-15 mg/kg, i.p.) or the MOP receptor antagonist D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH(2) (CTOP) (0-3 microg/4 microL, i.c.v.). In Experiment 2, reinstatement was tested with the presentation of a discrete light + tone cue previously associated with alcohol delivery, following extinction without the cue. The effects of naltrindole (0-5 mg/kg, i.p.) or CTOP (0-3 microg/4 microL, i.c.v.) were assessed. For context-induced renewal, 7.5 mg/kg naltrindole reduced responding without affecting locomotor activity. Both doses of CTOP attenuated responding in the first 15 min of the renewal test session; however, total responses did not differ at the end of the session. For discrete-cue-induced reinstatement, 1 and 5 mg/kg naltrindole attenuated responding but CTOP had no effect. We conclude that whereas DOP receptors mediate alcohol-seeking induced by discrete cues and context, MOP receptors may play a modest role only in context-induced renewal. These findings point to a differential involvement of opioid receptor subtypes in the effects of different kinds of conditioned stimuli on alcohol-seeking and support a more prominent role for DOP receptors.

Fig. 1. Effects of naltrindole on context-induced renewal

Active (A & D) and inactive (B & E) lever presses on the last day of extinction (drug-free day) and on the renewal test day. In Experiment 1a (Panels A–C), ABB+NDL0 were tested in the extinction context and administered the vehicle. ABA groups were instead tested in the context where alcohol was previously available following treatment with: vehicle (ABA+NDL0), 5-mg/kg naltrindole (ABA+NDL5) or 15-mg/kg naltrindole (ABA+15NDL), IP. In experiment 1b (Panels D–F), all rats were tested in the context where alcohol was previously available following treatment with: vehicle (ABA+NDL0), 7.5-mg/kg naltrindole (ABA+NDL7.5) or 10-mg/kg naltrindole (ABA+NDL10), IP. Active lever presses are also graphed for each treatment group in 15-min intervals (panels C & F) over the course of the 1-h test session. * denotes a significant difference from the extinction day within the treatment group (P < 0.05), † denotes a significant difference from the ABA+NDL0 condition on the test day (P < 0.05), § denotes a significant difference from the ABB+NDL0 group on the test day (P < 0.05).

Fig. 2. Effects of CTOP on context-induced renewal

Active (A) and inactive (B) lever presses on the last day of extinction (drug-free day) and on the renewal test day. On the renewal test day, all groups were tested in the context where alcohol was previously available following pre-treatment with vehicle (ABA+CTOP0), 1-µg/4µl CTOP (ABA+CTOP1) or 3-µg/4µl CTOP (ABA+CTOP3), ICV. Active lever presses are also graphed for each treatment group in 15-min intervals (C) over the course of the 1-h test session. * denotes a significant difference from the extinction day (P < 0.05), and † denotes a significant difference from the ABA+CTOP0 group on the test day (P < 0.05).

Fig. 3. Effects of naltrindole on discrete cue-induced reinstatement

Active (A) and inactive (B) lever presses on the last day of extinction (drug-free day) and on the reinstatement test day. On the reinstatement test day all groups were tested in the presence of the response-contingent light+tone cue following pre-treatment with vehicle (NDL0), 1-mg/kg naltrindole (NDL1) or 5-mg/kg naltrindole (NDL5), IP. Active lever presses are also graphed for each treatment group in 15-min intervals (C) over the course of the 1-h test session. * denotes a significant difference from the extinction day within the treatment group (P < 0.05), and † denotes a significant difference from the NDL0 group on the test day (P < 0.05).

Fig. 4. Effects of CTOP on discrete cue-induced reinstatement

Active (A) and inactive (B) lever presses on the last day of extinction (drug-free day) and on the reinstatement test day. On the reinstatement test day all groups were tested in the presence of the response-contingent light+tone cue following pre-treatment with vehicle (CTOP0), 1-µg/4µl CTOP (CTOP1) or 3-µg/4µl CTOP (CTOP3), ICV. Active lever presses are also graphed for each treatment group in 15-min intervals (C) over the course of the 1-h test session. * denotes a significant difference from the extinction day (P < 0.05).