Repeated alcohol extinction sessions in conjunction with MK-801, but not yohimbine or propranolol, reduces subsequent alcohol cue-induced responding in rats

• Long- and short-duration extinction sessions decreased cue-induced responding.
• Adrenergic manipulation during extinction did not alter cue-induced responding.
• Repeated extinction sessions did not affect reacquisition of responding for alcohol.
• MK-801 blocked the effect of extinction sessions on cue-induced responding.
• NMDA antagonists may be better than adrenergic drugs at enhancing exposure therapy.

Cues associated with alcohol can stimulate subjective states that increase relapse. Alcohol-cue associations may be strengthened by enhancing adrenergic activity with yohimbine or weakened by blocking adrenergic activity with propranolol. Alcohol-cue associations may also be weakened by long cue exposure sessions or strengthened by short cue exposure sessions. A useful treatment approach for alcoholism may combine adrenergic manipulation with cue exposure sessions of a specific duration. The present study sought to determine if cue exposure during long- or short-duration extinction sessions with post-session yohimbine or propranolol would alter alcohol cue-induced responding and self-administration. Rats were trained to respond for alcohol during sessions that included an olfactory cue given at the beginning of the session and a visual/auditory cue complex delivered concurrently with alcohol. Cue-induced responding was assessed before and after the repeated extinction sessions. Repeated alcohol extinction sessions of long duration (45 min) or short duration (5 min) were followed immediately by injections of saline, yohimbine, or propranolol. After the second set of cue-induced responding tests, reacquisition of operant alcohol self-administration was examined. To determine if the experimental procedures were sensitive to memory manipulation through other pharmacological mechanisms, the NMDA receptor antagonist MK-801 was given 20 min prior to long-duration extinction sessions. Both the long- and short-duration extinction sessions decreased cue-induced responding. Neither yohimbine nor propranolol, given post-session, had subsequent effects on cue-induced responding or alcohol self-administration. MK-801 blocked the effect of extinction sessions on cue-induced responding but had no effect on self-administration. The present study shows that manipulation of the NMDA system in combination with alcohol cue exposure therapy during extinction-like sessions may be more effective than manipulation of the adrenergic system in reducing the strength of alcohol-cue associations in this specific model of alcohol relapse.