Reversal of morphine conditioned behavior by an anti-dopaminergic post-trial drug treatment during re-consolidation

Abstract

Morphine has potent pro-dopamine effects that can be manifested as hyper-locomotion and these behavioral effects can undergo conditioning and sensitization. The aim of the present study was to assess whether an inhibitory dopaminergic post-trial treatment (0.05 mg/kg apomorphine) given during re-consolidation could reduce morphine conditioning. To induce conditioned morphine hyperactivity and control for morphine exposure, a paired/unpaired Pavlovian conditioning protocol was used. The morphine paired groups received morphine in the open-field test arena and the unpaired groups received the same morphine (10 mg/kg) treatments but in a different environment. The morphine treatments were administered once per day for 5 days. With repeated treatments, the paired morphine groups developed a sensitized hyper-locomotion response whereas the unpaired morphine groups did not differ from vehicle groups. Subsequently, the paired, unpaired and vehicle groups were given four daily non-drug 5 min conditioning tests. In these conditioning tests, the paired but not the unpaired and vehicle groups exhibited a conditioned locomotor stimulant response. These groups were subdivided into matched groups and received either vehicle or 0.05 mg/kg apomorphine either during re-consolidation immediately post-test or after re-consolidation 15 min post-test. In the immediate post-trial treatment groups, the morphine conditioned response in the paired group was eliminated after only one post-trial apomorphine treatment. The same immediate 0.05 mg/kg apomorphine post-trial treatments had no effect on the unpaired morphine or vehicle groups. In the paired group that received vehicle immediately post-trial, the conditioned response remained robust and unchanged over the four conditioning tests. In the post-trial 15 min delay treatment groups, the post-trial apomorphine treatments had no effect on the morphine conditioned response. These results showed that the inhibition of dopamine activity by apomorphine during the re-consolidation of a cue activated morphine conditioned response eliminated morphine conditioned effects. In that morphine conditioned effects are important for the initiation of addiction and in triggering drug craving and relapse, this finding has potential relevance to opioid addiction treatment.

Keywords: Apomorphine; Conditioning; Locomotor activity; Memory reconsolidation; Morphine; Sensitization.