Previous spatial learning is required for the development of place preference in rats following chronic administration of and withdrawal from morphine

The positive reinforcing properties of addictive drugs have a primary role in the development of drug dependence. In the field of opiates, great attention has been given to this phenomenon, as well as to the negative properties eliciting craving and inducing relapse during withdrawal. This study was designed to evaluate whether elevated plus-maze (EPM) experienced rats withdrawn from low doses of subcutaneous (s.c.) morphine (10 mg/kg), in which a high anxiety level is the most prominent withdrawal symptom, acquire place preference when submitted to a conflict paradigm in which drug effects are paired with an aversive context: the distal part of the open arms of an EPM. Both the anxiety test and place preference conditioning were measured in the same apparatus, a biased version of the plus-maze. In order to verify the influence of previous EPM spatial learning on the performance of morphine-withdrawn rats, half the animals in this study experienced the EPM prior to treatment. Additional groups were also tested under the influence of morphine effects. The effects of the treatments were quantified through the analysis of three types of measures: anxiety was inferred from the use of the conventional measures (percentage of entries and time spent in the open-arms) and risk-assessment behaviours (frequency of stretched-attending postures – SAP, and time spent at the centre of the maze). Place preference conditioning was evaluated through analysis of the number of entries, total time spent and distance run in the open-arm extremities, which is where the animals were conditioned. The number of closed-arm entries was taken as an index of locomotor activity. Our results showed that (i) EPM naïve rats pre-treated with morphine did not develop place preference, behaving like control rats; (ii) rats that had previous experience in the EPM showed no changes in open-arm avoidance on the second exposure, when compared with rats naïve for this condition; (iii) previous spatial learning of the EPM contextual cues was, in fact, a requirement for anxiety-inducing place preference for the openarms in morphine-withdrawn rats and, (iiii) conditioned place preference was achieved both in rats under the effects of morphine and in withdrawal, probably through the influence of the positive or negative reinforcing effects promoted by the presence or absence of the drug in the central nervous system.