Long-term methadone treatment impairs novelty preference in rats both when present and absent in brain tissue

Behavioral consequences of long-term methadone treatment have received little attention either in humans or experimental animals. In this work, we show that methadone (2.5-10 mg/kg) administered (sc) once daily for three weeks with repeated withdrawal on Saturday and Sunday impairs the novelty preference in rats. One hour after the last injection, when methadone was still present in brain tissue, the rats were too affected by the sedative effects of the drug to perform the test. This was confirmed by an almost total lack of locomotor activity or exploratory behavior. One day after the last injection, the methadone treated rats showed a 70% reduction (p < 0.05) in novelty preference compared to rats administered saline. No methadone was detected in the brain tissue at this time. Moreover, there were no differences in locomotor activity or total exploratory behavior between the groups, indicating a specific impairment of cognitive functioning. In brain tissue, the methadone concentration versus time profile was shifted to the left after long-term treatment, indicating a change in uptake and distribution of the drug. The area under the two concentration versus time curves was, however, similar. Methadone disappeared completely from the brain within one day. Together, these results suggest that long-term methadone treatment may have a negative impact on cognitive functioning in rats, regardless of whether methadone is present in brain tissue.