Lysosomal and Dopaminergic D2 Inhibition Reversed the Effect of Morphine on Learning and Memory in Male Wistar Rats Relating Mitochondrial Biogenesis

Opiates dependence has many side effects on body especially brain neuroplasticity leading to changes in behavior. In this study, we evaluated the effects of morphine dependence on learning and memory as well as on Peroxisome proliferator-activated receptor gamma coactivator -1 alpha (PGC-1α) protein level as a key regulator of mitochondrial biogenesis. Also, by using Chloroquine (lysosomal inhibitor) and dopaminergic system inhibitor (Sulpiride), the molecular mechanism, underling morphine addiction related to lysosome, dopamine receptors and mitochondria, has been considered in this study.

Male albino Wiastar rats received morphine in their water for 21 days; during the ending 4 days, they received daily intracerebroventricular (i.c.v.) injection of Chloroquine diphosphate (50 mM). Also, i.c.v. injection of Sulpiride (0.25μg/rat) was done before behavioral test. Shuttle box apparatus was used for learning and memory evaluation. After behavioral test, the brains of rats were extracted and the level of PGC-1α protein was investigated by western blotting.

Results indicated that morphine oral administration has reduced learning and memory-like behavior. Pre-training i.c.v. injection of Chloroquine and Sulpiride improved learning and memory. PGC-1α protein level in rats which received Chloroquine and also in the morphine group increased and there was a more significant increase in rats which received morphine, Chloroquine and Sulpiride altogether.

Morphine has an adverse effect on learning and memory as it has been shown with spending more time in dark rooms of Shuttle box apparatus, which was reversed by Chloroquine (lysosomal inhibitor) and dopamine inhibitor (Sulpiride). Increasing PGC-1α protein level may imply the important role of mitochondrial biogenesis in morphine-dependent learning changes. Overall, data suggest dopaminergic system along with lysosome and mitochondrial activity play an important role in morphine addiction status.