The present study has demonstrated that self-administration models exhibit a relatively stable drug addiction plateau, extinction and recrudescence phases, which satisfies the current primary criteria for recrudescence models (10
). Thus, this study succeeded in establishing self-administration rat models and simulating the three phases of addiction, maturation, extinction and recrudescence.
Fifteen disparate proteins were identified. Among these proteins, three are associated with energy metabolism, NDP kinase A, fatty acid-binding protein and NADH dehydrogenase (ubiquinone) 1 α subcomplex subunit 10. These proteins participate in the energy supply process through oxidation reduction. The results of this study revealed that their expression significantly decreased in the morphine group during the recrudescence phase. This finding suggests a decrease in hippocampal energy metabolism during the morphine addiction maturation or addiction recrudescence process. NDP kinase A is highly expressed in the sera of stroke patients and therefore serves as a marker for apoplectic seizure. This indicates that its overexpression is a manifestation of an increase in brain function compensation and a stress-induced change due to brain injury (12
). NDP kinase A, together with a series of other individual proteins, is linked to performance in the Morris water maze (13
). Serotonin 1A receptor knockout mice are commonly used in anxiety and cognitive function tests. NDP kinase A expression decreases in these rat models (14
Of the disparate proteins identified in this study, two were ionic channel regulatory proteins: K+
channel-interacting protein 2 and mitogen-activated protein kinase 11. The former regulates the density of potassium ion receptors in cell membranes and promotes complex formation in the ionic channel (15
) and the latter transmits the pressure on the cell membranes and induces gliocytes to activate the p38 mitogen-activated protein kinase channel (16
). Thus, the two proteins function in intra and extracellular substance transportation. This study has demonstrated that the expression of K+
channel-interacting protein 2 and mitogen-activated protein kinase 11 decreased in the morphine recrudescence group. This finding indicates a decrease in substance transport ability and cell metabolism during the morphine recrudescence phase. Heat shock-related 70 kDa protein 2 is expressed in the hippocampus of normal rats (17
). The expression of this protein also significantly decreased in the morphine recrudescence group. Heat shock-related 70 kDa protein 2 functions in the accurate assembly, folding and transport of proteins. It also participates in the maintenance of normal projection transmission and inhibits apoptosis (18
). A decrease in its expression may therefore accelerate apoptosis. This finding is in line with the hippocampal atrophy observed following long-term addiction (19
A decrease in carboxylesterase 3 expression was also observed in the morphine recrudescence group. Carboxylesterase 3 performs a significant role in exogenous material metabolism and specifically binds with morphine in the liver (20
). It is also involved in cocaine and morphine metabolism. Therefore, the significant decrease in its expression in the morphine recrudescence group may be closely correlated with the mechanism of recrudescence. In addition, the expression of cytoskeleton-associated protein 4 and 14-3-3 protein β/α decreased in the experimental group, which is consistent with a previous study reporting the decreased expression of these proteins in rats with morphine addiction (20
). Presumably, these changes are associated with neural cell reduction and protein fibre demyelination. However, whether the low expression of these two proteins occurs in whole brain tissues or is confined to the hippocampus remains to be explored.
The present study has a number of limitations. Firstly, the changes in brain proteins following addiction are complicated, involving other brain regions, including the hippocampus, nucleus accumbens septum and mesencephalic ventral tegmental area. This study only focused on the hippocampus, thus investigation into these other brain sections should be conducted. Secondly, protein databases are not complete. Consequently, certain proteins may still not be listed. Additionally, the roles of some proteins remain uncertain. Further role verifications for key proteins are therefore necessary.