Acta Pharmacologica Sinica 2005 November; 26 (11): 1290-1296; doi: 10.1111/j.1745-7254.2005.00179.x

Aim: Anticonvulsant tolerance and dependence are two obstacles that restrict the clinical use of benzodiazepines (BDZ). In order to explore the mechanism of these two adverse reactions, changes of neuropeptide Y (NPY) and its receptors in the hippocampus of rat models, in relation to flurazepam (FZP, a member of BDZ) tolerance and dependence, were investigated.

Methods: The mRNA of preproNPY and its receptors (Y₁, Y₂, and Y₅) in the hippocampus were determined by competitive RT-PCR, and the distribution of NPY in the hippocampus was examined by immunohistochemistry.

Results: A decrease of preproNPY mRNA in the hippocampus was found in tolerant and dependent rats. The level of preproNPY mRNA in the hippocampus was reversely correlated with the degree of tolerance and dependence, measured by the threshold of pentylenetetrazol-induced seizures. Immunohistochemistry indicated a decrease of NPY-immunoreactive material in neurons of the CA1, CA3, and dentate gyrus regions of both tolerant and dependent rats. The mRNA of NPY receptors Y₁ and Y₅ decreased in tolerant rats but did not change in dependent rats. The mRNA of NPY receptor Y₂ increased in tolerant rats but decreased in dependent rats.

Conclusion: A decrease of NPY in the hippocampus might be involved in anticonvulsant tolerance and dependence following long-term treatment with FZP. Y₁, Y₂, and Y₅ mRNA were also altered in FZP tolerance and dependence.

Keywords: benzodiazepines; neuropeptide Y; flura-zepam