Abstract
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.
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Brown MJ, Wood MD, Coldwell MC, Bristow DR . Gamma-aminobutyric acid A receptor function is desensitised in rat cultured cerebellar granule cells following chronic flunitrazepam treatment. J Neurochem 1998; 71: 1232–40.
Bonavita C, Ferrero A, Cereseto M, Velardez M, Rubio M, Wikinski S . Adaptive changes in the rat hippocampal gluta-matergic neurotransmission are observed during long-term treatment with lorazepam. Psychopharmacology (Berl) 2003; 166: 163–7.
Byrnes JJ, Miller LG, Perkins K, Greenblatt DJ, Shader RI . Chronic benzodiazepine administration. XI. Concurrent administration of PK11195 attenuates lorazepam discontinuation effects. Neuropsychopharmacology 1993; 8: 267–73.
Gupta N, Bhargava VK, Pandhi P . Tolerance and withdrawal to anticonvulsant action of clonazepam: role of nitric oxide. Methods Find Exp Clin Pharmacol 2000; 22: 229–35.
Mizoguchi H, Yoshiike M, Suzuki T, Misawa M . Effects of Ca2+ channel blockers on physical dependence on diazepam in mice. Life Sci 1993; 53: PL365–70.
Lilly SM, Zeng XJ, Tietz EI . Role of protein kinase A in GABAA receptor dysfunction in CA1 pyramidal cells following chronic benzodiazepine treatment. J Neurochem 2003; 85: 988–98.
Zeng XJ, Tietz EI . Role of bicarbonate ion in mediating decreased synaptic conductance in benzodiazepine tolerant hippocampal CA1 pyramidal neurons. Brain Res 2000; 868: 202–14.
Blomqvist AG, Herzog H . Y-receptor subtypes — how many more? Trends Neurosci 1997; 20: 294–8.
Colmers WF, Lukowiak K, Pittman QJ . Neuropeptide Y action in the rat hippocampal slice: site and mechanism of presynaptic inhibition. J Neurosci 1988; 8: 3827–37.
Bison S, Crews F . Alcohol withdrawal increases neuropeptide Y immunoreactivity in rat brain. Alcohol Clin Exp Res 2003; 27: 1173–83.
Rosenberg HC . Differential expression of benzodiazepine anticonvulsant cross-tolerance according to time following flurazepam or diazepam treatment. Pharmacol Biochem Behav 1995; 51: 363–8.
Rosenberg HC, Chiu TH . Tolerance during chronic benzodiazepine treatment associated with decreased receptor binding. Eur J Pharmacol 1981; 70: 453–60.
Lau CE, Falk JL, Dolan S, Tang M . Simultaneous determination of flurazepam and five metabolites in serum by high-performance liquid chromatography and its application to pharmaco-kinetic studies in rats. J Chromatogr 1987; 423: 251–9.
Izzo E, Auta J, Impagnatiello F, Pesold C, Guidotti A, Costa E . Glutamic acid decarboxylase and glutamate receptor changes during tolerance and dependence to benzodiazepines. Proc Natl Acad Sci USA 2001; 98: 3483–8.
Sammbrook J, Fritsch EF, Maniatis T . Molecular cloning, a laboratory manual, 3rd Ed. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 2001. p 8. 86–9.
Loscher W, Ebert U . The role of the piriform cortex in kindling. Prog Neurobiol 1996; 50: 427–81.
Weiss SR, Clark M, Rosen JB, Smith MA, Post RM . Contingent tolerance to the anticonvulsant effects of carbamazepine: relationship to loss of endogenous adaptive mechanisms. Brain Res Brain Res Rev 1995; 20: 305–25.
Qian J, Colmers WF, Saggau P . Inhibition of synaptic transmission by neuropeptide Y in rat hippocampal area CA1: modulation of presynaptic Ca2+ entry. J Neurosci 1997; 17: 8169–77.
Parker RM, Herzog H . Regional distribution of Y-receptor subtype mRNAs in rat brain. Eur J Neurosci 1999; 11: 1431–48.
Gariboldi M, Conti M, Cavaleri D, Samanin R, Vezzani A . Anticonvulsant properties of BIBP3226, a non-peptide selective antagonist at neuropeptide Y Y1 receptors. Eur J Neurosci 1998; 10: 757–9.
Kaga T, Fujimiya M, Inui A . Emerging functions of neuropeptide Y Y(2) receptors in the brain. Peptides 2001; 22: 501–6.
Woldbye DP, Larsen PJ, Mikkelsen JD, Klemp K, Madsen TM, Bolwig TG . Powerful inhibition of kainic acid seizures by neuropeptide Y via Y5-like receptors. Nat Med 1997; 3: 761–4.
Wu YF, Li SB . Neuropeptide Y expression in mouse hippocampus and its role in neuronal excitotoxicity. Acta Pharmacol Sin 2005; 26: 63–8.
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Project supported by the National Natural Science Foundation of China (No 30170994).
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Zhang, Lp., Wang, L. Changes of brain neuropeptide Y and its receptors in rats with flurazepam tolerance and dependence. Acta Pharmacol Sin 26, 1290–1296 (2005). https://doi.org/10.1111/j.1745-7254.2005.00179.x
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DOI: https://doi.org/10.1111/j.1745-7254.2005.00179.x
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