The role of mPer1 in morphine dependence in mice

Abstract

Investigations using Drosophila melanogaster have shown that the circadian clock gene period can influence behavioral responses to cocaine, and the mouse homologues, mPer1 and mPer2, modulate cocaine sensitization and reward. In the present study, we applied DNAzyme targeting mPer1 to interfere the expression of mPer1 in CNS in mice and studied the role of mPer1 on morphine dependence. We found that the DNAzyme could attenuate the expression of mPer1 in CNS in mice. Mice treated with DNAzyme and morphine synchronously did not show preference to the morphinetrained side, whereas the control group did. In contrast, mice treated with DNAzyme after morphine showed preference to the morphine-trained side as well as the control group did. These results indicate that drug dependence seems to be influenced at least partially by mPer1, but mPer1 cannot affect morphine dependence that has been formed. Keywords drug dependence; DNAzyme; learning and memory; circadian; i.c.v.Circadian clocks are molecular time-keeping mechanisms that reside in a diverse range of cell types in a variety of organisms. The primary role of these cell-autonomous clocks is to maintain their own approximately 24 h molecular rhythm and to drive the rhythmic expression of genes involved in physiology, metabolism and behavior. Components of the endogenous master clock were first identified in the fruit fly Drosophila melanogaster. The Period (Per) encodes one of the essential elements involved in the transcription/translation-based auto-regular loop of the endogenous master clock (Reppert and Weaver, 2001). Three homologues of Drosophila Per genes were subsequently identified in mice (mPer1, mPer2, and mPer3) (Albrecht, 2002), leading to great progress in elucidation of the molecular mechanism underlying circadian rhythm in the CNS.It has been shown that repeated administration of methamphetamine caused behavioral sensitization as well as sensitized expression of mPer1 (Nikaido et al., 2001). Some studies implicate a role for Per genes in drug-induced behavioral sensitization processes. This suggestion is supported by investigations using Drosophila flies. Flies mutant in the Per gene did not sensitize after repeated exposure to volatilized free-base cocaine (Andretic et al., 1999;Hirsh, 2001). In mice, the mPer1 and mPer2 genes influence cocaine-induced sensitization and reward in an opposite manner. The lack or dysfunction of the mPer1 gene *Corresponding author. Tel: +86-28-8550-2051; fax: +86-28-8550-3204. E-mail address: wangzhengrong@126.com (Z. Wang). abolishes cocaine sensitization and reward whereas the dysfunction of the mPer2 gene induces a hypersensitized response to cocaine (Abarca et al., 2002). NIH Public AccessDNAzyme is a suitable tool for studying gene function. The typical DNAzyme, known as the "10-23" model, is capable of cleaving single-stranded RNA at specific sites. The "10-23" model of DNAzymes has a catalytic domain of 15 highly conserved deoxyribonucleotides, flanked by two substrate-recognition domains, which can cl...

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