Morphine administration modulates expression of A rgonaute 2 and dopamine‐related transcription factors involved in midbrain dopaminergic neurons function

Background and Purpose Alterations in transcription factors that regulate the development and maintenance of dopamine ( DA ) neurons (such as N urr1 and P itx3) play an important role in the pathogenesis of addiction diseases. We have examined the effects of acute and chronic morphine and morphine withdrawal on TH expression and activity as well as expression of N urr1, P itx3 and A go2 in the ventral tegmental area ( VTA ) and nucleus accumbens ( NAc ) of the rat. Experimental Approach Rats were injected acutely with morphine and decapitated 1 or 2 h later. Another set of rats were made dependent on morphine by implantation of two morphine pellets. Precipitated withdrawal was induced by injection of naloxone. A go2, P itx3, N urr1, total TH ( tTH ), TH phosphorylated at S er31 and at S er40, and 3,4‐Dihydroxyphenylacetic acid, and DA determination in the VTA and/or NAc were measured using immunoblotting, HPLC and immunofluorescence. Key Results Acute morphine produced a marked increase in TH activity and DA turnover in the NAc , concomitantly with increased N urr1 and P itx3 expression in the VTA . In contrast, precipitated morphine withdrawal decreased TH activation, TH expression and did not increase DA turnover in the NAc . These effects paralleled decreases in A go2 expression, which was accompanied by increased N urr1 and P itx3, TH activity and normalized TH protein levels in the VTA . Conclusions and Implications The combined decrease in A go2 and increases in N urr1 and P itx3 might represent some of the mechanisms that served to protect against accumbal TH regulation observed in morphine withdrawn rats, which may be critical for DA bioavailability to influence behaviour.