Normal circadian rhythms of behavior are disrupted in disorders involving the dopamine (DA) system, such as Parkinsons disease. We have reported previously using unilateral injections of the catecholamine toxin, 6-hydroxydopamine (6-OHDA), into the medial forebrain bundle that DA signaling regulates daily expression of the clock protein, PERIOD2 (PER2), in the dorsal striatum of the rat. In the present study, we made widespread lesions of DA fibers using large injections of 6-OHDA into the third ventricle to determine the involvement of DA in normal daily rhythms of wheel-running activity and PER2 patterns in the suprachiasmatic nucleus (SCN) and several regions of the limbic forebrain. Rats injected with 6-OHDA and housed in constant darkness were less active in the wheel and showed a disorganized pattern of activity in which wheel running was not confined to a specific phase over 24 h. The 6-OHDA injection had no effect on the daily PER2 pattern in the SCN, but blunted the normal rise in PER2 in the dorsal striatum. 6-OHDA also blunted PER2 expression in the periventricular nucleus of the hypothalamus, a region in which a daily PER2 pattern has not been previously reported in male rats, and in the oval nucleus of the bed nucleus of the stria terminalis, but not in the central nucleus of the amygdala. These results indicate that DA plays a prominent role in regulating circadian activity at both behavioral and molecular levels.
A role for dopamine (DA) in the regulation of clock genes in the mammalian brain is suggested by evidence that manipulations of DA receptors can alter the expression of some clock genes outside the suprachiasmatic nucleus (SCN), the master circadian clock. The role of endogenous DA in the regulation of clock gene expression is unknown. Here, we demonstrate a direct relationship between extracellular DA levels and the rhythm of expression of the clock protein PERIOD2 (PER2) in the dorsal striatum of the male Wistar rat. Specifically, we show that the peak of the daily rhythm of extracellular DA in the dorsal striatum precedes the peak of PER2 by ?6 h and that depletion of striatal DA by 6-hydroxydopamine or ?-methyl-para-tyrosine or blockade of D(2) DA receptors by raclopride blunts the rhythm of striatal PER2. Furthermore, timed daily activation of D(2) DA receptors, but not D(1) DA receptors, restores and entrains the PER2 rhythm in the DA-depleted striatum. None of these manipulations had any effect on the PER2 rhythm in the SCN. Our findings are consistent with the idea that the rhythm of expression of PER2 in the dorsal striatum depends on daily dopaminergic activation of D(2) DA receptors. These observations may have implications for circadian abnormalities seen in Parkinsons disease.
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