Global Depletion of Dopamine Using Intracerebroventricular 6-Hydroxydopamine Injection Disrupts Normal Circadian Wheel-Running Patterns and PERIOD2 Expression in the Rat Forebrain

Abstract

Normal circadian rhythms of behavior are disrupted in disorders involving the dopamine (DA) system, such as Parkinson's 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.

Sleep-wake disturbances in the premotor and early stage of Parkinson's disease

“…Second, the loss of dopaminergic transmission in Parkinson's disease not only affects the nigro-striatal projection but also dopaminergic circuits between basal ganglia and brainstem structures (particularly the pedunculopontine and laterodorsal tegmental nucleus), where important neurons of the arousal pathway and for the modulation of sleep stages are located [1,101,108]. Finally, mesocortical dopamine neurons innervate limbic areas (thalamus and hypothalamus) [1,101], where important regulators of sleep-wake cycle are located: a) the master circadian clock in the suprachiasmatic nuclei of the hypothalamus, which mainly involves coordinated expression and activation of various clock genes [109][110][111][112][113][114] and regulation of melatonin production [115], and b) orexin/hypocretin-containing neurons, important excitatory neuromodulators of sleep homeostasis [116], which interestingly seem to be progressively reduced over the course of Parkinson's disease [117].…”

Dispensable, Redundant, Complementary, and Cooperative Roles of Dopamine, Octopamine, and Serotonin inDrosophila melanogaster

“…In addition, expression using TH-Gal4 showed effects on other aspects of the startle response, suggesting a potentially complementary role for the serotonergic system in regulating arousal or startle behaviors. Gravotta et al 2011). However, it is unknown whether the different aminergic systems function independently, cooperatively, or in a complementary manner in the regulation of rhythmicity.…”

Diurnal influences on electrophysiological oscillations and coupling in the dorsal striatum and cerebellar cortex of the anesthetized rat

“…Endogenous extracellular dopamine levels show cyclic fluctuations throughout the day and peak during the middle of the dark phase in rodents (Owasoyo et al, 1979; Hood et al, 2010; Ferris et al, 2014). Furthermore, activation of D2 dopamine receptors has been linked with normal expression of Per 2, one of the core circadian genes, in the rat dorsal striatum (Hood et al, 2010; Gravotta et al, 2011). Per2 is involved in regulating daily physiological and behavioral cycles and is found in most tissues throughout the body (Albrecht et al, 2007).…”