136 Dopaminergic activity also follows a strong rhythm, and manip

136 Dopaminergic activity also follows a strong rhythm, and manipulations of clock genes within brain dopaminergic structures leads to abnormal animal behaviors that closely resemble human bipolar disorder,137-139 while some genetic variants of the same clock genes are associated with a worse bipolar phenotype in human patients.140,141

The locus coeruleus produces a relatively constant tonic noradrenergic firing throughout all behavioral states, except during rapid eye movement (REM) sleep when NA discharge is absent,142 and it was hypothesized that modifications of NA activity during chronotherapeutics could be Inhibitors,research,lifescience,medical necessary for its effects.99,143 Remarkably, Inhibitors,research,lifescience,medical all antidepressant chronotherapeutic interventions cause a phase advance of biological rhythms. Light therapy in the morning is the main environmental synchronizer of the internal clock and influences timing and entrainment of the SCN circadian clock by inducing CREB.144 The circadian pacemaker is sensitive to short-duration light pulses

with a nonlinear relationship between light duration and the amount of resetting, Inhibitors,research,lifescience,medical and a 1-hour bright white light pulse phase shifts the circadian pacemaker following a clear-cut phase-response curve145: phase advances are obtained when administering light in the morning, Inhibitors,research,lifescience,medical and phase delays when administering it in the evening (the so-called type I phase response).146 SD directly targets the sleep-wake rhythm and can influence SCN function by modifying vigilance state transitions and sleep states,147 specifically modifies the binding of the molecular components of the biological clock,148 and

is clinically synergistic with the administration of phase-advancing morning light149: in agreement with these findings, an A-1210477 research buy actimetric advance Inhibitors,research,lifescience,medical of the activity-rest circadian cycle correlates with positive, antidepressant response to SD.49 Surprisingly, very little data are available on the effects of antidepressant drugs on the biological clock, but a single study showed that fluoxetine induces a phase advance of the SCN in rats,150 while the antidepressant agomelatine can induce a phase advance in normal humans,151 thus supporting the hypothesis that chronotherapeutics and druginduced changes on monoaminergic function Metalloexopeptidase may result in similar long-lasting effects on the master clock of depressed patients, possibly correcting yet poorly understood abnormalities in the phase-angle relationships between biological rhythms.81,152 Brain plasticity and metabolism Genes of the biological clock are expressed in many brain structures other than in the SCN153,154 and their genetic variants can bias “non-clock” brain functions such as information processing and decision making in bipolar depression.

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