Regulatory actions of therapeutic drugs for affective disorders on circadian rhythm of rat behviors.

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1) Effects of lithium (LiCl), clomipramine (CMP), imipramine (IMP), and thyrotropin releasing hormone (TRH): Male Sprague-Dawley rats chronically implanted with a cannula in the lateral ventricle were bilaterally eye-enucleated and released into constant light. After 3-5 weeks of free-running, the rats received a 2-week continuous intraventricular (ivt) infusion of a drug solution (flow rate, 0.5 <micro> l/h) via a silicone tubing connected with a mini-osmotic pump (Alzet, #2002) implanted subcutaneously under halothane anesthesia. In eat rat, ambulation, drinking and eating were simultaneously measured at 10-min intervals. A change in free-running circadian period ( <tau> ) was calculated as <delta> <tau> (post-implantation <tau> minus pre-implantation <tau> ). 0.35-567.5 nM/kg/h ivt infusions of CMP (n=10) produced <delta> <tau> of -0.02 <+!-> 0.02 h (mean <+!-> SE) ranging from -0.12 h to +0.07; the correlation coefficient (r) between <delta> <tau> and doses was -0.84 (P<0.001). 0.3 … More 6-828.7 nM/kg/h ivt infusions of IMP (n=10) caused <delta> <tau> of +0.01 + 0.01 h ranging from -0.05 h to +0.09; the r was -0.56 (<0.05). 5.7 -6.6 nM/kg/h ivt infusions of TRH (n=5) produced <delta> <tau> of 0.00 <+!-> 0.01 h (range, -0.03 to +0.06 h). LiCl was ivt infused at the rates of 0.2-17.9 <micro> M/kg/h in 36 rats. Ten rats died from Li intoxication when the rate was over 6 <micro> M/kg/h. In the remaining 26 rats, LiCl produced <delta> <tau> of +0.07 <+!-> 0.02 h ranging from -0.07 h to +0.36; the r was +0.24 (ns). On the other hand, 18.6 -66.4 <micro> M/kg/h subcutaneous infusions of LiCl (n=4) caused <delta> <tau> of +0.12 <+!-> 0.04 h (range, 0.00 to +0.20 h). As a control, 0.5 <micro> l/h ivt infusion of physiological saline (n=4) produced <delta> <tau> ranging from +0.04 h to +0.08. In conclusion, CMP and IMP shortens <tau> at higher doses whereas LiCl prolongs it.2) The range of entrainment of circadian rhythm to light-dark (LD) cycle and the effect of lithium. In order to determine the range of entrainment of circadian behavioral rhythms of Sprague-Dawley rats, the LD cycle was shortened (n=10) or lengthened (n=10) gradually by 20-min steps from 24 h period (LD 12:12), during which the L period length always equaled the D period length and the light intensity was 100 lux. The upper limit of entrainment was between 27 h 40 m and 29 h for drinking rhythm, and between 28 h 20 m and 29 h 20 m for ambulatory rhythm. During exposure to the longer LD periods, the behavioral rhythms were phase-advanced to the LD cycle. During exposure to LD 14:14, 2-week subcutaneous infusion of LiCl at the rate of 22.5 <micro> M/h via a mini-osmotic pump did not alter the degree of entrainment and the advanced phase of circadian rhythms. The lower limit of entrainment was 23 h 20 m for sleep, ambulation, drinking and eating. During exposure to this LD cycle, the behavioral rhythms was phase-delayed to the LD cycle. Less