Psychopharmacology (1989) 97:343 348 Psychopharmacology 9 Springer-Verlag 1989 Effects of selective monoaminergic reuptake blockade on activity rhythms in developing rats Nataeha I. Barber, Martin H. Teicher, and Ross J. Baldessarini Departments of Psychiatry and Neuroscience Program, Harvard Medical School, Mailman Research Center, McLean Hospital, 115 Mill Street, Belmont MA 02178, USA Abstract. Developing rats display prominent ultradian rhythms of locomotor activity when separated from the litter. A pharmacological analysis was undertaken to pro- vide preliminary data on the role of monoaminergic neu- rotransmitter systems in the modulation or manifestation of this fundamental biological rhythm. Twenty-four hour activity profiles were monitored in 15-day-old rats, tested in darkness, after intraperitoneal treatment with desipra- mine (DMI), zimelidine (ZMD, or GBR-13069 (GBR), se- lective uptake inhibitors of norepinephrine, serotonin, and dopamine, respectively. Time series data were analyzed by low-resolution variance spectral analysis. DMI significantly diminished ultradian (> 1 cycle per day; cpd) rhythmicity, and enhanced the circadian rhythm. Equimoiar doses of ZMI had little effect on the ultradian band (7 15 cpd), but slightly reduced the circadian peak. The effects of acute GBR administration were complex, as this agent produced prominent effects on basal activity. In a second study these agents were administered continuously over a 5-day period, using subcutaneously implanted Alzet osmotic minipumps, to avoid the confounding effects of acute administration. Continuously-infused DMI virtually eliminated characteris- tic ultradian rhythms in the 9-15 cpd bandwidth. Z1M di- minished ultradian osci!lations oniy in the 14~d5 cpd range, and GBR-12909 had little effect on ultradian rhythms throughout the usually prominent 7-16 cpd domain. All three reuptake inhibitors increased the prominence of slow ultradian rhythms with frequencies of 3 4 cpd. Continuous reuptake blockade had no significant effects on circadian amplitude or phase, as determined by cosinor analysis. Overall, these results indicate that modulation of activity rhythms in the neonatal rat are prominently affected by drugs which enhar~ce certain centrai monoaminergic sys- tems, particularly norepinephrine. Key words: Monoamines Locomotor activity- Ultradian rhythms - Biological rhythms - Uptake inhibhors Ultradian rhythms with a periodicity of about 1-4 h have been described for many behavioral, physiological and neu- roendocrine processes, including REM sleep, cortisol secre- tion, gastric motility, and rest activity cycles (Kripke 1974; Lavie and Kripke 1981). Richter (1922) was the first to describe a robust 1-2 h activity rhythm in neonatal rats, Of Jj~rint requests to. M.H. Teicher which is also found in newborn humans (Kleitman 1963). These activity rhythms emerge in advance of circadian (1 cycle per day; cpd) oscillations and are most prominent during early development (Teicher and Flaum I979). They become much less distinct in adulthood when circadian ac- tivity rhythms are at a peak, but many re-emerge during aging or under certain pathological conditions (Teicher et al. J986 b). The relationship between ultradian and circa- dian rhythms remains unclear, though it may be partially reciprocal, with the circadian rhythm often masking or strongly modulating an underlying ultradian oscillation (Teicher et al. 1988b). An excellent example of joint circa- dian and u!tradian modulation occurs with cortisol produc- tion, which is released in about eight secretory episodes per day (a 3 h ukradian rhythm), which are very intense in the early morning (6-Ji0 A.M.), and virtually absent at night (8 P.M. - midnight) (Sachar etal. 1973). Despite the prominence of ultradian rhythms and their widespread distribution throughout the animal kingdom, very little is known about their control mechanisms or phys- iological significance. Unlike circadian rhythms, ultradian rhythms seem to "free-run" at different and variable fre- quencies, and are not modulated by any known zeitgeber, making identification and analysis difficult. Furthermore, the oscillators that govern these rhythms are poorly defined, although evidence suggests that multiple independent oscil- iators exist for different biological processes (Lavie and Kripke 1981). Disturbances of normal uitradian and circadian rhythms have been linked to several clinical neuropsychiat- ric disorders. Sachar (1973), for example, found abnormal rhythms of cortisol secretion in psychotic depression. De- pressed patien*~s also display prominent alterations of sleep- wake cycles (Beersma et al. 1984; Teicher et al. 1988b, c) and an increase in the frequency of REM periods (Kupfer and Foster 1973). In addition, ultradian activity rhythm disturbances have been demonstrated in cases of cortical damage or disturbance including stroke, dementia and tu- mor (Teicher et al. 1986b). A better understanding of the neuroanatomy and pharmacology of CNS osci!tators may help provide a conceptual framework for explaining such neuropathologic disorders. In recent years, considerable progress had been made toward understanding the neurophysiological basis of ultra- dian oscillators that regulate REM sleep (Hobson and McCarley 1975), as welI as those that control pulsatile hor- mone secretions (e.g., Millard et al. 1981). However, studies exploring the neuropharmacological mechanisms governing