Psychopharmacology (1994) 115 : 237-244 Psychopharmacolog © Springer-Verlag 1994 Neonatal desipramine treatment alters free-running circadian drinking rhythms in rats Alan M. Rosenwasser, Marie J. Hayes Department of Psychology, 301 Little Hall, University of Maine, Orono, ME 04469, USA Received: 1 July 1993 / Final version: 8 October 1993 Abstract. Neonatal treatment with monoamine reuptake inhibitorsresults in a constellation of neurobehavioral alterations in adult rats that may model human depress- ion. Since alterations in circadian rhythmicity have been reported in both depressed patients and in animal de- pression models, the present study examined the effects of neonatal desipramine treatment (5.0 mg/kg SC from postnatalday 7 through 22) on free-running circadian drinking rhythms. Rhythmicity was examined in constant darkness (DD), constant light (LL), and during adult desip- ramine treatment (0.25 mg/ml via the drinking water). Compared with saline-treated controls, neonatal desip- ramine lengthened free-running period in DD, blunted the period-altering effect of LL, and potentiated the period- altering effect Of adult desipramine treatment. Neonatal desipramine treatment also increased circadian amplitude and spectral magnitude, but did not modify the effects of light or adult desipramine on these parameters. These results provide further evidence that behavioral depress- ion is associated with alterations in circadian rhythmicity, and are consistent with the hypothesis that such relation- ships are mediated by brain monoaminergic systems. Key words: Neonatal ..... Desipramine - Circadian - Rats Exposure to psychoactive agents during early develop- ment may result in permanent alterations in both brain and behavior. For example, rats treated neonatally with antidepressant monoaminereuptakeinhibitors display a constellation of behavioral effects in adulthood; these alterations include increases in open-field activity, volun- tary alcohol intake, and swim-test immobility, decreases in sexual, aggressive, and reward-seeking behaviors, and impaired startle response (Mirmiran et al. 1985; Hilakivi et al. 1987; Vogel et al. 1990). In addition, neonatal antide- pressant treatment permanently altersthe amount and timing of REM sleep (Mirmiran et al. 1981; Vogel et al. 1990), as well as regional brain monoamine content Correspondence to: A. M. Rosenwasser and receptor density (De Ceballos et al. 1985; Hilakivi et al. 1987). Although the specific mechanisms are unknown, it is reasonable to hypothesize that developmental alterations in monoaminergic systems mediate these effects. Since similar effects are seen with serotonin-selective (e.g., clomipramine, zimeldine)and norepinephrine-selective (e.g., desipramine) reuptake inhibitors (Hilakivi and Sin- clair 1986; Hilakivi and Hilakivi 1987; Hilakivi et al. 1988; Fernandez-Pardo and Hilakivi 1989; Velasquez-Moc- tezuma and Ruiz 1992), it is difficult to attribute these changes to perturbation of any particular neurotransmit- ter or receptor system. On the other hand, both serotonin- selective and norepinephrine-selective reuptake inhibitors suppress active (REM) sleep in rat pups, and it has bee suggested that chronic inhibition of active sleep during early development may be critical to these effects (Mir miran et al. 1985; Hilakivi et al. 1988). Whatever the underlying mechanisms, the marked similarity between these effects and the neurobehavioral symptoms of clinical depression supports the validity of neonatal antidepress- ant administration as a pharmacogenic animal model of depression (Vogel et al. 1990). Alterations in circadian phase, period, and amplitude have been described in both depressed patients (e.g., Wehr et al. 1983) andin several putativeanimal models of depression (Rosenwasser 1992). Indeed, it is now recog- nized that circadian periodicity in animals can be potently influenced by feedback associated with normal variations in behavioral arousal state, although the exact nature o the relevant state-related signals has not been identified (Mrosovsky et al. 1989; Turek 1989; Edgar et al. 1991; Shioiri et al. i991). Therefore, the present study was de signed to extend these observations by comparing the effects of neonatal desipramine and saline administration on free-running circadian rhythmicity in adulthood. Two fundamental properties of a circadian pacemaker system are its free-running period in constant darkness and its response to photic stimulation. Since either or both of these properties may be affected by a given condition or treatment, this study examined free-running rhythms in both constant darknessand in constant light. Since a number of pharmacological treatments, including chro- nic desipramine administration (Wollnik 1992), have been