European Journal of Pharmacology, 74 ( 1981) 295- 301 295 Elsevier/North-Holland Biomedical Press IRON DEFICIENCY-INDUCED CIRCADIAN RHYTHM REVERSAL OF DOPAMINERGIC-MEDIATED BEHAVIOURS AND THERMOREGULATION IN RATS MOUSSA B.H. YOUDIM, SHLOMO YEHUDA * and YEHUDA BEN-URIAH * Department of Pharmacology, Faculty of Medicine, Technion, Haifa, Israel, and * Psychopharmaeology Laborato~, Department of Psychology, Bar-Ilan University, Ramat Gan, Israel Received 27 February 1981, revised MS received 22 May 1981, accepted 22 June 1981 M.B.H. YOUDIM, S. YEHUDA and Y. BEN-URIAH, Iron deficiency-reduced circadian rhythm reversal of dopaminergic-mediated behaviours and thermoregulation in rats, European J. Pharmacol. 74 (1981) 295-301. An iron-free diet for 28 days caused a reduced level of iron in the blood. Iron deficient rats exhibited a lower level of motor activity and reversed circadian rhythms of thermoregulation and motor activity. The hypothermic effect of d-amphetamine was significantly reduced in iron deficient rats, and the magnitude of this effect was correlated with the decrease in iron in the blood and brain. The hypermotility effect of d-amphetamine was also significantly reduced. Apomorphine-induced s!ereotyped behaviour was greater during the light period in contrast to that of control rats. The results of this study indicate that iron plays a major role in the normal function of the monoaminergic system in the brain, particularly in the dopaminergic system, via modification of dopaminergic receptors. Reversed circadian rhythm Stereotyped behaviour Dopamine receptor Motor activity Iron dificiency d-Amphetamine Hypothermia 1. Introduction Iron deficiency is the most prevalent nutritional disorder in man (Garby, 1973; Kersner and Kalk, 1973) and is thought to affect behaviour in children and adults (Jacobs and Worwood, 1974; Pollitt and Liebel, 1976; Oski, 1979; Youdim and Ashkenazi, 1981). Recently Youdim et al. (1979) have shown that rats made nutritionally iron defi- cient exhibited abnormal behaviour. However, very few studies were done on specific behaviour in these animals. The monoamine neurotransmitters, dopamine (DA), noradrenaline (NA), and 5- hydroxytryptramine (5-HT), have been implicated in psychiatric and neurological diseases in man as well as in certain behaviours in the rat. In view of the involvement of iron as a possible co-factor for the metabolic enzymes of monoanaine neurotrans- mitters and in supplying oxygen to the tissues, it is conceivable that iron deficiency would result in altered behaviour. Motor activity is one of the behaviours which has been examined in iron deficient rats. It has been shown that the 24-h motor activity of iron- deficient rats was significantly reduced (Youdim et al., 1979). Moreover, iron deficient rats exhibited a lower level of drug-induced motor activity without a significant change in the level of brain DA, NA or 5-HT. These studies indicated a possible reduc- tion in the activity of the dopaminergic pathway, most probably at a post-synaptic site (Youdim and Green, 1977; Ashkenazi et al., 1980; Youdim et al., 1981). Central dopaminergic neurons are known to mediate among others, d-amphetamine-induced poikilothermia (Yehuda and Wurtman, 1975) and stereotyped behaviour (Costal and Naylor, 1977). d-Amphetamine induces hyperthermia in rats kept at 20-37°C, but causes hypothermia in rats kept at 4°C (Yehuda and Wurtman, 1972a,b; 1975). The thermoregulatory effect of amphetamine is mediated via the release of DA in the mesolimbic dopaminergic pathway (Yehuda and Wurtman, 1972b), whereas stereotyped behaviour is mediated by the nigrostriatal DA pathways when 6- hydroxydopamine lesions are made. However if 0014-2999/81/0000-0000/$02.50 © 1981 Elsevier/North-Holland Biomedical Press