ELSEVIER Ontogenetic Development of the Locomotor Response to Levodopa in the Rat Nikolaos Grigoriadis, MD, Constantina Simeonidou, PhD, Sotirios A. Parashos, MD, Maria Albani, MD, PhD, and Olympia Guiba-Tziampiri, MD, PhD Administration of exogenous levodopa triggers loco- motion in young rats prior to the onset of quadripedal movement. The same substance decreases locomotion in adult animals. The ontogenetic development of the response to ievodopa was investigated in rats. Intra- peritoneal injection of levodopa (150 mg/kg body weight) caused characteristic "crawling" or "swim- ming-like" locomotion patterns in 5- to 6-day-old an- imals. Noradrenergic mechanisms may be involved in this behavior. In 18- to 20-day-old rats, levodopa caused excessive locomotor activity, including running, jumping, and wall climbing. This effect can be attrib- uted to the activation of postsynaptic dopaminergic re- ceptors that are already present during the early stages of life. At 25-30 days of age, levodopa-induced motor activity was decreased in comparison with that of the 18- to 20-day-old rats, possibly due to changing pat- terns of D1/D2-dopamine receptor subtype interactions. In contrast to observations in younger rats, the same dose of levodopa suppressed motor activity in 60- to 75-day-old rats. The presence of functional dopamine autoreceptors at this age may account for the change. Grigoriadis N, Simeonidou C, Parashos SA, Albani M, Guiba-Tziampiri O. Ontogenetic development of the loco- motor response to levodopa in the rat. Pediatr Neurol 1996;14:41-45. Introduction Dopamine agonists induce well-described motor behav- iors in laboratory animals. In rats, such agonists elicit a set of "particular motor and behavioral symptoms" [1], that may include locomotor or stereotypic behaviors. Both D~- and D2-dopamine receptors must be activated for the full expression of dopamine-mediated behaviors [2]. Strong synergistic interactions between the two dopamine recep- tor subtypes have been observed in certain behavioral ef- fects of both agonists and antagonists of these receptors [3,4]. Unlike dopamine agonists, levodopa, a precursor of do- pamine, has an inhibitory effect on locomotor behavior and produces only minimal stereotypies at high doses in adult rats [1,5,6]. In contrast, both levodopa and direct catecholamine receptor agonists enhance locomotion in neonate, infant, and adolescent rats [ 1,7-10]. The cause of this reversal of the response to levodopa remains unclear. Recent studies have elucidated the maturational process of the dopaminergic system in the rat basal ganglia with regard to its different components. Tyrosine hydroxylase activity (evidence of functional dopaminergic terminals) is present in the caudate-putamen prenatally [11], and the dopaminergic innervation of the striatum is complete by the third or fourth week of life [ 12]. D ~- and D2-dopamine receptors are already present on postnatal day 1 and 5 respectively [13], reaching adult levels on approximately postnatal day 30. D~ sites do not increase significantly before the seventh postnatal week, whereas D 2 receptors become functional during the third to fourth week [14]. Dopamine autoreceptors are not functionally significant until after postnatal day 28 [15]. Dopamine uptake sites are present at birth and their numbers seem to parallel D~ numbers thereafter [13,14]. The enzymes responsible for converting levodopa to dopamine and subsequently to nor- adrenaline (aromatic-L-amino acid decarboxylase and do- pamine-[3-hydroxylase, respectively), as well as the major monoamine catabolizing enzymes (catechol-O-methyl transferase and monoamine oxidase), are present in the rat brain prenatally [16-19]. Our study was undertaken to identify the locomotor response to levodopa during development and to investi- From the Departmentof Physiologyand Pharmacology;Faculty of Medicine; Aristotle University of Thessaloniki; Thessaloniki, Greece. Communications should be addressed to: Dr. Parashos; Departmentof Neurology; Mayo Clinic: Rochester, MN 55905. Received July 3l, 1995; accepted October 13, 1995. © 1996 by Elsevier Science Inc. ° 0887-8994/96/$15.00 Grigoriadis et al: Ontogeny of the Response to Levodopa 41 SSDI 0087-8994(95)00225-1