Delayed Plasticity of the Mesolimbic Dopamine System Following Neonatal 6-OHDA Lesions PAUL A. FROHNA, BETHANY S. NEAL-BELIVEAU, AND JEFFREY N. JOYCE* Christopher Parkinson’s Disease Research Center, Sun Health Research Institute, Sun City, Arizona 85372 KEY WORDS tyrosine hydroxylase; dopamine transporter; gene; basal ganglia; substantia nigra ABSTRACT In this study, we determined the ontogenetic profile (at postnatal days 7, 14, 35, and 90) of tyrodine hydroxylase (TH) mRNA in the ventral mesencephalon, and the levels of TH immunoreactivity (TH-IR) and dopamine (DA) transporter (DAT) sites in the striatum of rats that had received intrastriatal 6-hydroxy dopamine (6-OHDA) or vehicle lesions on day of birth (DO) or postnatal day 1 (P1). TH-IR was significantly decreased in all quadrants of the caudate-putamen at all time points, while TH-IR in the nucleus accumbens was unchanged, as compared to controls. Relative to the earliest time point (P7 lesion group), TH-IR recovered significantly in the medial caudate-putamen (CPu) of the P14, P35 and P90 6-OHDA-lesioned groups. Quantitative autoradiography of [ 3 H]-mazindol binding to DAT sites showed significant, lesion-induced losses throughout the caudate- putamen of the 6-OHDA-lesioned groups at all time points and did not show appreciable recovery. Using in situ hybridization, significant (P , .05) decreases in TH mRNA levels were found at all time points in the lateral and medial substantia nigra pars compacta of 6-OHDA-lesioned animals. TH mRNA levels in the rostral ventral tegmental area (VTA), which were significantly decreased at P7, P14 and P35, returned to control levels at P90. TH mRNA levels in the caudal VTA were unchanged through P35 and became significantly elevated as compared to controls (122%, P , .05) by P90. Thus, recovery of TH-IR in the medial caudate-putamen occurred prior to the elevation in levels of TH mRNA of the VTA. Our findings suggest that compensation exists in early development in certain subpopulations of mesostriatal DA neurons that differs from that in the adult. Synapse 25:293–305, 1997. r 1997 Wiley-Liss, Inc. INTRODUCTION Administration of the dopaminergic neurotoxin, 6-hy- droxydopamine (6-OHDA), during development has allowed the study of the developmental plasticity of the dopamine (DA) systems of the rodent basal ganglia (See Joyce et al., 1996, for review). Neonatal 6-OHDA lesions are known to cause behavioral deficits that are very different from those seen following adult 6-OHDA le- sions (Breese et al., 1984; 1987; Criswell et al., 1989; Neal and Joyce, 1991). Extensive lesions of the striatal DA systems in adult rats produce a Parkinson-like syndrome consisting of bradykinesia, aphagia, adipsia, and sensory neglect (Marshall et al., 1974; Zigmond et al., 1984), that can recover over time, while neonatally lesioned animals fail to show similar behavioral sensi- tivity to even complete (.99%) loss of striatal DA (Breese et al., 1984; Bruno et al., 1985; Criswell et al., 1989). Neonatal and adult 6-OHDA lesions induce a number of compensatory responses in the presynaptic DA sys- tems that are thought to be involved in the recovery of function (Castaneda et al., 1990; Frohna et al., 1993; Pasinetti et al., 1989, 1992; Snyder et al., 1990; Stachow- iak et al., 1987; Zigmond et al., 1984). An important mechanism of recovery is the increase in DA efflux from the remaining dopaminergic terminals (Castaneda et al., 1990; Onn et al., 1986; Robinson et al., 1990; Snyder et al., 1990; Stachowiak et al., 1987). In adult rats with partial DA lesions, increases in the rate of DA synthesis occur by increasing the affinity of tyrosine hydroxylase (TH) for its cofactor and by increasing the amount of TH present (Onn et al., 1986; Wolf et al., 1989; Zigmond et al., 1984), which leads to higher extracellular levels of PaulA. Frohna’s current address is Department of Pharmacology, The Univer- sity of Pennsylvania School of Medicine, Philadelphia, PA 19104. Bethany S. Neal-Beliveau’s current address is Department of Psychology, Purdue School of Science, IUPUI, Indianapolis, IN 46202. *Correspondence to: Dr. Jeffrey N. Joyce, Christopher Parkinson’s Disease Research Ctr., Sun Health Research Institute, 10515 W. Santa Fe Dr., Sun City, AZ 85372. Received 6 May 1996; Accepted 16 July 1996. SYNAPSE 25:293–305 (1997) r 1997 WILEY-LISS, INC.