Dopamine Cell Degeneration Induced by Intraventricular Administration of 6-Hydroxydopamine in the Rat: Similarities with Cell Loss in Parkinson’s Disease Manuel Rodrı ´guez,* Pedro Barroso-Chinea,† Patricio Abdala,* Jose ´ Obeso,‡ and Toma ´s Gonza ´ lez-Herna ´ ndez§ *Department of Physiology and §Department of Anatomy, Faculty of Medicine, University of La Laguna, †Canary University Hospital, La Laguna, Tenerife, Spain; ‡Movement Disorders and Basal Ganglia Unit, Department of Neurology and Neurosurgery, Area of Neuroscience, Clı´nica Universitaria and Medical School, University of Navarra, Pamplona, Spain Received July 7, 2000; accepted December 19, 2000 In an attempt to find a convenient rat model to study cell vulnerability in Parkinson’s disease, we have in- vestigated the cell-loss profile in different midbrain dopaminergic nuclei and subnuclei of rats injected with 6-hydroxydopamine (6-OHDA) in the third ventri- cle. Following administration of different doses (5– 1000 g) of 6-OHDA, motor behavior was evaluated and tyrosine hydroxylase-immunostained neurons were counted in the A8 group and different subdivi- sions of A9 and A10 groups. Animals developed hypo- kinesia, repetitive chewing movements, and catalep- sia. Signs of cell degeneration were evident from the first day after injection, reaching the definitive pat- tern at the end of the first week. There was a similar degeneration in both brain sides, the A9 group show- ing the highest degree of cell-loss, followed by A8 and A10 groups. In the A9 group, the degeneration mostly affected those subgroups located in its ventral, lateral, and posterior regions. In the A10 group the degenera- tion mainly affected the parabrachial pigmented nu- cleus, the paranigral nucleus and the ventral tegmen- tal area. This topographic pattern of degeneration is very similar to that previously described in Parkin- son’s disease, suggesting that this model may be a useful tool in the study of the cell vulnerability mech- anisms in this neurodegenerative disorder. In addi- tion, our results also showed that small dopaminergic neurons are more resistant to degeneration than the large ones. In some DA subgroups, the cells that con- tained calbindin but not calretinin were less vulnera- ble to the neurotoxic effect of 6-OHDA. © 2001 Academic Press Key Words: dopamine; 6-hydroxydopamine; Parkin- son’s disease; animal model; vulnerability. INTRODUCTION Parkinson’s disease (PD) is a basal ganglia disorder induced by the degeneration of mesencephalic dopami- nergic cells (DA cells). Although different mechanisms have been proposed (40, 45, 47, 53, 57, 61, 68, 93, 101, 103, 111, 126), the cause of this degeneration remains unknown (93). Because it cannot be easily studied in the patients’ brains, there is considerable interest in finding suitable animal models to explore the underly- ing mechanisms of DA-cell degeneration and to test new therapeutic strategies directed toward the preven- tion of this degenerative process. Parkinsonian brains show a very specific pattern of DA-cell loss. Different studies (5, 21, 39, 48, 49, 50, 51) have reported that the degeneration is highest in the ventral, posterior, and lateral regions of substantia nigra (SN, A9 DA group). A8 and A10 groups also degenerate, the A8 cells being less susceptible than A9 cells but more susceptible than A10 cells (21, 38, 39, 55). In the A10 group, the degeneration is particularly evident in the parabraquial and paranigral nuclei (63– 65, 88). Agents involved in the differential vulnerabil- ity of each mesencephalic DA-cell group may be key factors in the origin of PD (15, 26, 56, 60, 89, 105, 127). An animal model mimicking the topographic pattern of cell loss of PD could be very useful for studying why particular cells display a higher resistance (or vulner- ability) to degeneration than others. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) are the main neuro- toxins used to degenerate DA cells in animal models of PD. Although MPTP induces a motor disturbance similar to that observed in PD (37, 78), the topographical pattern of MPTP-lesion in the mouse and monkey is not exactly the same as that reported in these patients (23, 100, 116, 125). In addition, it is not very effective in the rat, where the unilateral injection of 6-OHDA in the SN, the medial forebrain bundle or striatum is the procedure which is the most extensively used (3, 8, 9, 14, 16, 19, 24, 42– 44, 54, 73, 74, 98, 106, 110, 112, 118 –120, 124). However, the direct injection of 6-OHDA in the brain tissue causes a focal lesion around the cannula tip (or a global destruc- Experimental Neurology 169, 163–181 (2001) doi:10.1006/exnr.2000.7624, available online at http://www.idealibrary.com on 163 0014-4886/01 $35.00 Copyright © 2001 by Academic Press All rights of reproduction in any form reserved.