Neonatal 6-Hydroxydopamine Administration to Mice Is Fatal

Abstract

Depletion of dopamine in adult rats by treatment with the neurotoxin 6-hydroxydopamine (6-OHDA) causes severe deficits in feeding, drinking, and movement that often lead to death. However, when neonatal rats are treated similarly, they survive normally, suggesting that compensatory adaptation to dopamine depletion occurs. In contrast, dopamine-deficient mice that have a selective genetic deficiency in dopamine production die 2–4 weeks after birth. Thus, we tested the hypothesis that killing dopaminergic neurons with 6-OHDA might promote survival of dopamine-deficient mice. Body weights, motor coordination, catecholamine levels, and survival were monitored for several weeks after bilateral administrations of 6-OHDA to 3-day-old mice. Some treated mice were raised in a heated chamber to help them conserve energy. The results demonstrate that regardless of genotype or environmental temperature, bilateral neonatal 6-OHDA lesions are lethal to mice.

Dopamine Signaling in the Dorsal Striatum Is Essential for Motivated Behaviors

“…However, subsequent experiments suggest that the lesions were incomplete in those studies, because surviving rats died if residual dopamine synthesis was inhibited 21,22 . We demonstrated that neonatal ablation of dopamine neurons in dopamine‐deficient (DD) mice does not rescue them, contrary to what would be predicted if killing the neurons allowed dopamine‐independent compensatory adaptations 23 . Furthermore, killing dopamine neurons of DD mice does not hasten starvation, indicating that these neurons do not make other signaling molecules that are essential for survival.…”

“…21,22 We demonstrated that neonatal ablation of dopamine neurons in dopamine-deficient (DD) mice does not rescue them, contrary to what would be predicted if killing the neurons allowed dopamine-independent compensatory adaptations. 23 Furthermore, killing dopamine neurons of DD mice does not hasten starvation, indicating that these neurons do not make other signaling molecules that are essential for survival. Because complete bilateral 6-OHDA lesions produce severe aphagia that requires hand-feeding to keep animals alive, those animals are difficult to maintain and to study.…”

Restriction of dopamine signaling to the dorsolateral striatum is sufficient for many cognitive behaviors

“…However, these models make no distinction between loss of DA signaling versus loss of DA neurons and do not separate performance from cognitive deficits. They have also been difficult to interpret because rodents with complete lesions are very hypoactive and can only be kept alive by forced feeding (38,47); the animals that eat on their own have incomplete lesions (48). Because restoring DA to 5% of normal levels is sufficient for mice to eat adequately (29), we argue that most experiments performed with DA lesions in the dorsal striatum were done on animals with incomplete lesions.…”