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The familial form of amyotrophic lateral sclerosis (FALS) has been linked in some cases to dominant mutations in the gene encoding the Cu/Zn superoxide dismutase (SOD1) mutation. Transgenic mice bearing the G93A SOD1 mutation develop clinical symptoms and pathological features similar to those described in the human disease and represent a good model to explore the potential benefit of therapeutic agents. Using this animal model, we tested the efficacy of morphine and tianeptine treatments, separately and in association, on both disease progression and survival. Acute injection of either of them, administered daily and before the onset of the disease, significantly prolonged the survival of the transgenic mice.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease which affects cortical, bulbar and spinal motoneurones. The cause of the disease, probably due to several factors, is still unknown and the survival delay of patients with ALS generally does not exceed 3-5 years. Animals models provide a unique opportunity to study pathological features and to evaluate potential therapeutic effects of news treatments. Natural disease models, neurotoxins or viral-induced models and more recently transgenic models with genetic anomalies mimicking those found in ALS patients have been extensively studied. This review summarizes the most relevant clinical and pathological advances issuing from these animal studies.

The present study was undertaken to examine the adaptive changes occurring 1 and 6 months after moderate or severe unilateral 6-hydroxydopamine-induced lesions confined to the lateral part of the rat substantia nigra pars compacta (SNC). The expression of tyrosine hydroxylase (TH) enzyme was analyzed in the remaining dopaminergic nigral cell bodies and in the corresponding striatal nerve endings. In the cell bodies of the lesioned SNC, TH mRNA content was increased (+20 to +30%) 6 months after the lesion without changes in cellular TH protein amounts. The depletion of TH protein in the nerve terminal area was less severe than the percentage of cell loss observed in the SNC at 1- and 6-month postlesion intervals. Moreover, the decrease in TH protein in the ipsilateral striatum was less pronounced 6 months after lesion than 1 month after. That no corresponding change in TH protein content was observed in the cell bodies at a time when TH increased in nerve terminals suggests that the newly synthesized protein is probably rapidly transported to the striatal fibers. These results suggest the existence of a sequence of changes in TH expression between cell bodies and fibers, occurring spontaneously after partial denervation of the nigrostriatal pathway.

The ascending dopaminergic pathway of 3-day-old rats has been unilaterally destroyed by the injection of 6-hydroxydopamine into the lateral hypothalamus. Five days later, a suspension containing embryonic dopaminergic neurones was injected in the lesioned neostriatum. Rotational responses to dopaminergic agonists were tested eight months after grafting and animals were killed one month later. Neostriatal dopaminergic D1 and D2 receptors were examined using autoradiography while changes in D2 receptor mRNA levels were studied by in situ hybridization. The lesion induced a behavioural hypersensitivity - as manifested in contralateral rotations - to dopaminergic D1 (SKF 38393) or D2 (LY 171555) agonists which was abolished by the graft. Density of D1 receptors was not affected by the lesion while D2 receptors density was increased by 20-25% in the more rostral part of the neostriatum. Changes in D2 mRNA after the lesion paralleled those observed for D2 receptor density, i.e. D2 mRNA level was increased by 15-19% in the rostral neostriatum. The graft did not influence D1 receptor densities but reversed the post-lesion increase of D2 receptors associated parameters. It is concluded that dopaminergic grafts implanted in neonatal hosts are able to normalise the density of D2 receptors by an action on their synthesis.

Unilateral 6-hydroxydopamine (6-OHDA)-induced lesion of the nigrostriatal dopamine (DA) pathway causes a significant increase of preproenkephalin (PPE) messenger RNA (mRNA) levels in the DA-depleted striatum in rat brain. Using an in situ hybridization (ISH) technique and computer-assisted microdensitometry, we quantified the changes in PPE mRNA levels in the striatum. Seven months after lesion, levels of PPE mRNA were 75% higher in the DA-depleted striatum than in the contralateral control striatum of the same animal or in the striatum of sham control animals. The implantation of embryonic dopaminergic neurons into the denervated striatum led to a complete reversal of this increase and, in grafted animals, levels of PPE mRNA were at control values. Moreover, this reversal extended beyond the areas reinnervated by the grafted dopaminergic neurons.