Altered melatonin MT1 receptor expression in the ventral midbrain following 6-hydroxydopamine lesions in the rat medial forebrain bundle

The indoleamine hormone melatonin protects dopamine neurons in the rat nigrostriatal pathway following 6-hydroxydopamine lesioning, and an increase in striatal melatonin levels has been detected in this model of Parkinson's disease. Melatonin induces the expression of tyrosine hydroxylase, the rate-limiting enzyme for dopamine synthesis, in the ventral midbrain, where G protein-coupled melatonin receptors are present. Based on the interaction between the melatonergic and dopaminergic systems, we hypothesized that 6-hydroxydopamine-induced degeneration of dopamine neurons would affect the expression of melatonin receptors in the nigrostriatal pathway. Following unilateral injection of 6-hydroxydopamine into the rat striatum or medial forebrain bundle, there was a significant increase in apomorphine-induced contralateral rotations in lesioned animals as compared to sham controls. A loss of tyrosine hydroxylase immunoreactivity and/or immunofluorescence in the striatum and substantia nigra was seen in animals lesioned in either the striatum or medial forebrain bundle, indicating degeneration of dopamine neurons. There were no significant differences in melatonin MT₁ receptor protein expression in the striatum or substantia nigra, between intrastriatally lesioned animals and sham controls. In contrast, lesions in the medial forebrain bundle caused a significant increase in MT₁ receptor mRNA expression (p<0.03) on the lesioned side of the ventral midbrain, as compared with the contralateral side. Given the presence of MT₁ receptors on neurons in the ventral midbrain, these results suggest that a compensatory increase in MT₁ transcription occurs to maintain expression of this receptor and neuroprotective melatonergic signaling in the injured brain.