In adult rats, the expression of transcription factor proteins c-Jun and CREB and their colocalization with tyrosine hydroxylase (TH) were investigated in neurons of the substantia nigra compacta (SNC) axotomized by stereotaxic unilateral transection of the medial forebrain bundle (MFB). Axotomized SNC neurons were identified by injection of the retrograde tracer horseradish-peroxidase-coupled-gold (HRP-gold) into the ipsilateral striatum 5 days prior to MFB transection. Nuclear c-Jun immunoreactivity (IR) appeared 36 h after MFB transection in SNC neurons, was maximal after 5 days, and declined after 10 days. c-Jun-IR was visible in HRP-gold-labeled SNC neurons, demonstrating that c-Jun is in fact expressed in axotomized neurons. The constitutively expressed CREB (calcium/cAMP response element-binding protein, syn. CREB-1) was present in apparently all neuronal and glial cells in the brains of untreated rats including those SNC neurons that coexpressed TH. Three days following MFB transection, the nuclear CREB-IR disappeared in the axotomized SNC neurons labeled by TH-IR and was almost completely absent after 20 days in this neuronal population. The TH-IR rapidly declined 5 days after MFB transection, and 10 and 100 days post-axotomy the number of TH-labeled neurons was reduced by 52 and 80%, respectively. During this period, the majority of surviving TH positive neurons coexpressed c-Jun but were immunonegative for CREB. Between 3 and 60 days following MFB transection, the number of CREB-labeled glial cell nuclei increased in the ipsilateral substantia nigra by about 80%. Concomitantly, expression of GFAP, a marker protein for astrocytes, was also enhanced whereas nuclear c-Jun-, JunD-, and c-Fos-IR did not change in glial cells. These findings demonstrate that c-Jun can be expressed in axotomized neurons during the absence of CREB and suggest a role of c-Jun in the transcriptional control of the TH gene.