The endocannabinoid system is emerging as a potential alternative to the dopaminergic system for the treatment of Parkinson's disease. Like all emerging targets, validation of this system's potential for treating human Parkinsonism necessitates testing in animal models of the condition. However, if components of the endocannabinoid system are altered by the induction of a Parkinsonian state in animal models, this could have an impact on the interpretation of such preclinical experiments. This study sought to determine if expression of the CB1 subtype of cannabinoid receptor is altered in the two most commonly used rat models of Parkinson's disease. Parkinsonian lesions were induced by stereotaxic injection of 6-hydroxydopamine into the axons (medial forebrain bundle) or terminals (striatum) of the nigrostriatal pathway. On days 1,3,7,14 and 28 post-lesion, rats were sacrificed and brains were processed for tyrosine hydroxylase and CB1 receptor immunohistochemistry. The CB1 receptor was expressed strongly in the substantia nigra pars reticulata, minimally overlapping with tyrosine hydroxylase immunoreactivity in the pars compacta. Interestingly, while there was little change in CB1 receptor expression following axonal lesion, expression of the receptor was significantly reduced following terminal lesion. Loss of CB1 receptor expression in the pars reticulata correlated significantly with the loss of striatal and nigral volume after terminal lesion indicating this may have been due to 6-hydroxydopamine-induced non-specific damage of striatonigral neurons which are known to express CB1 receptors. Thus, this result has implications for the choice of model and interpretation of studies used to investigate potential cannabinoid-based therapies for Parkinson's disease as well as striatonigral diseases such as Huntington's disease and Multiple Systems Atrophy. (C) 2010 Elsevier Inc. All rights reserved.