The putative presence of the cannabinoid receptor type 2 (CB₂-R) in the central nervous system is still a matter of debate. Although first described in peripheral and immune tissues, evidence suggesting the existence of CB₂-Rs in glial cells and even neurons has been made available more recently. By taking advantage of newly designed CB₂-R mRNA riboprobes, we have demonstrated by in situ hybridization and PCR the existence of CB2-R transcripts in a variety of brain areas of the primate Macaca fascicularis, including the cerebral cortex and the hippocampus, as well as in the external and internal divisions of the globus pallidus, both pallidal segments showing the highest abundance of CB₂-R transcripts. In this regard, the presence of the messenger coding CB₂-Rs within the pallidal complex highlights their consideration as potential targets for the treatment of movement disorders of basal ganglia origin.

Although type 1 cannabinoid receptors (CB₁Rs) are expressed abundantly throughout the brain, the presence of type 2 cannabinoid receptors (CB₂Rs) in neurons is still somewhat controversial. Taking advantage of newly designed CB₁R and CB₂R mRNA riboprobes, we demonstrate by PCR and in situ hybridization that transcripts for both cannabinoid receptors are present within labeled pallidothalamic-projecting neurons of control and MPTP-treated macaques, whereas the expression is markedly reduced in dyskinetic animals. Moreover, an in situ proximity ligation assay was used to qualitatively assess the presence of CB₁Rs and CB₂Rs, as well as CB₁R–CB₂R heteromers within basal ganglia output neurons in all animal groups (control, parkinsonian and dyskinetic macaques). A marked reduction in the number of CB₁Rs, CB₂Rs and CB₁R–CB₂R heteromers was found in dyskinetic animals, mimicking the observed reduction in CB₁R and CB₂R mRNA expression levels. The fact that chronic levodopa treatment disrupted CB₁R–CB₂R heteromeric complexes should be taken into consideration when designing new drugs acting on cannabinoid receptor heteromers.