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Open Access Publications from the University of California

Role of the endogenous cannabinoid system as a modulator of dopamine transmission: Implications for Parkinson's disease and schizophrenia

  • Author(s): Rodríguez de Fonseca, F
  • Gorriti, MA
  • Bilbao, A
  • Escuredo, L
  • García-Segura, LM
  • Piomelli, D
  • Navarro, M
  • et al.
Creative Commons Attribution 4.0 International Public License

The endogenous cannabinoid system is a new signaling system composed by the central (CB1) and the peripheral (CB2) receptors, and several lipid transmitters including anandamide and 2-arachidonylglycerol. This system is the target of natural cannabinoids, the psychoactive constituents of Cannabis sativa preparations (marijuana, hashish). Acute and chronic cannabis exposure has been associated with subjective feelings of pleasure and relaxation, but also to the onset of psychiatric syndromes, a decrease of the efficacy of neuroleptics and alterations in the extrapyramidal system regulation of motor activity. These actions points to a tight association of the cannabinoid system with the brain dopaminergic circuits involved in addiction, the clinical manifestation of positive symptoms of schizophrenia and Parkinson's disease. The present work discuss anatomical, biochemical and pharmacological evidences supporting a role for the endogenous cannabinoid system in the modulation of dopaminergic transmission. Cannabinoid CB1receptors are present in dopamine projecting brain areas. In primates and certain rat strains it is also located in dopamine cells of the A8, A9 and A10 mesencephalic cell groups, as well as in hypothalamic dopaminergic neurons controlling prolactin secretion. CB1receptors co-localize with dopamine D1/D2receptors in dopamine projecting fields. Manipulation of dopaminergic transmission is able of altere the synthesis and release of anandamide as well as the expression of CB1receptors. Additionally, CB1receptors can switch its transduction mechanism to oppose to the ongoing dopamine signaling. Acute blockade of CB1receptor potentiates the facilitatory role of dopamine D2receptor agonists on movement. CB1stimulation results in sensitization to the motor effects of indirect dopaminergic agonists. The dynamics of these changes indicate that the cannabinoid system is an activity-dependent modulator of dopaminergic transmission, an hypothesis relevant for the design of new therapeutic strategies for dopamine-related diseases such as the psychosis and Parkinson's disease.

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