Abstract
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 point 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 discusses anatomical, biochemical and pharmacological evidences supporting a role for the endogenous cannabinoid system in the modulation of dopaminergic transmission. Cannabinoid CB1 receptors 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. CB1 receptors co-localize with dopamine D1/D2 receptors in dopamine projecting fields. Manipulation of dopaminergic transmission is able to alter the synthesis and release of anandamide as well as the expression of CB1 receptors. Additionally, CB1 receptors can switch its transduction mechanism to oppose to the ongoing dopamine signaling. Acute blockade of CB1 receptor potentiates the facilitatory role of dopamine D2 receptor agonists on movement. CB1 stimulation 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.
Highlights
The endocannabinoid system in the brain is configured by the central cannabinoid receptor, CB1 (Devane et al, 1988), and the endogenous ligands anandamide (Devane et al, 1992) and 2-arachidonyl glycerol (Mechoulam et al, 1995; Stella et al, 1997)
In order to understand that contribution to dopamine-related neuropsychiatric conditions we need to solve one of the striking challenges in the cannabinoid field: the explanation of the physiological rote of a system densely present in dopamine-projecting brain areas, with a highly preserved neurobiological properties throughout the evolution, but with a low tonic activity as revealed by functional antagonism studies (Howlett, 1995; Gueudet et al, 1995; Navarro et al, 1997)
We will propose a model under which explore the potential relevance of these interactions for the understanding and treatment of neurodegenerative disorders such as Parkinson's disease, and psychiatric syndromes such as schizophrenia
Summary
Neurotoxicity Research,Vol 3, pp. 23-35 Reprints available directly from the publisher Photocopying permitted by license only 9 2001 OPA (Overseas Publishers Association) N.V. Published by license under the Harwood Academic Publishers imprint, part of The Gordon and Breach Publishing Group.
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