Motor effects of the non-psychotropic phytocannabinoid cannabidiol that are mediated by 5-HT1A receptors.
The broad presence of CB1 receptors in the basal ganglia, mainly in GABA- or glutamate-containing neurons, as well as the presence of TRPV1 receptors in dopaminergic neurons and the identification of CB2 receptors in some neuronal subpopulations within the basal ganglia, explain the powerful motor effects exerted by those cannabinoids that can activate/block these receptors. By contrast, cannabidiol (CBD), a phytocannabinoid with a broad therapeutic profile, is generally presented as an example of a cannabinoid compound with no motor effects due to its poor affinity for the CB1 and the CB2 receptor, despite its activity at the TRPV1 receptor. However, recent evidence suggests that CBD may interact with the serotonin 5-HT1A receptor to produce some of its beneficial effects. This may enable CBD to directly influence motor activity through the well-demonstrated role of serotonergic transmission in the basal ganglia. We have investigated this issue in rats using three different pharmacological and neurochemical approaches. First, we compared the motor effects of various i.p. doses of CBD with the selective 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OH-DPAT; i.p.). Second, we investigated whether the motor effects of CBD are sensitive to 5-HT1A receptor blockade in comparison with CB1 receptor antagonism. Finally, we investigated whether CBD was able to potentiate the effect of a sub-effective dose of 8-OH-DPAT. Our results demonstrated that: (i) only high doses of CBD (>10 mg/kg) altered motor behavior measured in a computer-aided actimeter; (ii) these alterations were restricted to vertical activity (rearing) with only modest changes in other parameters; (iii) similar effects were produced by 8-OH-DPAT (1 mg/kg), although this agonist affected exclusively vertical activity, with no effects on other motor parameters, and it showed always more potency than CBD; (iv) the effects of 8-OH-DPAT (1 mg/kg) and CBD (20 mg/kg) on vertical activity were reversed by the 5-HT1A receptor antagonist WAY-100,635 (0.5 mg/kg; i.p.); (v) the effects of CBD (20 mg/kg) on vertical activity were not reversed by the CB1 receptor antagonist rimonabant (0.1 mg/kg; i.p.); (vi) the effect of 8-OH-DPAT on vertical activity was associated with an increase in serotonin content in the basal ganglia, a neurochemical change not produced by CBD (20 mg/kg); and (vii) CBD at a dose of 20 mg/kg was able to enhance motor effects of a sub-effective dose of 8-OH-DPAT (0.1 mg/kg), producing the expected changes in serotonergic transmission in the basal ganglia. Collectively, these results suggest that CBD may influence motor activity, in particular vertical activity, and that this effect seems to be dependent on its ability to target the 5-HT1A receptor, a mechanism of action that has been proposed to account for its anti-emetic, anxiolytic and antidepressant effects.
Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Investigación en Neuroquímica, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Spain.
Francisco
F
Espejo-Porras
Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Investigación en Neuroquímica, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Spain. Electronic address: jjfr@med.ucm.es.
Javier
J
Fernández-Ruiz
School of Medical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen, UK.
Roger G
RG
Pertwee
Department of Medicinal Chemistry and Natural Products, Medical Faculty, Hebrew University, Jerusalem, Israel.
Raphael
R
Mechoulam
Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Investigación en Neuroquímica, Facultad de Medicina, Universidad Complutense, Madrid, Spain; Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), Spain; Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), Spain. Electronic address: conchig@med.ucm.es.
Concepción
C
García
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002185:Cannabidiol / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000378:metabolism; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D018490:Serotonin Agents / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000378:metabolism
D018490:Serotonin Agents; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; D015102:3,4-Dihydroxyphenylacetic Acid; D044282:Receptor, Serotonin, 5-HT1A; D002185:Cannabidiol; D012701:Serotonin; D018698:Glutamic Acid; D006897:Hydroxyindoleacetic Acid; D004298:Dopamine
5-HIAA; 5-HT; 5-HT(1A) Receptors; 5-HT(1A) receptor; 5-hydroindolacetic acid; 8-OH-DPAT; 8-hydroxy-2-(di-n-propylamino) tetralin; CB(1) receptor; CB(2) receptor; CBD; CBDA; Cannabidiol; DOPAC; GABA; L-3,4-dihydroxyphenylacetic acid; Motor effects; PPAR; Serotonin; TRPV1; TRPV2; Transient receptor potential vanilloid type 1; Transient receptor potential vanilloid type 2; Vertical activity; cannabidiol; cannabidiolic acid; cannabinoid type 1 receptor; cannabinoid type 2 receptor; peroxisome-proliferating activator receptor; serotonin (5-hydroxytryptamine); serotonin type 1A receptor; Δ;(9)-THC; Δ;(9)-tetrahydrocannabinol; γ-aminobutiric acid