Nigrostriatal denervation changes the effect of cannabinoids on subthalamic neuronal activity in rats.
BACKGROUND
It is known that dopaminergic cell loss leads to increased endogenous cannabinoid levels and CB1 receptor density.


OBJECTIVE
The aim of this study was to evaluate the influence of dopaminergic cell loss, induced by injection of 6-hydroxydopamine, on the effects exerted by cannabinoid agonists on neuron activity in the subthalamic nucleus (STN) of anesthetized rats.


RESULTS
We have previously shown that Δ(9)-tetrahydrocannabinol (Δ(9)-THC) and anandamide induce both stimulation and inhibition of STN neuron activity and that endocannabinoids mediate tonic control of STN activity. Here, we show that in intact rats, the cannabinoid agonist WIN 55,212-2 stimulated all recorded STN neurons. Conversely, after dopaminergic depletion, WIN 55,212-2, Δ(9)-THC, or anandamide inhibited the STN firing rate without altering its discharge pattern, and stimulatory effects were not observed. Moreover, anandamide exerted a more intense inhibitory effect in lesioned rats in comparison to control rats.


CONCLUSIONS
Cannabinoids induce different effects on the STN depending on the integrity of the nigrostriatal pathway. These findings advance our understanding of the role of cannabinoids in diseases involving dopamine deficits.
Department of Pharmacology, Faculty of Medicine, University of the Basque Country, 48940, Leioa, Vizcaya, Spain.
Teresa
T
Morera-Herreras
José Angel
JA
Ruiz-Ortega
Gurutz
G
Linazasoro
Luisa
L
Ugedo
D000200:Action Potentials; D000704:Analysis of Variance; D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D001479:Basal Ganglia / Q000187:drug effects / Q000378:metabolism*; D048588:Benzoxazines / Q000494:pharmacology; D002186:Cannabinoids / Q000008:administration & dosage / Q000494:pharmacology*; D016009:Chi-Square Distribution; D003714:Denervation / Q000379:methods; D004298:Dopamine / Q000172:deficiency*; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000494:pharmacology; D063388:Endocannabinoids; D007267:Injections; D007276:Injections, Intraventricular; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D009433:Neural Inhibition / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D016627:Oxidopamine / Q000008:administration & dosage; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism*; D020531:Subthalamic Nucleus / Q000187:drug effects* / Q000378:metabolism
D001095:Arachidonic Acids; D048588:Benzoxazines; D002186:Cannabinoids; D063388:Endocannabinoids; D009025:Morpholines; D009281:Naphthalenes; D053284:Polyunsaturated Alkamides; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D013759:Dronabinol; D016627:Oxidopamine; C078814:anandamide; D004298:Dopamine