Opposite function of dopamine D1 and N-methyl-D-aspartate receptors in striatal cannabinoid-mediated signaling.
It is well established that the cannabinoid and dopamine systems interact at various levels to regulate basal ganglia function. Although it is well known that acute administration of cannabinoids to mice can modify dopamine-dependent behaviors, the intraneuronal signaling pathways employed by these agents in the striatum are not well understood. Here we used knockout mouse models to examine the regulation of striatal extracellular-signal-regulated kinases 1 and 2 (ERK1/2) signaling by behaviorally relevant doses of cannabinoids. This cellular pathway has been implicated as a central mediator of drug reward and synaptic plasticity. In C57BL/6J mice, acute administration of the cannabinoid agonists, (-)-11-hydroxydimethylheptyl-Δ8-tetrahydrocannabinol (HU-210) and delta-9-tetrahydrocannabinol (Δ(9) -THC), promoted a dose- and time-dependent decrease in the phosphorylation of ERK1/2 in dorsal striatum. Co-administration of the CB1 cannabinoid receptor antagonist N-(Piperidin-1-yl)-5-(4-iodophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide(AM251) with HU-210 prevented ERK1/2 inactivation, indicating a requirement for activation of this receptor. In dopamine D1 receptor knockout animals treated with HU-210, the magnitude of the HU-210-dependent decrease in striatal ERK1/2 signaling was greater than in wild-type controls. In contrast, HU-210 administration to N-methyl-D-aspartate receptor knockdown mice was ineffective at promoting striatal ERK1/2 inactivation. Genetic deletion of other potential ERK1/2 mediators, the dopamine D2 receptors or β-arrestin-1 or -2, did not affect the HU-210-induced modulation of ERK1/2 signaling in the striatum. These results support the hypothesis that dopamine D1 receptors and N-methyl-D-aspartate receptors act in an opposite manner to regulate striatal CB1 cannabinoid receptor signal transduction.
Department of Cell Biology, Duke University Medical Center, Durham, NC, USA. t.daigle@cellbio.duke.edu
Tanya L
TL
Daigle
William C
WC
Wetsel
Marc G
MG
Caron
D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D019390:Arrestins / Q000172:deficiency; D001831:Body Temperature / Q000187:drug effects; D002186:Cannabinoids / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000172:deficiency; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000031:analogs & derivatives / Q000494:pharmacology; D004338:Drug Combinations; D018691:Excitatory Amino Acid Antagonists; D005260:Female; D046352:Freezing Reaction, Cataleptic / Q000187:drug effects; D005625:Frontal Lobe / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D058748:Pain Perception / Q000187:drug effects; D010766:Phosphorylation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000172:deficiency / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000172:deficiency; D016194:Receptors, N-Methyl-D-Aspartate / Q000172:deficiency / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins
D018712:Analgesics, Non-Narcotic; C000605255:Arrb1 protein, mouse; D019390:Arrestins; D002186:Cannabinoids; D050483:Dopamine Plasma Membrane Transport Proteins; D004338:Drug Combinations; D018691:Excitatory Amino Acid Antagonists; C409466:NR1 NMDA receptor; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D016194:Receptors, N-Methyl-D-Aspartate; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins; C103505:AM 251; D013759:Dronabinol; C062018:HU 211