Delta 9-tetrahydrocannabinol-induced MAPK/ERK and Elk-1 activation in vivo depends on dopaminergic transmission.
It is now well established that central effects of Delta 9-tetrahydrocannabinol (THC), the main psychoactive component of marijuana, are mediated by CB1 cannabinoid receptors. However, intraneuronal signalling pathways activated in vivo by THC remain poorly understood. We show that acute administration of THC induces a progressive and transient activation (i.e. phosphorylation) of the mitogen activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) in the dorsal striatum and the nucleus accumbens (NA). This activation, corresponding to both neuronal cell bodies and the surrounding neuropil, is totally inhibited by the selective antagonist of CB1 cannabinoid receptors, SR 141716A. However, blockade of dopaminergic (DA) D1 receptors by administration of SCH 23390, prior to THC, totally prevents ERK activation in the striatum, thus demonstrating a critical involvement of DA systems in THC-induced ERK activation. DA-D2 and glutamate receptors of NMDA subtypes also participate, albeit to a lesser extent, to THC-induced ERK activation in the striatum, as shown after injection of selective antagonists (raclopride and MK801, respectively). Furthermore, THC-induced phosphorylation of the transcription factor Elk-1, and up-regulation of zif268 mRNA expression are blocked by SL327, a specific inhibitor of MAPK/ERK kinase (MEK), the upstream kinase of ERK, as well as SCH 23390. Finally, using the place-preference paradigm, we show that ERK inhibition blocks THC-induced rewarding properties. Altogether, our data strongly support that ERK activation in the striatum is critically involved in long-term neuronal adaptive responses underlying THC-induced long-term behaviours.
Valjent
E
E
Laboratoire Signalisation Neuronale et Régulations Géniques, CNRS/Université Pierre et Marie Curie, FRE 2371, 9 quai Saint Bernard, 75005 Paris, France.
Pagès
C
C
Rogard
M
M
Besson
M J
MJ
Maldonado
R
R
Caboche
J
J
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001552:Benzazepines / Q000494:pharmacology; D003213:Conditioning, Psychological / Q000187:drug effects / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism*; D018492:Dopamine Antagonists / Q000494:pharmacology; D013759:Dronabinol / Q000494:pharmacology*; D051766:Early Growth Response Protein 1; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D017874:Immediate-Early Proteins; D008297:Male; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000187:drug effects / Q000378:metabolism*; D017072:Neostriatum / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D009714:Nucleus Accumbens / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D010599:Pharmacokinetics; D010766:Phosphorylation / Q000187:drug effects; D011518:Proto-Oncogene Proteins / Q000187:drug effects / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D043882:Receptors, Cannabinoid; D017447:Receptors, Dopamine D1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D011955:Receptors, Drug / Q000187:drug effects / Q000378:metabolism; D017470:Receptors, Glutamate / Q000187:drug effects / Q000378:metabolism; D012201:Reward; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D014157:Transcription Factors / Q000235:genetics; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology; D050807:ets-Domain Protein Elk-1
D001552:Benzazepines; D004268:DNA-Binding Proteins; D018492:Dopamine Antagonists; D051766:Early Growth Response Protein 1; C486109:Egr1 protein, mouse; C494113:Elk1 protein, mouse; D018691:Excitatory Amino Acid Antagonists; D017874:Immediate-Early Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D043882:Receptors, Cannabinoid; D017447:Receptors, Dopamine D1; D011955:Receptors, Drug; D017470:Receptors, Glutamate; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D016291:Dizocilpine Maleate; D013759:Dronabinol; D020928:Mitogen-Activated Protein Kinases; D004298:Dopamine