Cannabinoids excite circadian clock neurons.
Cannabinoids, the primary active agent in drugs of abuse such as marijuana and hashish, tend to generate a distorted sense of time. Here we study the effect of cannabinoids on the brain's circadian clock, the suprachiasmatic nucleus (SCN), using patch clamp and cell-attached electrophysiological recordings, RT-PCR, immunocytochemistry, and behavioral analysis. The SCN showed strong expression of the cannabinoid receptor CB1R, as detected with RT-PCR. SCN neurons, including those using GABA as a transmitter, and axons within the SCN, expressed CB1R immunoreactivity. Behaviorally, cannabinoids did not alter the endogenous free-running circadian rhythm in the mouse brain, but did attenuate the ability of the circadian clock to entrain to light zeitgebers. In the absence of light, infusion of the CB1R antagonist AM251 caused a modest phase shift, suggesting endocannabinoid modulation of clock timing. Interestingly, cannabinoids had no effect on glutamate release from the retinohypothalamic projection, suggesting a direct action of cannabinoids on the retinohypothalamic tract was unlikely to explain the inhibition of the phase shift. Within the SCN, cannabinoids were excitatory by a mechanism based on presynaptic CB1R attenuation of axonal GABA release. These data raise the possibility that the time dissociation described by cannabinoid users may result in part from altered circadian clock function and/or entrainment to environmental time cues.
Acuna-Goycolea
Claudio
C
Department of Neurosurgery, Yale University School of Medicine, New Haven, CT 06520, USA.
Obrietan
Karl
K
van den Pol
Anthony N
AN
D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000221:Adaptation, Ocular / Q000187:drug effects / Q000502:physiology; D000700:Analgesics / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D048588:Benzoxazines / Q000494:pharmacology; D001703:Biophysics / Q000379:methods; D002186:Cannabinoids / Q000235:genetics / Q000378:metabolism*; D002940:Circadian Rhythm / Q000187:drug effects / Q000502:physiology*; D004558:Electric Stimulation / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D005968:Glutamate Decarboxylase / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009025:Morpholines / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009281:Naphthalenes / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D018408:Patch-Clamp Techniques / Q000379:methods; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D043884:Receptor, Cannabinoid, CB1 / Q000235:genetics / Q000378:metabolism; D013493:Suprachiasmatic Nucleus / Q000166:cytology*; D013779:Tetrodotoxin; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology
D000700:Analgesics; D048588:Benzoxazines; D002186:Cannabinoids; D018691:Excitatory Amino Acid Antagonists; D009025:Morpholines; D009281:Naphthalenes; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D049452:Green Fluorescent Proteins; C103505:AM 251; D013779:Tetrodotoxin; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; C056639:2-amino-5-phosphopentanoic acid; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D014633:Valine