Genetic dissection of behavioural and autonomic effects of Delta(9)-tetrahydrocannabinol in mice.
Marijuana and its main psychotropic ingredient Delta(9)-tetrahydrocannabinol (THC) exert a plethora of psychoactive effects through the activation of the neuronal cannabinoid receptor type 1 (CB1), which is expressed by different neuronal subpopulations in the central nervous system. The exact neuroanatomical substrates underlying each effect of THC are, however, not known. We tested locomotor, hypothermic, analgesic, and cataleptic effects of THC in conditional knockout mouse lines, which lack the expression of CB1 in different neuronal subpopulations, including principal brain neurons, GABAergic neurons (those that release gamma aminobutyric acid), cortical glutamatergic neurons, and neurons expressing the dopamine receptor D1, respectively. Surprisingly, mice lacking CB1 in GABAergic neurons responded to THC similarly as wild-type littermates did, whereas deletion of the receptor in all principal neurons abolished or strongly reduced the behavioural and autonomic responses to the drug. Moreover, locomotor and hypothermic effects of THC depend on cortical glutamatergic neurons, whereas the deletion of CB1 from the majority of striatal neurons and a subpopulation of cortical glutamatergic neurons blocked the cataleptic effect of the drug. These data show that several important pharmacological actions of THC do not depend on functional expression of CB1 on GABAergic interneurons, but on other neuronal populations, and pave the way to a refined interpretation of the pharmacological effects of cannabinoids on neuronal functions.
Monory
Krisztina
K
Department of Physiological Chemistry, Johannes Gutenberg University Mainz, Mainz, Germany.
Blaudzun
Heike
H
Massa
Federico
F
Kaiser
Nadine
N
Lemberger
Thomas
T
Schütz
Günther
G
Wotjak
Carsten T
CT
Lutz
Beat
B
Marsicano
Giovanni
G
D000818:Animals; D001341:Autonomic Nervous System / Q000187:drug effects*; D001522:Behavior, Animal / Q000187:drug effects*; D001831:Body Temperature / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013759:Dronabinol / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D020868:Gene Silencing; D018698:Glutamic Acid / Q000378:metabolism; D007395:Interneurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D019579:Neocortex / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D009619:Nociceptors / Q000187:drug effects / Q000378:metabolism; D017288:Pain Threshold / Q000187:drug effects; D011619:Psychotropic Drugs / Q000494:pharmacology*; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D011619:Psychotropic Drugs; D043884:Receptor, Cannabinoid, CB1; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D013759:Dronabinol