Estradiol impacts the endocannabinoid system in female rats to influence behavioral and structural responses to cocaine.
Compared with men, women show enhanced responses to drugs of abuse, and consequently are thought to be more vulnerable to addiction. The ovarian hormone estradiol has emerged as a key facilitator in the heightened development of addiction in females. These actions of estradiol appear mediated by estrogen receptor (ER) activation of metabotropic glutamate receptor type 5 (mGluR5). However, the downstream effectors of this ER/mGluR5 signaling pathway are unknown. Here we investigate whether cannabinoid 1 receptor (CB1R) activation is a part of the mechanism whereby estradiol influences behavioral and synaptic correlates of addiction. Following repeated cocaine administration, estradiol-treated ovariectomized rats exhibited both sensitized locomotor responses and decreases in the dendritic spine density of nucleus accumbens core medium-spiny neurons in comparison to oil-treated controls. Both effects of estradiol were blocked by AM251, a CB1R inverse agonist. These results indicate that part of the signaling mechanism through which estradiol impacts behavioral and synaptic correlates of addiction in female rats requires activation of CB1Rs.
Graduate Program in Neuroscience, 6-145 Jackson Hall, 321 Church Street SE, University of Minnesota, Minneapolis, MN, 55455, USA; Department of Neuroscience, 6-145 Jackson Hall, 321 Church Street SE, University of Minnesota, Minneapolis, MN, 55455, USA. Electronic address: bmpete@umn.edu.
Brittni M
BM
Peterson
Department of Neuroscience, 6-145 Jackson Hall, 321 Church Street SE, University of Minnesota, Minneapolis, MN, 55455, USA. Electronic address: lamartin@umn.edu.
Luis A
LA
Martinez
Graduate Program in Neuroscience, 6-145 Jackson Hall, 321 Church Street SE, University of Minnesota, Minneapolis, MN, 55455, USA; Department of Neuroscience, 6-145 Jackson Hall, 321 Church Street SE, University of Minnesota, Minneapolis, MN, 55455, USA. Electronic address: meisel@umn.edu.
Robert L
RL
Meisel
Graduate Program in Neuroscience, 6-145 Jackson Hall, 321 Church Street SE, University of Minnesota, Minneapolis, MN, 55455, USA; Department of Neuroscience, 6-145 Jackson Hall, 321 Church Street SE, University of Minnesota, Minneapolis, MN, 55455, USA. Electronic address: pmerm@umn.edu.
Paul G
PG
Mermelstein
D000818:Animals; D016739:Behavior, Addictive / Q000139:chemically induced / Q000378:metabolism*; D003042:Cocaine / Q000008:administration & dosage*; D049229:Dendritic Spines / Q000187:drug effects / Q000473:pathology; D063388:Endocannabinoids / Q000819:agonists / Q000378:metabolism*; D004958:Estradiol / Q000494:pharmacology* / Q000633:toxicity; D005260:Female; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009714:Nucleus Accumbens / Q000187:drug effects / Q000473:pathology*; D010052:Ovariectomy; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000819:agonists / Q000378:metabolism; D012727:Sex Characteristics
D063388:Endocannabinoids; D010880:Piperidines; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; C103505:AM 251; D004958:Estradiol; D003042:Cocaine
Behavioral sensitization; Dendritic spine plasticity; Drug addiction; Estrogen; Nucleus accumbens core; Type 1 cannabinoid receptors