Estradiol Facilitation of Cocaine Self-Administration in Female Rats Requires Activation of mGluR5.
In comparison to men, women initiate drug use at earlier ages and progress from initial use to addiction more rapidly. This heightened intake and vulnerability to drugs of abuse is regulated in part by estradiol, although the signaling mechanisms by which this occurs are not well understood. Recent findings indicate that within the nucleus accumbens core, estradiol induces structural plasticity via membrane-localized estrogen receptor α, functionally coupled to metabotropic glutamate receptor subtype 5 (mGluR5). Hence, we sought to determine whether mGluR5 activation was essential for estradiol-mediated enhancement of cocaine self-administration. Ovariectomized (OVX) female rats were allowed to freely self-administer cocaine under extended access conditions (6 h/d) for 10 consecutive days. The mGluR5 antagonist 2-methyl-6-(phenylethynyl)pyridine hydrochloride (MPEP) or vehicle was administered before estradiol (or oil), on a 2 d on/2 d off schedule throughout the extended access period. MPEP treatment prevented the estradiol-dependent enhancement of cocaine self-administration in OVX females. In a separate experiment, potentiation of mGluR5 function with the positive allosteric modulator 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (in the absence of estradiol treatment) failed to increase cocaine self-administration. These data suggest that mGluR5 activation is necessary for estradiol-mediated enhancement of responses to cocaine, but that direct mGluR5 activation is insufficient to mimic the female response to estradiol. Building on previous studies in male animals, these findings further highlight the therapeutic potential of mGluR5 antagonism in the treatment of addiction and suggest that there may be added therapeutic benefit in females.
Department of Neuroscience, University of Minnesota , Minneapolis, MN 55455.
Luis A
LA
Martinez
Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455; Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN 55455.
Kellie S
KS
Gross
Department of Neuroscience, University of Minnesota , Minneapolis, MN 55455.
Brett T
BT
Himmler
College of Veterinary Medicine and Doctor of Veterinary Medicine Program, University of Minnesota , Minneapolis, MN 55455.
Nicole L
NL
Emmitt
Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455; Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN 55455.
Brittni M
BM
Peterson
Department of Anatomy and Neurobiology, University of Maryland School of Medicine , Baltimore, Maryland, 21201.
Natalie E
0000-0002-6681-6171
NE
Zlebnik
Department of Psychology and Interdisciplinary Graduate Program in Neuroscience, Arizona State University , Tempe, AZ 85287.
M
M
Foster Olive
Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN 55455; Department of Psychiatry, University of Minnesota, Minneapolis, MN 55455.
Marilyn E
ME
Carroll
Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455; Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN 55455.
Robert L
RL
Meisel
Department of Neuroscience, University of Minnesota, Minneapolis, MN 55455; Graduate Program in Neuroscience, University of Minnesota, Minneapolis, MN 55455.
Paul G
PG
Mermelstein
D000818:Animals; D003042:Cocaine / Q000008:administration & dosage*; D019970:Cocaine-Related Disorders / Q000378:metabolism*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage*; D004958:Estradiol / Q000008:administration & dosage / Q000378:metabolism*; D004967:Estrogens / Q000008:administration & dosage / Q000378:metabolism; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D010052:Ovariectomy; D011725:Pyridines / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D064529:Receptor, Metabotropic Glutamate 5 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012646:Self Administration
D018765:Dopamine Uptake Inhibitors; D004967:Estrogens; D018691:Excitatory Amino Acid Antagonists; C578937:Grm5 protein, rat; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D004958:Estradiol; C121465:6-methyl-2-(phenylethynyl)pyridine; D003042:Cocaine
drug addiction; estrogen; glutamate; nucleus accumbens; plasticity; psychostimulant