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 alpha, 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 (six hours per day) for 10 consecutive days. The mGluR5 antagonist MPEP (or vehicle) was administered prior to estradiol (or oil), on a two days on/two days 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 CDPPB (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 upon 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.
Significance Statement: Gonadal steroid hormones, including estradiol, contribute to the enhanced progression of drug addiction in women. The mechanisms responsible for this effect, however, remain poorly understood. Here we show that activation of the group I metabotropic glutamate receptor subtype 5 (mGluR5) is required for the facilitative effects of estradiol on cocaine self-administration in ovariectomized female rats. Given recent work demonstrating that the estradiol-mGluR5 signaling is found only in females, the present findings suggest that pharmacological blockade of mGluR5 may have particular therapeutic potential for treating addiction in women.
Authors report no conflict of interest.
This research was supported by NIH grants DA035008 (P.G.M. and R.L.M.), DA035008-S1 (L.A.M. and P.G.M.), DA024355 (M.F.O.), and T32DA007234 (L.A.M., K.S.G., and B.T.H.).