- Examined why females are more sensitive than males to the rewarding and motivational effects of stimulant drugs.
- Demonstrated that the female hormone estradiol is responsible for the increased sensitivity.
- Identified two signaling pathways—mGluR5 and the cannabinoid CB1R pathways—through which estradiol mediates enhanced escalation of drug administration and greater euphoria in females.
Women report more intense highs from cocaine than men do, and they become addicted to the drug more rapidly. Studies have shown that the female hormone estradiol contributes to these differences, but not how. New NIDA-supported research supplies a possible answer.
Drs. Paul Mermelstein and Robert Meisel and colleagues at the University of Minnesota, Minneapolis, propose that the key is estradiol’s ability to activate a particular receptor, called mGluR5, on neurons. This activation causes the neurons to release more endocannabinoid neurotransmitters into the brain’s reward system, an effect that prior research has linked to stronger responses to cocaine and other stimulant drugs.
Sex-Specific Responses to Cocaine
The Minnesota researchers demonstrated that specifically in female rats, estradiol activates the mGluR5 and the cannabinoid receptor CB1R signaling pathways, resulting in heightened behavioral responses to cocaine. The affected responses are ones that female rats exhibit more markedly than male rats. These differences are thought to parallel observed differences between women’s and men’s responses to the rewarding and motivational effects of stimulant drugs:
- Escalation of cocaine self-administration: Both female and male rats will push a lever to self-administer cocaine. If allowed to self-administer across several days, females will more rapidly increase their lever pressing to receive progressively higher amounts of drug. This behavior is believed to parallel the more rapid escalation of drug use in women versus men.
- Locomotor sensitization: Cocaine increases locomotor activity, spurring increased movement, in both female and male rats. However, females exhibit more rapid locomotor sensitization, where the locomotor response increases with each repeated exposure to the drug. This difference is believed to model the greater euphoria women experience over men with initial dosing of psychostimulants.
Process of Elimination
For their experiments, the University of Minnesota team used female rats that produced no estrogen of their own, allowing the researchers to control the animals’ estrogen concentrations through hormone injections. They injected half of the rats with estradiol to bring their levels up to what is approximately normal for a female rat and let the others remain without the hormone.
- Text description of Figure 1
The figure shows the daily cocaine intake by female rats with and without estrogen and in the presence and absence of the mGluR5 inhibitor MPEP. The horizontal x-axis shows the experimental days from 1 to 10, and the vertical y-axis shows the daily cocaine intake from 0 mg/kg body weight to 105 mg/kg body weight. The graph includes 4 curves: The red curve with measurement points indicated as circles represents animals without estrogen and with functional mGluR5. The yellow curve with measurement points indicated by triangles represents animals without estrogen but without functional mGluR5. The blue curve with measurement points indicated as squares represents animals with estrogen and with functional mGluR5. The green curve with measurement points indicated as upside-down triangles represents animals with estrogen but without functional mGluR5. The red, yellow, and green curves all indicate a cocaine intake of about 55 to 65 mg/kg bodyweight throughout the experimental period. Only the blue curve for animals with estrogen and with functional mGluR5 (i.e., no MPEP treatment) shows an increasing cocaine intake from about 55 mg/kg bodyweight on day 1 to about 90 mg/kg on day 10.
In the first experiment led by post-doctoral fellow Dr. Luis Martinez (currently an Assistant Professor at Trinity College), the researchers injected half the rats in each of those two groups with a compound (MPEP) that blocks mGluR5 receptors. The researchers then had four groups of rats: one with both estrogen and intact mGluR5 signaling, the rest with either one or the other or neither. They allowed the rats to self-administer cocaine once daily for 10 days. Only the group that had estrogen and functional mGluR5 signaling exhibited a pronounced increase in cocaine intake (see Figure 1).
Dr. Brittni Peterson, a graduate student in the laboratories of Drs. Mermelstein and Meisel, followed up these results by showing that along with mGluR5 signaling, CB1 signaling is also essential to female rats’ heightened response to psychostimulants. This study employed the same four-group design as the first, but replaced MPEP with a compound (AM251) that prevents endocannabinoids from accessing the CB1 receptor. The results, this time measuring locomotor stimulation, paralleled those of the first experiment. Only animals that had both estradiol and functional CB1R signaling exhibited robust locomotor sensitization (see Figure 2). These animals covered roughly 60 percent more ground after their 5th cocaine injection than after their first, while the other groups increased their locomotor activity about 20 percent.
- Text description of Figure 2
The bar chart shows the number of movements, or ambulations, after cocaine administration of female rats with or without estrogen and in the presence or absence of the CB1R inhibitor AM251. The vertical y-axis shows the number of ambulations on a scale from zero to 15,000. There are four pairs of bars representing the four different experimental groups: Animals with no estrogen (No E) and with functional CB1R, animals with both estrogen (E) and functional CB1R, animals with no estrogen and no functional CB1R, and animals with estrogen and no functional CB1R. For each pair of bars, the left (red) bar indicates the ambulations on day 1 of the experiment and the right (blue) bar indicates the ambulations on day 5 of the experiment. For both groups without functional CB1R (that is, which were treated with AM251) and for the group without estrogen and with functional CB1R, the number of ambulations is about 5,000 on day 1 and increases to about 7,000 on day 5. Only the group with both estrogen and functional CB1R shows higher levels of ambulations of about 7,000 on day 1 and an increase to about 12,000 on day 5.
Steps on a Pathway
These experiments demonstrate that estradiol, mGluR5, and CB1R all play critical roles in female rats’ enhanced responses to cocaine. The researchers point to prior research to explain how the three link up in a pathway (see Figure 3).
Studies have established that estradiol receptors are coupled to mGluR5 in females, but not in males. As a result, in females only, estradiol can activate mGluR5 through direct interaction between the coupled receptors. Consequently, the researchers propose that whereas cocaine triggers an increase in glutamate that strongly activates mGluR5 in the reward system of both males and females, estradiol augments the effect in females only. Because mGluR5 activation contributes to cocaine’s addictive effects, these, too, are enhanced in females.
Studies have further shown that mGluR5 activation causes neurons to release endocannabinoid neurotransmitters (anandamide and 2-arachidonoylglycerol) that activate CB1R signaling. Accordingly, estradiol augmentation of cocaine-induced mGluR5 activation in the nucleus accumbens of female rats increases CB1R signaling in that region, which is a central component of the reward system. CB1R activation facilitates plasticity in the reward system, which has been linked to locomotor and motivational responses to many drugs.
The researchers confirmed this culmination of the estradiol-initiated pathway by showing that estradiol alters synaptic connections within the nucleus accumbens of female rats. Like the behavioral effects of estradiol, the resulting changes in neuronal signaling were blocked by either MPEP or AM251.
- Text description of Figure 3
The figure illustrates the pathway through which estradiol enhances the locomotor and motivational responses to cocaine in females compared with males, especially the roles of mGluR5 and CB1R signaling. The left half of the figure illustrates the pathway in females, the right half in males. Cocaine (indicated in green) induces the release of glutamate (indicated by blue circles) in the nucleus accumbens. Glutamate interacts with and activates mGluR5 (indicated by 5 blue rods). In females, mGluR5 also interacts with the estrogen receptor (indicated by the brown shape). Binding of estradiol (indicated by the red oval) to the estrogen receptor leads to heightened mGluR5 activity in females compared with males, as indicated by a thicker blue arrow. Heightened mGluR5 activity results in enhanced endocannabinoid release (indicated by yellow circles) in females. Endocannabinoids bind to CB1R (indicated by the purple shape). Enhanced endocannabinoid release in females results in heightened CB1R signaling (indicated by a thicker yellow arrow) and, consequently, increased locomotor and motivational responses (indicated by a thicker gray arrow) in females.
An Expanding Role
Drs. Mermelstein’s and Meisel’s experiments implicate mGluR5 signaling in both men’s and women’s responses to cocaine, and suggests that women respond more strongly to the drug because estrogen amplifies mGluR5 signaling. The team continues to investigate the role of mGluR5 signaling in cocaine abuse and addiction. In collaboration with Dr. Mark Thomas of the University of Minnesota, they have produced evidence that it can act as a trigger for drug craving and relapse.
These studies were supported by NIH grants DA007234, DA024355, DA035008, and DA040345.
Martinez, L.A., Gross, K.S., Himmler, B.T., et al. Estradiol facilitation of cocaine self-administration in female rats requires activation of mGluR5. eNeuro 3(5) e0140-16.2016: 1-10, 2016. Full text
Martinez, L.A., Peterson, B.M., Meisel, R.L., et al. Estradiol facilitation of cocaine-induced locomotor sensitization in female rats requires activation of mGluR5. Behavioral Brain Research 271: 39-42, 2014. Full text
Peterson, B.M., Martinez, L.A., Meisel, R.L., et al. Estradiol impacts the endocannabinoid system in female rats to influence behavioral and structural responses to cocaine. Neuropharmacology 10: 1180-124, 2016. Abstract
Peterson, B.M., Mermelstein, P.G., Meisel, R.L. Estradiol mediates dendritic spine plasticity in the nucleus accumbens core through activation of mGluR5. Brain Structure and Function 220: 15-22, 2015. Full text