In experimental studies, researchers have been able to induce conditions which mimic behavioral patterns seen in clinical human populations of drug addicts. These conditions provide support for the idea that females are more susceptible to the initial use, escalation of use, addiction, and relapse due to biological markers. As is noted by Becker and Hu (2008) most of this research has been conducted in rodent models testing for psychostimulants (i.e. cocaine and amphetamine). While this is the case, it is also noted by the authors that all drugs of abuse have shown to have similar biological influences when it comes dosing, escalation, and relapse (Becker & Hu, 2008). Mechanisms which underlie these differences include GABA inhibition, menstrual (humans) and estrous (rodents) phase vulnerability, D2 down-regulation, chromosomal influenced brain organization, and increased striatal dopamine release. These mechanism have been shown to be influenced by circulating levels of estradiol.
It has been demonstrated in other studies and mentioned in lecture that GABA receptors are present at dopamine synapses in the central nervous system (Donaldson, 2017). Beck and Hu (2008) cite “whole cell clamp studies” which show that estradiol causes rapid GABA inhibition via decreased Ca2+ channels. According to the authors this is dependent on a G-protein receptor as the same dosage of estradiol was shown to alter signal pathways in female but not male rats. Supplementing this is Roth et al’s (2004) observation that estrogen causes striatal GABA neurons to decrease firing on GABAB receptors at dopamine terminals. Becker and Hu (2008) cite their previous studies which demonstrated that thirty minutes after estradiol treatment GABA concentrations were increased in the dialysate in significant amounts when compared to control groups. Considering Hu et al.’s (2004) discussion that neither testosterone nor testosterone aromatized to estradiol played a role in sensitization to psychomotor stimulants, it stands to reason that this GABA inhibition could be the mechanism by which sensitization is occurring as the ion channels open up leading to alteration in GABA functioning.
As is commonly understood in addiction studies, the process of addiction is in many ways a chase of the original high. As stated in lecture, women tend to experience a greater first high due to increased dopamine fluctuation (Donaldson, 2017). This could also help explain why over 50% of cocaine users in the 12-17 year old age group are female (Becker and Hu, 2008). In Becker and Hu’s (2008) review of thirteen studies, they found that women had a more difficult time quitting nicotine when their menstrual cycle was in the late luteal phase when estrogen and progesterone are beginning to decrease. In contrast the authors cite studies that found the positive effects of d-AMPH becoming attenuated when estradiol was injected during follicular phase of menstruation.
In their experiment with rats, Hu et al. (2004) found that ovariectomized rats given estradiol injections demonstrated more motivation in self administration paradigms (i.e. more lever presses following extinction). Consistent with what is known about compulsive drug seeking, it is unsurprising that estradiol’s effects on the nucleus accumbens are critical in sexually dimorphic differences in addiction patterns. As previously mentioned, one way this interaction occurs is through GABA inhibition. Referencing studies with cultured striatal neurons of embryonic mice Becker and Hu (2008) mention that estradiol injections changed adenylate cyclase activity via stimulation of D1 and D2 dopamine receptor agonists resulting in changes in the G-protein coupling process. Roth et al. (2004) also noted estrogen’s ability to modify dopamine gene transcription citing a Lee and Mouradian (1999) study that found that estrogen treatment and not progesterone or glucocorticoid alone led to up-regulation of D1A gene transcription.
Down-regulation of D2 receptors can result in the need for more dopamine release to obtain similar behavioral responses. This behavioural sensitization occurs as Levesque et al. (1988) explains striatal D2 dopamine receptors go through a rapid change where they go from a high to a low affinity state. This change is mediated by increased circulating estradiol and the interplay of estradiol and D2 down-regulation leads to an increase in addictive behavior and the vulnerability to addictive patterns seen in women such as enhanced or accelerated negative outcomes.
Taken together, the effects of estradiol on mesocorticolimbic dopamine release sharply increases the behavioral responses seen in women at all stages of drug abuse resulting in accelerated negative consequences and more susceptible to relapse.
Becker, J.B. and M. Hu (2008) Sex differences in drug abuse. Front Neuroendocrinol, 29, 36-47.
Donaldson, T (2017). UMass Boston. Class lecture.
Hu, M., et al., (2004) Biological basis of sex differences in the propensity to self-administer cocaine. Neuropsychopharmacology, 29, 81-5.
Roth, M.E., Cosgrove, K.P. & Carroll, M.E. (2004) Sex differences in vulnerability to to drug abuse: A review of preclinical studies. Neurosci Biobehav Rev, 28, 533-46.