However, other studies suggest that steroid hormones can modulate cocaine cravings, which could help to reduce the risk of relapse in people with cocaine-use disorders.
Researchers at University of Guelph and University of Florida have recently reviewed several past studies exploring the link between steroid hormones and cocaine-related behaviors. Their paper, published in Neuroscience & Biobehavioral Reviews, summarizes some of the most crucial findings gathered by neuroscientists so far, highlighting possible avenues for the development of new treatments for cocaine-use disorders.
The recent review paper was a joint effort between Davin Peart, a student at University of Guelph, and Carly Logan, then a student at University of Florida, supervised by Jennifer Murray and Lori Knackstedt, respectively. Peart and Logan had initially written two separate review papers, which were later integrated and revised by their supervisors and another student of Murray, Allyson Andrade, with the aim of identifying the endocrinological mechanisms underlying observed gender differences in vulnerabilities to cocaine-use disorder.
“We hoped that synthesizing this information would bring potential pharmacological targets for the treatment of this disorder to the attention of readers,” Murray and Peart told Medical Xpress, via email. “We started by reviewing studies that worked with humans with cocaine use disorder.”
The studies reviewed by Murray, Peart and their colleagues showed that women tend to progress more quickly from casual cocaine use to cocaine abuse. In addition, women appear to be more vulnerable to cocaine craving than men when presented with cues that are related to cocaine.
Interestingly, past research found that a woman’s heightened sensitivity to cue-related cocaine craving appears to be lower during the luteal phase of the menstrual cycle (i.e., the time between ovulation and the start of a woman’s next menstruation). On the other hand, these cravings appeared to increase during the follicular phase of the menstrual cycle (i.e., the time between the end of menstruation and the beginning of ovulation). The follicular phase is known to be characterized by low levels of progesterone in the body.
“These findings suggests that women may be more vulnerable than men to cocaine use disorder in a hormone-dependent way,” Murray and Peart explained. “Therefore, we determined that estrogen and progesterone receptors could be targets with high therapeutic potential for the treatment of cocaine use disorder. To investigate this further, we reviewed animal literature to identify the brain regions mediating endocrinological influences on cocaine use.”
Specifically, female rats also appeared to be more sensitive to cocaine-induced behaviors than male rats, but that this sex difference can be eliminated by blocking the effects of estrogen (but not progesterone) in the brain.
On the other hand, the injection of estrogen in areas of the brain associated with motivation-related behaviors appeared to increase cocaine-induced behaviors in female rats.
“For example, cocaine-induced dopamine release in the nucleus accumbens and dorsal striatum (both are brain regions linked with reward processing and motivation) underly its rewarding and reinforcing properties and this induction of dopamine release is increased by estrogen,” Murray and Peart said.
“Additionally, the activation of glutamate output from the medial prefrontal cortex (a brain region associated with goal-directed behavior) is involved in the resumption of cocaine use following abstinence, and glutamate neurons in this brain region are activated by estrogen.”
Based on the findings they reviewed, the researchers concluded that estrogen might facilitate the transmission of dopamine and glutamate. This means that the higher vulnerability to cocaine use disorder observed in women could ultimately be linked to differences in hormone, specifically estrogen, production.
Murray, Peart and their colleagues also wanted to examine the potential of progesterone as a therapeutic agent to reduce cocaine cravings. In fact, past studies with humans have found that administering progesterone can reduce cocaine cravings and reward-seeking behaviors.
“Administering progesterone has also been shown to decrease cocaine seeking elicited by stress, cocaine cues, or cocaine itself in male and female rats using a model of relapse,” Peart and Murray explained. “Indeed, administering progesterone or its metabolite allopregnanolone decreases dopamine release in the medial prefrontal cortex and nucleus accumbens. Therefore, we propose that it may be an option for treatment of cocaine use disorder in humans trying to maintain abstinence from cocaine use to prevent relapse.”
Overall, the recent review paper by this team of researchers suggests that researchers and physicians should pay greater attention to the relationship between cocaine use disorder and estrogenic medications, such as some birth control pills, breast cancer treatments, and bone health medications, among others.
Currently, selective estrogen receptor modulators (i.e., drugs that can activate or block estrogen receptors in various tissues and thus alter estrogen in different parts of the body) are widely prescribed for a variety of clinical purposes. Examples of these drugs are tamoxifen, typically used to treat breast cancer, and raloxifene, used to prevent or treat bone loss (osteoporosis) after menopause.
Some studies have already found that selective estrogen receptor modulators can act on brain circuits underlying cocaine-induced behaviors in female rats. Peart, Murray and their colleagues hope that their review paper will encourage other research teams to assess these effects further and explore the utility of steroids as possible treatments for cocaine-use disorder.
“Specifically, future research may continue to identify brain regions mediating the effects of estrogen on cocaine sensitivity and evaluate the effects of selective estrogen receptor modulators in these regions in animal models of cocaine use disorder,” Peart and Murray said. “These types of studies may aid in identifying selective estrogen receptor modulators with maximum therapeutic efficacy against cocaine use disorder and minimum side effects.”
The goal of the current study was to more closely examine the neuroactive steroid (NAS) synthesis pathway in individuals with chronic cocaine use, as the dynamic changes and adaptations that may occur to this neuroendocrine system are not well understood in individuals with CUD. Preclinical evidence demonstrates that multiple NAS are active in the brain. As such the goal of this study was to assess those that are impacted by progesterone and those that are not.
The findings in the current study illustrated distinct progesterone-related neuroactive steroids and those that are precursors of progesterone and unrelated to progesterone in the NAS synthesis pathways. Furthermore, findings showed that chronic cocaine use was associated with lower levels of specific GABAergic NAS, pregnenolone and androstanediol. On the other hand and as expected, progesterone administration increased levels of the potent GABAergic NAS pregnanolone and allopregnanolone, while having no effect on the NAS precursor pregnenolone as well as other NAS that are not in the progesterone pathway (see Figure 2).
Figure 2.Neuroactive steroid synthesis pathway.
The neuroactive steroids assessed in the study are shown in bold font. The progesterone pathway is highlighted in shaded grey area.
The role of progesterone and its 3α-reduced neuroactive metabolites in addiction has been assessed in our laboratory and in that of others [11–13, 18, 22–26]. The novel finding in this study is that lower levels of pregnenolone were significantly associated with years of cocaine use in men and women with CUD. Pregnenolone is the precursor to all downstream steroids and neurosteroids, i.e. those that influence neuronal functioning via extracellular receptors.
It is metabolized from cholesterol, and then converted into all steroids, including progestins, estrogen and testosterone, as well as glucocorticoids such as cortisol. Recent basic science and clinical evidence indicate that GABAergic NAS such as ALLO and their neuroactive precursor pregnenolone normalize the HPA axis stress response and reduce drug craving, anxiety, and drug intake [5, 9, 13, 27, 28], suggesting that pregnenolone may be acting by normalizing stress system upregulation and potentially decreasing related compulsive drug seeking .
Although the precise role of pregnenolone in addiction is only emerging, preclinical evidence shows that it reduces alcohol self-administration in alcohol-preferring rats  and leads to reductions in cannabis intoxication effects in mice and rats . In other clinical populations, pregnenolone has demonstrated significant improvements in clinical outcomes, such as improved negative symptoms, cognitive deficits, and functional capacity in schizophrenia, as compared to placebo [30, 31].
Pregnenolone-induced increases in ALLO also enhanced activation of the emotion regulation neurocircuitry in healthy controls . A randomized placebo-controlled trial of pregnenolone in men and women with bipolar depression improved depressive symptoms . The precise mode of action for pregnenolone remains an open question . While it has been shown to act via Sigma 1 receptors , cytoplasmic microtubules and cannabinoid system (CB1) receptors , it is also rapidly metabolized into downstream neuroactive steroids, making it difficult to distinguish the effects of pregnenolone versus its metabolites.
The current findings also show that increased years of cocaine use predict lower levels of the NAS androstanediol. Androstanediol is a testosterone-derived, powerful anticonvulsant and highly potent positive allosteric modulator of GABAA receptors . Acute doses of cocaine have been shown to significantly increase concentrations of androstanediol in the frontal cortex of male rats in a dose-dependent way .
This finding also suggests that repeated cocaine exposure could promote chronic adaptations that lead to decreased tonic levels of androstanediol, as is observed in the current study. Moreover, a human study found that genetic variation in a neurosteroid synthesis gene previously found to be associated with risk for alcohol dependence  was shown to also be associated with lower synthesis of androstanediol , implying that lower levels of androstanediol may be associated with increased risk of alcohol and/or drug use disorders.
We also examined the effects of age on levels of all NAS assessed in the current study, and found that only DHEA levels decreased with age, whereas DHEA levels did not associate with years of cocaine use, arguing that in the current study we were able to measure distinct effects of chronicity of cocaine use rather than age on levels of NAS. While age is an important factor to always consider when assessing steroids, it is possible that the current sample was fairly young with a mean age of 41 years and therefore age did not confound the results.
It is important to note that an association between pregnanolone and ALLO levels and years of cocaine use was potentially not observed in the current study due to the fact that both NAS were exogenously elevated by progesterone administration and hence did not represent a natural state. Therefore, a study in which endogenous levels of ALLO and pregnanolone are measured in cocaine dependent individuals and then assessed for associations with cocaine use chronicity is needed. While we tested this association in the placebo group (data not shown), no effect was observed likely due to an underpowered sample.
One limitation of this study is that it did not include a control sample. A comparison group of healthy individuals without a history of cocaine use would have informed us on the relative changes in the examined NAS levels that occur with chronic cocaine use, and such a study is timely and necessary. In the current study, we also assessed whether amounts of both cocaine and alcohol associated with NAS levels but didn’t find any significant associations. The important limitation here was that we only had information on amounts used in the past month, which may not accurately represent an individual’s pattern over the years of use, and a more extensive history of amounts and patterns of use might have been more informative. This should be assessed in a future study. However, the present findings are of value in that they highlight that chronic cocaine use may impact select NAS and result in neuroadaptations in the neuroactive steroid pathway.
Figure 1.Association of years of cocaine use with levels of pregnenolone (left) and androstanediol (right).
Regression analyses show that more years of cocaine use predict lower levels of pregnenolone and androstanediol.
reference link : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6542258/
More information: Davin R. Peart et al, Regulation of cocaine-related behaviours by estrogen and progesterone, Neuroscience & Biobehavioral Reviews (2022). DOI: 10.1016/j.neubiorev.2022.104584