Behavioral sex differences in cocaine and opioid use disorders: The role of gonadal hormones
Introduction
Substance use disorder (SUD) is a growing public health crisis in the United States, with overdose deaths steadily increasing through 1999ā2018 (Hedegaard et al., 2020). While the ongoing opioid epidemic is a large driver of this, overdose deaths involving cocaine are also rising. Rates of age-adjusted overdose deaths involving synthetic opioids other than methadone increased by 10 % from 2017 to 2018 and overdose deaths involving cocaine more than tripled from 2012 to 2018 (Hedegaard et al., 2020). While there are FDA-approved pharmacotherapies to treat opioid use disorder, many of them are limited in efficacy and none are currently approved to treat cocaine use disorder. Furthermore, the available pharmacotherapies for opioid use disorder do not yield the same treatment outcomes in males and females. After 2 weeks of treatment with buprenorphine, a larger percentage of males remain abstinent from illicit opioids than females (Johnson et al., 1995). This eventually reverses, however, and more females remain abstinent from illicit opioids than males at 17 and 24 weeks of treatment (Jones et al., 2005; Schottenfeld et al., 1998). This is possibly due to sex differences in the development and experience of substance use disorder. The information on opioid use disorder is less extensive, though existing research shows that males and females also do not develop and experience opioid use disorder in the same manner. Across the board, it appears that females are more vulnerable than males to cocaine and opioid use disorders.
While the behavioral sex differences in opioid and cocaine use disorder overlap, the neural mechanisms underlying these differences are less understood. Cocaine and opioids produce their rewarding effects through similar mechanisms, though their effects on the brain diverge in numerous ways. This makes it difficult to determine whether behavioral sex differences in SUD develop through the same mechanisms for different drugs of abuse. While various mechanisms have been implicated, ovarian hormones are likely the primary driver of the behavioral sex differences seen in cocaine use disorder. It is unclear, however, whether ovarian hormones also drive the behavioral sex differences seen in opioid use disorder. It seems plausible, given that cocaine and opioids have many overlapping effects on the brain. The opioid literature is limited, however, and paints a slightly different story. Overall, it seems overlapping behavioral sex differences in drug abuse might not be driven by the same biological mechanisms. This review highlights the need for further exploration of the mechanisms underlying sex differences in opioid use disorder.
Section snippets
Behavioral sex differences in substance use disorder
Both preclinical and clinical research have traditionally ignored sex as a biological variable. The majority of research was conducted in males, leading to heavily biased results (Greenfield et al., 2007). Unfortunately, male biases in biomedical research have led to economic loss and unintended fatalities (Lee, 2018).These consequences led to NIH mandates for the inclusion of female subjects in research, which has exponentially increased the number of published reports about substance abuse in
The influence of gonadal hormones on behavior
Biological sex can influence behavior via actions of the different complement of genes on sex chromosomes and via circulating gonadal hormones (Arnold, 2009). Gonadal hormones are capable of modulating behavior in two ways: through organizational and activational effects. The organizational-activational hypothesis of gonadal hormones was first proposed by Phoenix and colleagues (Phoenix et al., 1959). Organizational effects of hormones permanently shape the brain. These effects can occur
Cocaine
It is well-established that ovarian hormones play a key role in sex differences in cocaine abuse. The human menstrual cycle lasts approximately 28 days and is divided into luteal and follicular phases. Estrogen levels peak about halfway through the cycle, followed by a peak in progesterone (Staley and Scharfman, 2005). In rodents, the estrus cycle lasts approximately 4 days and is divided into 4 stages: proestrus, estrus, metestrus, and diestrus. Estrogen levels peak during proestrus and
Neural mechanisms underlying the reinforcing properties of cocaine and opioids
Given the existing literature on gonadal hormones and substance use disorder, it seems behavioral sex differences in cocaine and opioid abuse might be driven by different mechanisms. This seems in direct contradiction to the fact that cocaine and opioids both produce their rewarding effects through activation of the mesolimbic dopamine system. Put simply, both drugs increase dopamine release from the ventral tegmental area (VTA) to the nucleus accumbens (NAc), albeit through slightly different
Effects of gonadal hormones on dendritic spine density
In addition to drugs of abuse, gonadal hormones also modulate spine density in the brain. It is possible drugs of abuse interact with gonadal hormones to modulate synaptic plasticity. While the behavioral outcomes of these interactions may be similar, different drugs of abuse might interact with gonadal hormones to modulate synaptic plasticity in different manners. The predominant portion of studies investigating gonadal hormones and spine density examine their effects on hippocampal circuits
Conclusion
Though there are FDA approved treatments for opioid use disorder, many are limited in efficacy and there are none currently approved to treat cocaine use disorder. As there are sex differences in treatment outcomes, these therapies are likely limited by factors related to biological sex. Males and females do not develop and experience cocaine and opioid use disorder in the same manner. As females are more vulnerable to many aspects of SUD, biological sex is an important factor to consider in
Acknowledgements
This work was supported by National Institute on Drug Abuse (NIDA) Grant R01 DA047265 (L.A.B.), R01 DA049837 (L.A.B). and T32 DA007273 (M.C.K.).
References (138)
The organizational-activational hypothesis as the foundation for a unified theory of sexual differentiation of all mammalian tissues
Horm. Behav.
(2009)- et al.
Sex differences in drug abuse
Front. Neuroendocrinol.
(2008) - et al.
Acute estradiol treatment affects the expression of cocaine-induced conditioned place preference in ovariectomized female rats
Brain Res. Bull.
(2014) - et al.
Organizational and activational effects of testosterone on carrageenan-induced inflammatory pain and morphine analgesia
Neuroscience
(2006) - et al.
Gender differences in substance use disorders
Psychiatr. Clin. North Am.
(1999) - et al.
Plasma hormonal profiles and dendritic spine density and morphology in the hippocampal CA1 stratum radiatum, evidenced by light microscopy, of virgin and postpartum female rats
Neurosci. Lett.
(2008) - et al.
Strain and sex differences in the locomotor response and behavioral sensitization to cocaine in hyperactive rats
Brain Res.
(1999) - et al.
Organizational manipulation of gonadal hormones and systemic morphine analgesia in female rats: effects of adult ovariectomy and estradiol replacement
Brain Res.
(2005) - et al.
The role of exogenous testosterone in cocaine-induced behavioral sensitization and plasmalemmal or vesicular dopamine uptake in castrated rats
Neurosci. Lett.
(2003) - et al.
Endogenous gonadal hormones modulate behavioral and neurochemical responses to acute and chronic cocaine administration
Brain Res.
(2002)