Elsevier

Neuroscience & Biobehavioral Reviews

Volume 128, September 2021, Pages 358-366
Neuroscience & Biobehavioral Reviews

Behavioral sex differences in cocaine and opioid use disorders: The role of gonadal hormones

https://doi.org/10.1016/j.neubiorev.2021.06.038Get rights and content

Highlights

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    Females are more vulnerable than males to both cocaine and opioid use disorders.

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    Sex differences in cocaine abuse are predominantly driven by ovarian hormones.

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    Sex differences in opioid abuse may not be predominantly driven by ovarian hormones.

Abstract

Females are more vulnerable than males to many aspects of cocaine use disorder. This vulnerability also translates to opioid use disorder, with females exhibiting stronger behavioral responses than males to drugs such as heroin and morphine. While there is evidence for many overlapping neural mechanisms underlying cocaine and opioid abuse, there is also a breadth of evidence indicating divergent effects of the drugs on synaptic plasticity. This makes it unclear whether the behavioral sex differences seen in substance use disorder across different drugs of abuse rely on the same mechanisms. Ovarian hormones have consistently been implicated as drivers of the behavioral sex differences in cocaine taking and seeking. While there are far fewer studies on the role of ovarian hormones in opioid use disorder, the existing data suggest that ovarian hormones may not drive these behavioral effects in the same manner as in cocaine use disorder. This review highlights evidence that behavioral sex differences in substance use disorder might be driven by different mechanisms depending on drug class.

Introduction

Substance use disorder (SUD) is a growing public health crisis in the United States, with overdose deaths steadily increasing through 1999ā€“2018 (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)

  • T.J. Cicero et al.

    Gender differences in the intravenous self-administration of mu opiate agonists

    Pharmacol. Biochem. Behav.

    (2003)
  • Z.D. Cooper et al.

    Effects of menstrual cycle phase on cocaine self-administration in rhesus macaques

    Horm. Behav.

    (2013)
  • M. Cyr et al.

    Ovarian steroids and selective estrogen receptor modulators activity on rat brain NMDA and AMPA receptors

    Brain Res. Brain Res. Rev.

    (2001)
  • Z. Dong et al.

    Opiate withdrawal modifies synaptic plasticity in subicular-nucleus accumbens pathway in vivo

    Neuroscience

    (2007)
  • S.M. Evans et al.

    Does the response to cocaine differ as a function of sex or hormonal status in human and non-human primates?

    Horm. Behav.

    (2010)
  • M.W. Feltenstein et al.

    Plasma progesterone levels and cocaine-seeking in freely cycling female rats across the estrous cycle

    Drug Alcohol Depend.

    (2007)
  • M.W. Feltenstein et al.

    Attenuation of cocaine-seeking by progesterone treatment in female rats

    Psychoneuroendocrinology

    (2009)
  • E.D. Festa et al.

    Gonadal hormones provide the biological basis for sex differences in behavioral responses to cocaine

    Horm. Behav.

    (2004)
  • H.L. Fields et al.

    Understanding opioid reward

    Trends Neurosci.

    (2015)
  • T. Garelick et al.

    Testosterone regulates the density of dendritic spines in the male preoptic area

    Horm. Behav.

    (2014)
  • S.F. Greenfield et al.

    Substance abuse treatment entry, retention, and outcome in women: a review of the literature

    Drug Alcohol Depend.

    (2007)
  • D. Grove-Strawser et al.

    Membrane estrogen receptors activate the metabotropic glutamate receptors mGluR5 and mGluR3 to bidirectionally regulate CREB phosphorylation in female rat striatal neurons

    Neuroscience

    (2010)
  • Y. Hatanaka et al.

    Rapid increase of spines by dihydrotestosterone and testosterone in hippocampal neurons: dependence on synaptic androgen receptor and kinase networks

    Brain Res.

    (2015)
  • M. Hearing et al.

    Opioid and psychostimulant plasticity: targeting overlap in nucleus accumbens glutamate signaling

    Trends Pharmacol. Sci.

    (2018)
  • R.E. Johnson et al.

    A placebo controlled clinical trial of buprenorphine as a treatment for opioid dependence

    Drug Alcohol Depend.

    (1995)
  • K.S. Kau et al.

    Blunted cystine-glutamate antiporter function in the nucleus accumbens promotes cocaine-induced drug seeking

    Neuroscience

    (2008)
  • A.P. Kennedy et al.

    Sex differences in cocaine/heroin users: drug-use triggers and craving in daily life

    Drug Alcohol Depend.

    (2013)
  • L.A. Knackstedt et al.

    Ceftriaxone restores glutamate homeostasis and prevents relapse to cocaine seeking

    Biol. Psychiatry

    (2010)
  • E.G. Kovacs et al.

    Effects of testosterone on hippocampal CA1 spine synaptic density in the male rat are inhibited by fimbria/fornix transection

    Neuroscience

    (2003)
  • E.K. Krzanowska et al.

    Reversal of sex differences in morphine analgesia elicited from the ventrolateral periaqueductal gray in rats by neonatal hormone manipulations

    Brain Res.

    (2002)
  • E.B. Larson et al.

    Effect of short- vs. long-term estrogen on reinstatement of cocaine-seeking behavior in female rats

    Pharmacol. Biochem. Behav.

    (2005)
  • K.A. Leite-Morris et al.

    Extinction of opiate reward reduces dendritic arborization and c-Fos expression in the nucleus accumbens core

    Behav. Brain Res.

    (2014)
  • W.J. Lynch et al.

    Role of estrogen in the acquisition of intravenously self-administered cocaine in female rats

    Pharmacol. Biochem. Behav.

    (2001)
  • L.A. Martinez et al.

    Estradiol facilitation of cocaine-induced locomotor sensitization in female rats requires activation of mGluR5

    Behav. Brain Res.

    (2014)
  • K.J. McLaughlin et al.

    Assessment of estradiol influence on spatial tasks and hippocampal CA1 spines: evidence that the duration of hormone deprivation after ovariectomy compromises 17beta-estradiol effectiveness in altering CA1 spines

    Horm. Behav.

    (2008)
  • H. Mirbaha et al.

    Estrogen pretreatment modulates morphine-induced conditioned place preference in ovariectomized mice

    Pharmacol. Biochem. Behav.

    (2009)
  • S.D. Norrholm et al.

    Cocaine-induced proliferation of dendritic spines in nucleus accumbens is dependent on the activity of cyclin-dependent kinase-5

    Neuroscience

    (2003)
  • S.L. Parylak et al.

    Gonadal steroids mediate the opposite changes in cocaine-induced locomotion across adolescence in male and female rats

    Pharmacol. Biochem. Behav.

    (2008)
  • A.N. Perry et al.

    Impact of pubertal and adult estradiol treatments on cocaine self-administration

    Horm. Behav.

    (2013)
  • P. Popik et al.

    Morphine conditioned reward is inhibited by MPEP, the mGluR5 antagonist

    Neuropharmacology

    (2002)
  • Z. Qian et al.

    Downregulation of mGluR2/3 receptors during morphine withdrawal in rats impairs mGluR2/3- and NMDA receptor-dependent long-term depression in the nucleus accumbens

    Neurosci. Lett.

    (2019)
  • A.A. Rasia-Filho et al.

    Influence of sex, estrous cycle and motherhood on dendritic spine density in the rat medial amygdala revealed by the Golgi method

    Neuroscience

    (2004)
  • M.C. Ribeiro-Dasilva et al.

    Evaluation of menstrual cycle effects on morphine and pentazocine analgesia

    Pain

    (2011)
  • S.E. Back et al.

    Comparative profiles of men and women with opioid dependence: results from a national multisite effectiveness trial

    Am. J. Drug Alcohol Abuse

    (2011)
  • D.A. Baker et al.

    Neuroadaptations in cystine-glutamate exchange underlie cocaine relapse

    Nat. Neurosci.

    (2003)
  • M.A. Baptista et al.

    Preferential effects of the metabotropic glutamate 2/3 receptor agonist LY379268 on conditioned reinstatement versus primary reinforcement: comparison between cocaine and a potent conventional reinforcer

    J. Neurosci.

    (2004)
  • A.R. Bechard et al.

    The effects of ceftriaxone on cue-primed reinstatement of cocaine-seeking in male and female rats: estrous cycle effects on behavior and protein expression in the nucleus accumbens

    Psychopharmacology (Berl.)

    (2018)
  • J.B. Becker

    Direct effect of 17 beta-estradiol on striatum: sex differences in dopamine release

    Synapse

    (1990)
  • J.M. Bossert et al.

    Activation of group II metabotropic glutamate receptors in the nucleus accumbens shell attenuates context-induced relapse to heroin seeking

    Neuropsychopharmacology

    (2006)
  • J. Cao et al.

    Neonatal masculinization blocks increased excitatory synaptic input in female rat nucleus accumbens core

    Endocrinology

    (2016)
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