Sex Differences in Opioid and Psychostimulant Craving and Relapse: A Critical Review

Abstract

A widely held dogma in the preclinical addiction field is that females are more vulnerable than males to drug craving and relapse. Here, we first review clinical studies on sex differences in psychostimulant and opioid craving and relapse. Next, we review preclinical studies on sex differences in psychostimulant and opioid reinstatement of drug seeking after extinction of drug self-administration, and incubation of drug craving (time-dependent increase in drug seeking during abstinence). We also discuss ovarian hormones' role in relapse and craving in humans and animal models and speculate on brain mechanisms underlying their role in cocaine craving and relapse in rodent models. Finally, we discuss imaging studies on brain responses to cocaine cues and stress in men and women.The results of the clinical studies reviewed do not appear to support the notion that women are more vulnerable to psychostimulant and opioid craving and relapse. However, this conclusion is tentative because most of the studies reviewed were correlational, not sufficiently powered, and not a priori designed to detect sex differences. Additionally, imaging studies suggest sex differences in brain responses to cocaine cues and stress. The results of the preclinical studies reviewed provide evidence for sex differences in stress-induced reinstatement and incubation of cocaine craving but not cue- or cocaine-induced reinstatement of cocaine seeking. These sex differences are modulated in part by ovarian hormones. In contrast, the available data do not support the notion of sex differences in craving and relapse/reinstatement for methamphetamine or opioids in rodent models. SIGNIFICANCE STATEMENT: This systematic review summarizes clinical and preclinical studies on sex differences in psychostimulant and opioid craving and relapse. Results of the clinical studies reviewed do not appear to support the notion that women are more vulnerable to psychostimulant and opioid craving and relapse. Results of preclinical studies reviewed provide evidence for sex differences in reinstatement and incubation of cocaine seeking but not for reinstatement or incubation of methamphetamine or opioid seeking.

Fig. 1

Summary of clinical studies on sex differences in psychostimulant and opioid craving and relapse. Both craving (left) and relapse (right) panels depict the proportion of observations and list the total number of comparisons of sex differences in which F > M, F = M, and F < M for cocaine (A and D), methamphetamine (B and E), and opioids (C and F). Conditions under which craving was measured, and the abstinence period when relapse was assessed is also displayed. F, females; M, males; m, months. Note: The number of comparisons does not equal the number of studies for a given category in Supplemental Table S1 because in some studies investigators assessed more than one dependent measure (e.g., both cue- and stress-induced craving). Spontaneous craving refers to baseline nonprovoked subjective craving.

Fig. 2

Summary of preclinical studies on sex differences in psychostimulant and opioid reinstatement and incubation of craving. Both reinstatement of drug-seeking behavior (left) and incubation of craving and drug seeking after forced abstinence (right) panels depict the proportion of observations and list the total number of comparisons of sex differences in which F > M, F = M, and F < M for cocaine (A and D), methamphetamine (B and E), and opioids (C and F). The conditions under which drug seeking was measured are also displayed. F, females; M, males; Yoh, yohimbine. Note: the number of comparisons does not equal the number of studies for a given category in Supplemental Table S2 because in some studies investigators assessed more than one dependent measure (e.g., both cue- and stress-induced reinstatement).

Fig. 3

Effect of estrous cycle on incubation of craving after long-access and intermittent-access cocaine self-administration in female rats. Relapse (incubation) test. Mean ± S.E.M. number of active lever presses per session after continuous (nonestrus: n = 12 for day 2 and 29, estrus: n = 9/8 for day 2/29) and intermittent (nonestrus: n = 13/16 for day 2/29, estrus n = 10/7 for days 2/29) access drug self-administration. * Different from day 2 within each estrous phase, P < 0.05; # Different from nonestrus on day 29, P < 0.05. Adapted from Nicolas et al. (2019). Figure 3 was reproduced with permission from Elsevier.

Fig. 4

Schematic comparison of the menstrual cycle in humans and the estrous cycle in rodents and fluctuation of estradiol and progesterone levels across the cycle phases. In humans, the menstrual cycle is divided into the follicular and luteal phases separated by ovulation (Sherman and Korenman, 1975; Anker and Carroll, 2010a). The cycle begins with menses, and the onset of the follicular phase is characterized by high levels of estradiol, with a peak during the preovulation period before decreasing to a moderate level during the luteal phase. Conversely, progesterone is at its lowest level during the follicular phase and starts increasing during the preovulation period to peak at the midluteal phase. In female rodents, the estrous cycle is divided into late diestrus, proestrus, estrus, and early diestrus phases, with ovulation occurring between proestrus and estrus (Cora et al., 2015; Krentzel and Meitzen, 2018). Estradiol peaks twice at the middle of the early diestrus and proestrus phases and drops by ovulation. Progesterone peaks at the end of the early diestrus and proestrus phases, and low stable levels remain for the rest of the cycle. In many studies, investigators pool together early and late diestrus phases to a single phase called diestrus because of similar hormonal and cytologic characteristics. Additionally, when no behavioral differences are observed during proestrus and diestrus, investigators combine these phases and call the combined phase nonestrus. There are major differences in the reproductive cycle of women and female rodents: the duration of the cycle, the cycle pattern of estradiol and progesterone, and the amplitude of hormone level variations. However, when the hormonal ratio over the phases is compared, some analogies are conventionally made: the follicular phase is comparable to the estrus phase (progesterone < estradiol) and the luteal phase to the nonestrus phase (progesterone > estradiol) (Anker and Carroll, 2010a; Krentzel and Meitzen, 2018).

Fig. 5

A proposed brain mechanism model of the role of estradiol and progesterone in cocaine relapse in rodent models. There is evidence that estradiol potentiates striatal and NAc dopamine release by modulating GABAergic neurotransmission of medium spiny neurons (MSNs) through collaterals synapsing on dopamine neurons (Krentzel and Meitzen, 2018; Yoest et al., 2018). This effect is likely mediated by membrane estrogen receptors (ERs) (membrane-associated ERα and membrane-associated ERβ) expressed in MSNs (Almey et al., 2012). ERα and ERβ antagonists prevent estradiol enhancement of amphetamine-induced dopamine release (Xiao et al., 2003), and overexpression of ERα in the striatum increases the effect of estradiol on K+ induced GABA release (Schultz et al., 2009). Additionally, ERα and ERβ are expressed on VTA dopamine neurons terminals in NAc (Yoest et al., 2018), which play a critical role in reinstatement of cocaine seeking (Shaham et al., 2003; Schmidt et al., 2005). Together, these results suggest a role of ERα and ERβ in estradiol regulation of dopamine neurotransmission and, by implication, in reinstatement of cocaine seeking. Additionally, increased dopamine release by estradiol would be at least in part due to its action on dopamine receptors: striatal dopamine receptor 2 (Drd2) affinity decreases during estrus (Di Paolo et al., 1988), and estradiol injections in ovariectomized rats decrease Drd2 binding in striatum (Bazzett and Becker, 1994). In contrast to estradiol, progesterone decreases striatal dopamine release, as shown in estradiol-primed ovariectomized females treated with progesterone (Dluzen and Ramirez, 1984; Becker and Rudick, 1999). Progesterone and its metabolites are positive allosteric modulators of GABA_A receptors (Schumacher et al., 1989; Schumacher and McEwen, 1989; Lambert et al., 1995). Drugs that promote GABA_A function (e.g., imidazenil, diazepam) decrease cocaine-induced increases in dopamine release in NAc shell (Giorgetti et al., 1998). Consequently, progesterone could protect against estradiol-induced increases in cocaine seeking by inhibiting NAc dopamine release via increased GABA_A receptor transmission. Together, we propose that during the estrus/follicular phase, cocaine- or cocaine cue-induced NAc dopamine release is increased by estradiol through its action on ER in GABAergic medium spiny striatal neurons and dopamine neurons terminals, leading to disinhibition of dopamine neurons and directly enhanced VTA dopamine cell firing via decreased Drd2 signaling, resulting in increased cocaine reinstatement/relapse. In contrast, during nonestrus/luteal phase, high progesterone levels may inhibit dopamine release induced by drug or drug cues through its action on GABA_A receptors expressed in VTA dopamine terminals (Brodnik et al., 2019; Lopes et al., 2019), resulting in decreased cocaine relapse. DA, dopamine.

Fig. 6

Sex differences in cue- and stress-induced brain activation in humans who use cocaine. Schematic illustration of sex differences in (A) cocaine cue-induced and (B) stress-induced brain activation (assessed by PET or fMRI). F, female; M, male.