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. Author manuscript; available in PMC: 2022 Aug 1.
Published in final edited form as: Psychopharmacology (Berl). 2021 Apr 27;238(8):2213–2224. doi: 10.1007/s00213-021-05846-3

Females Develop Features of An Addiction-Like Phenotype Sooner During Withdrawal than Males

Eleanor Blair Towers 1, Anousheh Bakhti-Suroosh 1, Wendy J Lynch 1
PMCID: PMC8295229  NIHMSID: NIHMS1715642  PMID: 33907871

Abstract

Rationale

Women meet criteria for substance use disorder after fewer years of drug use than men; this accelerated time-course, or telescoping effect, has been observed for multiple drugs, including cocaine. Preclinical findings similarly indicate an enhanced vulnerability in females to developing an addiction-like phenotype; however, it is not yet known if this phenotype develops faster in females versus males.

Objectives

The goal of this study was to determine using a rat model whether two key features of addiction in humans, an enhanced motivation for cocaine and compulsive use, emerge sooner during withdrawal from extended-access cocaine self-administration in females versus males.

Methods

Motivation for cocaine, as assessed under a progressive-ratio reinforcement schedule, was determined prior to and following extended-access cocaine self-administration (24 h/day, 96 infusions/day, 10 days) and after 7, 14, or 60 days of withdrawal. Compulsive use, or use despite punishment, was evaluated once progressive-ratio responding stabilized by adding histamine, an aversive stimulus, to the cocaine solutions.

Results

Motivation for cocaine increased from baseline sooner during withdrawal in females than males (at 7 versus 14 days); motivation was also highest in the 60-day group. Histamine decreased progressive-ratio responding for cocaine in both sexes although effects were greatest in males in the 7-day withdrawal group; males reached the female-level of resistance to histamine-punishment by 14 days of withdrawal.

Conclusions

Female rats developed addition-like features sooner during withdrawal than male rats indicating that the telescoping effect observed in humans is biologically-based. Additionally, like drug-seeking/craving, motivation for cocaine and measures of compulsive use incubate over withdrawal.

Keywords: Sex differences, Enhanced motivation, Use despite negative consequences, Addiction-like phenotype, Telescope effect, cocaine, Extended-access, Self-administration

Introduction

Cocaine use disorder is a chronic, relapsing disease characterized by intense motivation for the drug along with compulsive use that occurs at the expense of other activities/obligations and despite negative consequences. Two million men and women in the US use cocaine and unfortunately the rate of drug overdose deaths involving cocaine continues to increase being second only to opioids as a cause of overdose deaths (Substance Abuse and Mental Health Services Administration, 2019; Hedegaard et al., 2020). Despite higher rates of cocaine use and addiction among men, an accumulating body of evidence suggests that women are at greater risk than men on many different aspects of the disease process (Center for Substance Abuse Treatment, 2009; Greenfield et al., 2010; Becker and Koob, 2016). One of the most striking examples is “the telescoping effect” where following initial drug use, women meet criteria for substance use disorder and seek treatment for the disorder after fewer years of drug use as compared to men (Anglin et al., 1987; Brady and Randall, 1999; Griffin et al., 1989; Hernandez-Avila et al. 2004; McCance-Katz et al., 1999; Westermeyer et al., 2000). This phenomenon has been reported not only for cocaine but also other stimulants (methamphetamine; Mayo et al., 2019) and drug classes (e.g., alcohol, cannabis, and opioids; Back et al. 2011 a; b; Haas and Peters 2000; Hernandez-Avila et al. 2004; Hser et al. 1987a;b; Sartor et al. 2014). Additionally, once women develop a substance use disorder they have higher levels of drug craving, greater difficulty controlling their drug use, and experience more drug-related medical and psychological complications than men (Robbins et al., 1999; Elman et al., 2001; Center for Substance Abuse Treatment, 2009; Greenfield et al., 2010; Kennedy et al., 2013; Becker and Koob, 2016).

Results from preclinical studies using extended-access (ExA) cocaine self-administration, the “gold standard” for inducing features characteristic of addiction in humans, similarly indicate an enhanced vulnerability in females versus males (Lynch and Carroll, 2000; Lynch and Taylor, 2004; Kawa and Robinson, 2019; Nicolas et al., 2019). For example, female rats given ExA to cocaine (6–24 h/day) self-administer more drug, show greater escalation of drug intake over time, and a greater disruption of diurnal control over drug intake than males (Algallal et al. 2020; Kawa and Robinson, 2019; Lynch and Taylor, 2004; 2005; Smith et al. 2011; Roth and Carroll, 2004), which may indicate a greater vulnerability to transition from controlled to dysregulated drug use in females (Lynch et al., 2000; Becker and Koob, 2016 ). Even more notable, females develop an enhanced motivation for cocaine, as assessed under a progressive-ratio (PR) reinforcement schedule, under conditions that do not induce this phenotype in males (e.g., following 7 days of ExA cocaine self-administration and 10 days of withdrawal; Lynch and Taylor, 2004). This phenotype is observed in both females and males when the conditions are optimized by lengthening the period of ExA self-administration (i.e. 10 days) and/or the withdrawal period (i.e. 14 days; Roberts et al., 2007; Ramôa et al., 2013). Together, these findings indicate that, like women, female rats have an enhanced vulnerability to developing key features characteristic of addiction; however, it is not yet known if these features develop faster in females versus males. Thus, the purpose of this study was to determine using a rat model whether there are sex differences in the time-course for the development of two key features of addiction in humans, an enhanced motivation for cocaine and compulsive use.

As with our previous studies, the development an enhanced motivation for cocaine was determined relative to levels of responding under progressive-ratio schedule of reinforcement prior to versus following ExA self-administration and withdrawal (Bakhti-Suroosh et al., 2019; Lynch and Taylor, 2004; also see Ramôa et al., 2013, 2014; Doyle et al., 2014;). We also included an assessment of compulsive use, or use despite negative consequences in this study, given that it is a defining feature of addiction in humans; there may also be gender/sex differences in compulsive use given results showing that women have a greater difficulty controlling drug use and/or a greater likelihood of continued use despite trying not to use (Kenney et al., 2013). Compulsive use was assessed using a histamine punishment procedure wherein histamine, an aversive stimulus that causes a delocalized itching or crawling sensation throughout the body (Lipman and Yosipovitch 2021), is added to the cocaine solution. Previous preclinical studies have shown that adding histamine (4.0 mg/kg/infusion) to the cocaine solution markedly decreases cocaine self-administration under short-access conditions with similar effects observed in females and males (Holtz et al., 2013). Effects were examined in this study following ExA self-administration and withdrawal once responding under the PR reinforcement schedule had stabilized. To our knowledge, sex differences have not yet been examined for measures of compulsive use following ExA self-administration. Based on previous findings indicating that addition-like features develop following ExA self-administration and increase, or “incubate”, over withdrawal (e.g., drug-craving, compulsive use; Grimm et al., 2001; Gancarz-Kausch et al., 2014), effects were examined during early withdrawal (7 days), which was expected to be threshold for inducing addition-like features, versus late withdrawal (14 days), which was expected to be optimal for inducing addition-like features. We also examined effects following protracted withdrawal (60 days) in order to assess the persistency of the behavioral phenotype and determine whether motivation for cocaine, like drug craving and compulsive use, incubates over withdrawal.

Based on reports of a telescoping effect in women, we hypothesized that female rats would develop an enhanced motivation for cocaine sooner during withdrawal than males (at 7 versus 14 days) and show a greater resistance to histamine punishment during early but not late withdrawal. We further predicted that like drug-craving and compulsive use, motivation for cocaine would incubate over withdrawal and remain elevated even after 60 days of withdrawal.

Methods and Materials

Subjects

Subjects were sexually mature female (N = 38) and male (N = 39) Sprague-Dawley rats (Charles River), weighing approximately 270 g (female) and 370 g (male) at the start of the study. Upon arrival, rats were individually housed in operant testing chambers (Med Associates, St. Albans, VT, USA). Rats had ad libitum access to water and food (Teklad LM-485 7912; except as noted below for some animals during cocaine self-administration training) and were maintained on a 12-h light/dark cycle (lights on at 7AM). Following a 2-day habituation period, in order to ensure rapid subsequent acquisition of cocaine self-administration, rats were pre-trained to lever-press for sucrose pellets (45 mg) using methods described previously (fixed-ratio 1, FR1; 24-h/day sessions; >50 sucrose pellets/session for 2 days; Lynch 2008). Rats were weighed three times/week and health was monitored daily. All procedures were conducted within animal care guidelines set by the National Institute of Health and were approved by The University of Virginia Animal Care and Use Committee.

Procedures

Surgery and Catheter Maintenance

Following lever pre-training, rats were anesthetized with ketamine/dexdomitor and implanted with an indwelling catheter (Silastic tubing; 0.51 and 0.94 mm o.d.; Dow Corning, Midland, MI, USA) into the right jugular vein using methods previously described (Lynch 2008). Catheters were flushed with heparinized saline 3 days/week to verify and help maintain patency. Patency was also verified periodically by administering methohexital (1.5 mg/kg). If a catheter was no longer patent (i.e., the catheter was leaking, pressure prevented flushing, or the animal did not lose the righting reflex immediately after methohexital), data collected between this assessment and the last patency check were discarded and a new catheter was implanted into the left jugular vein with testing resuming following a 1–2-day recovery period.

Cocaine Self-Administration Training

Rats were initially trained to self-administer cocaine (1.5 mg/kg/infusion) under a FR1 schedule with a maximum of 20 infusions/day using methods previously described (Figure 1; Lynch et al., 2010). Acquisition was defined as 2 consecutive days wherein all 20 infusions were obtained. A relatively high dose of cocaine was used to encourage rapid rates of acquisition and moderate food restriction (20 g/day) was used briefly (2–3 days) when necessary (i.e. fewer than 15 infusions/day by training day 5). All groups acquired rapidly under these high dose conditions and rates of acquisition did not differ between groups. Responses on the right (non-active) lever were counted during self-administration sessions as a measure of general activity, but they did not have any programmed consequence.

Figure. 1.

Figure. 1

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Summary of experimental events. Female and male rats were trained to self-administer (SA) cocaine. Following acquisition of cocaine SA (2 consecutive sessions wherein all 20 infusions available were obtained), a baseline level of motivation for cocaine SA was established with a progressive-ratio (PR) reinforcement schedule (Pre-ExA PR). After achieving a stable PR baseline, rats were given 24-hr/day, extended access (ExA) to cocaine (1.5 mg/kg/infusion) under a discrete trial procedure for 10 sessions. Following the last ExA session, rats started a 7-, 14-, or 60-day withdrawal period (Withdrawal). Following the withdrawal period, motivation for cocaine SA was retested (Post-ExA PR; also used as the Pre-histamine baseline PR). Then cocaine use despite negative consequences was assessed by addition of noxious agent histamine (4 mg/kg/infusion) to the cocaine solution. A stable PR (Hist PR) was established with the addition of histamine to the cocaine solution and then another stable PR was determined after removal of histamine from the cocaine solution (Post-Hist PR).

Motivation for cocaine

Following acquisition, motivation for cocaine was assessed using a PR reinforcement schedule (Richardson and Roberts, 1996) wherein the response requirement to obtain a cocaine infusion increased progressively throughout the session in the following steps: 1, 2, 4, 6, 9, 12, 15, 20, 25, 32, 40, 50, 62, 77, 95, 118, 145, 178, 219, 268, 328, 402, etc. Sessions were conducted as previously described (Ramôa et al., 2013; 22-hr/day, but responding typically ceased within 2–4 hours), and ran daily until a stable baseline was achieved (Pre-ExA PR; defined as no increasing or decreasing trend in the number of infusions obtained over 3 consecutive sessions; typically achieved within 3–4 sessions). The moderate dose of cocaine tested (0.5 mg/kg/infusion) has been shown to reveal motivational differences between females and males following ExA self-administration and withdrawal, while producing comparable levels of responding between the sexes at baseline (Ramôa et al., 2013).

ExA cocaine self-administration

After achieving a stable PR baseline, rats were given extended 24-hr/day access to cocaine under a discrete trial procedure using methods previously described (1.5 mg/kg/infusion, 4-discrete trials/hr, 10 days; Ramôa et al., 2013, 2014; also see Fitch and Roberts, 1993). Briefly, 10-minute trials began every 15 minutes (up to 96 infusions/day) with the extension of the active-lever into the chamber; after either 10 minutes or a response on the active-lever the trial was terminated and the lever retracted. These conditions have been shown to induce high levels of cocaine intake and dysregulated patterns of self-administration (Ramôa et al., 2013; Lynch and Taylor 2004). After the last ExA session, responding was again assessed under a FR1 schedule with a maximum of 20 infusions in order to equate levels of cocaine intake between the groups before a 7-, 14-, or 60-day withdrawal period began following the second FR1 session, during which animals remained in their test chambers.

Enhanced motivation for cocaine

In order to determine the impact of sex on the development of enhanced motivation for cocaine, motivation for cocaine was reassessed following ExA self-administration and 7- (n=12 females/13 males), 14- (n=12 females/15 males), or 60-days (n=14 females/12 males) of withdrawal. Sessions occurred daily until responding was stable for 3 days (Post-ExA PR; typically, within 3–4 sessions) using the same PR reinforcement schedule and conditions as described above for the Pre-ExA PR baseline. One female and male in the 7-day withdrawal group and two males from the 14-day withdrawal group were excluded from this analysis (due to either technical or patency issues) since these animals did not have a reliable PR baseline prior to ExA (Pre-ExA PR) to compare to the one obtained following ExA and withdrawal (Post-ExA PR; final n=11 females/12 males, 12 females/13 males, and 14 females/12 males for the 7-, 14-, and 60-day withdrawal groups, respectively).

Compulsive cocaine use

The impact of sex on compulsive cocaine use was determined within each of the withdrawal groups once a stable Post-ExA PR was obtained using a histamine punishment procedure. To do so, histamine, which induces an aversive response, was added to the cocaine solutions. We selected a moderate dose of histamine (4.0 mg/kg), which has previously been shown to similarly reduce cocaine self-administration in female and male rats following short access cocaine self-administration (Holtz et al. 2013). Responding was assessed for a total of 3 consecutive sessions using the same PR reinforcement schedule as described above (Hist PR). Following the third session, the cocaine-histamine solution was replaced with a cocaine-only solution and responding was assessed for an additional 3 days to assess recovery from punishment (Post-Hist PR).

The Post-ExA PR was the same as the Pre-Hist PR for all rats except 2 (one female in the 7-day group and one male in the 60-day group) which lost patency and required a new catheter implantation after the Post-ExA PR was obtained. For these rats, the Pre-Hist PR was obtained following recovery for surgery (their PR values were similar to their original Post-ExA PR and similar to the mean values observed within these groups). Seven rats were excluded from this component of the study due to patency issues (1 female in the 7-day group, 2 males in the 14-day group, and 2 females and 2 males in the 60-day group) and one rat due to illness (female in the 14-day withdrawal group). This analysis also included three rats that had been excluded from the enhanced motivation component of the study (due to issues with the Pre-ExA PR baseline) since we were able to establish a stable Pre-Hist PR following the ExA period (final n=11 females/13 males, 9 females/12 males, and 12 females/10 males for 7-, 14-, and 60-day withdrawal groups, respectively).

Drugs

Cocaine hydrochloride was obtained from the National Institute on Drug Abuse and prepared in sterile saline (7 mg/ml). The mg/kg dose was adjusted for changes in body weight three times a week by adjusting the infusion duration. Histamine dihydrochloride was purchased from Sigma-Aldrich (St. Louis, MO) and dissolved in sterile saline (58.14 mg/ml) with the cocaine.

Data Analysis

Differences in cocaine intake over the 10-day ExA period were examined using repeated measure ANOVA with session as the repeated measure and sex and withdrawal group as the between-subject factors. The development of an addiction-like phenotype was defined as an enhanced motivation for cocaine (Pre-ExA PR versus Post-ExA PR) as well as compulsive use despite histamine punishment (Pre-Hist PR versus Hist PR). We also analyzed recovery from histamine punishment (Pre-Hist PR versus Post-Hist PR)). These analyses were conducted using linear mixed effects models and a nested design for session within each phase (the three Pre-ExA PR sessions versus the three Post-ExA PR sessions, the three Pre-Hist PR session versus the three Hist PR sessions, or the three Pre-Hist PR sessions versus the three Post-Hist PR sessions, respectively) and with sex, phase, and withdrawal group as fixed-factors. Session was also initially included as a fixed-factor in each of these analyses, but since no overall or interactive effects of session were observed, this factor was removed. Sex and withdrawal-dependent differences were further examined by comparing changes relative to baseline (percent difference from control) using similar linear mixed effects models with sex and withdrawal group as fixed-factors. In order to determine whether the percent change observed was significantly greater than zero, one sample t-tests were performed using the average of the 3 PR sessions. Pearson correlations were conducted to determine associations between average drug intake during ExA and the average number of infusions obtained during each of the PR testing phases (Pre-ExA, Post-ExA, Pre-Hist, Hist, and Post-Hist PR) as well as associations between average drug intake during ExA and the average percent change during Post-ExA (relative to Pre-ExA), Hist (relative to Pre-Hist), and Post-Hist (relative to Post-Hist). All post-hoc comparisons were corrected for multiple comparisons using the Bonferroni method. Statistical analyses were performed using SPSS (V26). Alpha was set at 0.05. Data are presented as the mean±SEM.

Results

ExA Self-Administration

Females self-administered more cocaine than males over the 10-day ExA period (effect of sex, F1,71 = 16.403, P < 0.001; Figure 2). Also, females and males decreased their cocaine intake over the 10 sessions (effect of session, F9,639 = 20.038, P < 0.001) taking significantly less cocaine in sessions 2–10 compared to session 1 (P’s<0.05). There were no overall or interactive effects of withdrawal group for intake of cocaine (P>0.05). Thus, while females self-administered more cocaine under ExA conditions compared to males, there were no differences in intake between the different withdrawal groups prior to withdrawal and subsequent motivational testing.

Figure. 2.

Figure. 2

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Effect of sex on cocaine intake in female and male rats given ExA to cocaine under a discrete trial procedure. Mean (±SEM) number of infusions obtained during each of the 10 ExA sessions (a) and averaged across all ExA sessions (b) for females and males in the 7- (n = 12 and 13, respectively), 14- (n = 12 and 14, respectively), or 60- (n = 14 and 12, respectively) day withdrawal groups. Significantly higher cocaine intake in females compared to males (*). Significantly higher cocaine intake on day 1 compared to days 2–10 (#).

Incubation of Motivation

As predicted, the number of cocaine infusions obtained under a PR reinforcement schedule was higher Post-ExA versus Pre-ExA, in females versus males, and in groups tested following longer versus shorter periods of withdrawal with results revealing significant overall effects of phase (F1,432 = 94.333, P< 0.001; Table 1), sex (F1,432 = 19.289, P < 0.001), and group (F2,432 = 4.290, P <0.05) as well as significant interactions of group by phase (F 2,432 = 7.167, P<0.01) and phase by sex (F1,432 = 4.756, P < 0.05). As mentioned above, there were no significant overall or interactive effects of PR test session indicating that motivation was stable over the three test sessions at both phases (Pre- and Post-ExA PR) of the study. Given the significant interaction of phase and sex, we further analyzed effects within the Pre-ExA PR and Post-ExA PR phases. The analysis of number of infusions obtained within the Pre-ExA PR sessions revealed no significant overall or interactive effects of sex or group (P>0.05), indicating that the number of infusions obtained prior to the ExA period was similar between females and males and withdrawal groups. In contrast, analysis of the number of infusions obtained within the Post-ExA PR phase revealed a significant overall effect of group (F2,216 = 12.336, P < 0.001) indicating that the number of infusions obtained was higher following longer periods of withdrawal; post-hoc comparisons of the infusions obtained Post-ExA PR confirmed a significant difference between the 7- and 60-day withdrawal groups (P<0.001). Analysis within the Post-ExA PR phase of the study also revealed a significant effect of sex (F1,216 = 23.728, P < 0.001), but a non-significant interaction of sex by group (P>0.05), indicating that females had higher motivation for cocaine than males across each of the three-withdrawal time-points. This conclusion is further supported by results within females showing that while the number of infusions obtained increased significantly from Pre-ExA PR to Post-ExA PR (significant effect of phase, F1,216 = 70.165, P<0.001) it did so similarly across each of the withdrawal time-points (non-significant effect of withdrawal group, P>0.05). In contrast, the analysis within males revealed a significant overall effect of phase (F1,216 = 28.591, P<0.001) as well as a significant interaction of group and phase (F2,216 = 5.851, P < 0.01), with no difference in the number of infusions obtained between Pre-ExA PR and Post-ExA PR after 7 days of withdrawal (P>0.05), but an increase in the number of infusions obtained between Pre-ExA PR and Post-ExA PR after 14 days (P<0.001) and 60 days (P< 0.001) of withdrawal.

Table 1.

Mean (±SEM)number of cocaine infusions obtained under the progressive-ratio reinforcement schedule prior to (Pre-ExA) and following (Post-ExA) extended access cocaine self-administration for females and males in the 7-, 14-, and 60-day withdrawal groups.

Withdrawal Group 7 Day 14 Day 60 Day^
PR Testing Phase Pre-ExA Post-ExA Pre-ExA Post-ExA Pre-ExA Post-ExA
 Female* 13±0.9 16±0.9+ 13±0.9 17±0.8+ 13±1.1 18±0.6+
  Male 13±1.2 13±1.2 12±0.5 15±0.8+ 12±0.8 16±0.9+
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*

Significant sex difference during Post-ExA (*P<0.001)

^

Significant difference between the 60-day versus the 7-day withdrawal group during Post-ExA (P<0.001).

+

Significant difference between Pre-ExA versus Post-ExA in females and males (P<0.001).

Similar differences were observed in the analysis of percent change in the number of infusions obtained during Post-ExA PR testing relative to Pre-ExA PR testing (Figure 3), with results revealing significant overall effects of sex (F1,216 = 9.857, P < 0.01) and group (F2,216 = 13.214, P < 0.001), but a non-significant interaction of group by sex (P> 0.05), indicating that females compared to males and groups tested following longer versus shorter periods of withdrawal had a larger increase in number of infusion obtained from Pre-ExA PR to Post-ExA PR. Further analysis of percent change in the number of infusions obtained during Post-ExA PR testing relative to Pre-ExA PR testing confirmed an increase at 60 days of withdrawal versus both 7 and 14 days (P’s<0.001), but not at 14 days of withdrawal versus 7 days (P>0.05). Given our predicted hypothesis of a telescoping effect in females, sex differences were further examined within each of the withdrawal groups. These analyses revealed a significant effect of sex within the 7-day withdrawal group (F1,67 = 7.286, P<0.05), but not the 14- or 60-day groups (P>0.05) indicating that motivation for cocaine was different between females and males after 7 days of withdrawal, but similar by 14 and 60 days of withdrawal. Similarly, analysis of percent change in the number of infusions obtained from Pre-ExA PR to Post-ExA PR within females revealed a non-significant trend for an effect of group (F2,108= 3.589, P =0.062) indicating that motivation for cocaine increased similarly within each of the withdrawal groups. Additionally, post-hoc comparison revealed a significant increase in motivation for cocaine (versus no change, 0) across all the withdrawal groups in females (P<0.001). In contrast, this same analysis in males revealed a significant effect of group (F2,108 = 14.453, P <0.001) with post-hoc comparison within each withdrawal group revealing a significant increase in motivation for cocaine (versus no change, 0) within the 14 (P<0.001) and 60 (P<0.01) day withdrawal groups, but not within the 7-day withdrawal group (P>0.05). Together, these findings indicate that an enhanced motivation for cocaine develops sooner during withdrawal in females than males (7 days versus 14 days) and incubated to higher levels in females versus males. Level of motivation for cocaine also incubated over protracted withdrawal with motivation for cocaine being the highest in the 60-day withdrawal group.

Figure. 3.

Figure. 3

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Effect of sex on the development of enhanced motivation for cocaine. Percent change (±SEM) in the number of infusions obtained following ExA self-administration (Post-ExA) and withdrawal relative to baseline (Pre-ExA) for females and males in the 7- (n = 11 and 12, respectively), 14- (n = 12 and 13, respectively), or 60- (n = 14 and 12, respectively) day withdrawal groups. Significantly larger increase in the number of cocaine infusions obtained following ExA (Post-ExA) relative to baseline (Pre-ExA) in females compared to males (*) and in the 60-day withdrawal group compared to 7- and 14-day withdrawal groups (^). Significant increase (versus no change, 0) in the number of infusions obtained following ExA (Post-ExA) relative to the baseline (Pre-ExA) in females and males (+). ns, nonsignificant.

Compulsive Cocaine Use

Sex and withdrawal dependent effects were also observed in response to histamine punishment and recovery from histamine punishment (Table 2) with results from the overall analysis of PR testing during the three phases (pre-histamine baseline PR, Pre-Hist PR; histamine punishment PR, Hist PR; post-histamine recovery PR, Post-Hist PR) revealing significant overall effects of phase (F3,579 = 33.295, P<0.001), sex (F1,579 = 40.930, P<0.001), and withdrawal group (F2,579 = 10.510, P < 0.001) as well as a trend for a significant interaction of group by sex (F2,579 = 2.315, P =0.10). Linear analysis within each of these phases also revealed significant effects of sex and group within the Pre-Hist PR (sex, F1,195 = 15.753, P<0.001; group, F2,195 = 7.507, P<0.01), Hist PR (sex, F1,195 = 22.176, P<0.001; group, F2,195 = 6.200, P<0.01), and Post-Hist PR (sex, F1,195 = 17.517, P<0.001; group, F2,195 = 3.120, P<0.05) phases. We also observed a trend for a significant interaction of group by sex (F2,195 = 2.323, P=0.101) within the Hist PR phase.

Table 2.

Mean (±SEM)number of cocaine infusions obtained under the progressive-ratio reinforcement schedule prior to (Pre-Hist), during (HIST), and following (Post-Hist) histamine punishment for males and females in the 7-, 14-, and 60-day withdrawal groups.

Withdrawal^ Group 7 Day 14 Day 60 Day
PR Testing+ Phase Pre-Hist Hist Post-Hist Pre-Hist Hist Post-Hist Pre-Hist Hist Post-Hist
 Female* 16±1.0 14±1.1 16±1.1 17±1.0 14±0.9 16±0.9 18±0.8 14±1.0 17±0.9
  Male 14±1.1 10±1.0 13±1.2 15±0.7 11±0.8 15±0.8 16±1.0 13±0.7 14±0.9
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*

Significant overall effect of sex (P<0.001)

^

Significant overall effect of withdrawal group (P<0.001)

+

Significant overall effect of phase (P<0.001).

However, given that the sex and withdrawal group differences were apparent during the Pre-Hist PR baseline, effects were further explored as percent change from Pre-Hist PR baseline with separate analyses conducted for the Hist PR and Post-Hist PR phases. Results from the Hist PR phase revealed a significant effect of sex (Figure 4; F1,195 = 5.173, P<0.05) and group by sex interaction (F2,195 = 5.331, P<0.01), with females showing less of a response to histamine than males, particularly within the 7-day withdrawal group (F1,70 = 11.243, P<0.01). Indeed, subsequent linear analysis within each of the withdrawal groups revealed a significant effect of sex within the 7-day (P<0.01), but not the 14-day or 60-day withdrawal groups (P’s>0.05) indicating that males reached the female-level of resistance to histamine punishment after 14 days of withdrawal. This is further supported by results from the analysis within females, which revealed a non-significant effect of group (P >0.05) indicating that motivation for cocaine was similarly impacted by histamine punishment across each of the three-withdrawal time-points. Additionally, post-hoc comparison revealed a significant decrease in motivation for cocaine (versus no change, 0) as a result of histamine punishment within females across all withdrawal groups (P<0.001). In contrast, this same analysis in males revealed a significant effect of group (F2,102 = 5.089, P <0.05) with post-hoc comparison between each withdrawal group revealing a significant reduction in the effect of histamine punishment in the 60-day withdrawal group as compared to the 7-day withdrawal group (P <0.01). Like findings in females, however, post-hoc comparison within males revealed a significant decrease in motivation for cocaine (versus no change, 0) as a result of histamine punishment within each of the withdrawal groups (P<0.01). Together, these findings demonstrate that females have a greater resistance to histamine punishment during early withdrawal, but by 14 days of withdrawal, males reach the female-level of resistance to punishment.

Figure. 4.

Figure. 4

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Effect of sex on the development of compulsive cocaine use. Percent change (±SEM) in the number of infusions obtained during histamine punishment (Hist) relative to the pre-histamine baseline (Pre-Hist) for females and males in the 7- (n = 11 and 13, respectively), 14- ( n = 9 and 12, respectively), or 60- (n = 12 and 10, respectively) day withdrawal groups. Significantly larger decrease in the number of cocaine infusions obtained during histamine punishment relative to pre-histamine baseline in males compared to females (*). Significant increase in the number of cocaine infusions obtained during histamine punishment relative to baseline (Pre-Hist) in the 60-day withdrawal group compared to the 7-day withdrawal group in males (^). Significant decrease (versus no change, 0) in the number of infusions obtained during histamine punishment (Hist) relative to the baseline (Pre-Hist) in females and males (+).

Recovery from Punishment

We also observed withdrawal-dependent changes during recovery from histamine punishment (Post-Hist PR; Figure 5). However, unlike the Hist-PR phase, the analysis of effects within the Post-Hist PR phase (relative to the Pre-Hist PR baseline) revealed a significant effect of group (F1,195 = 4.220, P<0.05), but non-significant effects of sex (P>0.05) and sex by group (P>0.05) indicating that females and males recovered similarly from the histamine punishment. Subsequent linear analysis within each of the withdrawal groups revealed a significant difference between the 14- and 60-day withdrawal groups (P<0.01), but not the 7- and 14-day withdrawal groups (P>0.05) or 7- and 60-day withdrawal groups (P>0.05). Post-hoc comparison within each withdrawal group revealed a significant decrease (versus no change, 0) in the number of infusions obtained during Post- Hist PR relative to the Pre- Hist PR baseline (prior to histamine) within the 60-day withdrawal group (P <0.05), a trend for a significant difference in the 7-day withdrawal group (P=0.06), but a non-significant difference in the 14-day withdrawal group (P <0.05). Thus, motivation for cocaine recovered similarly in females and males, and rats tested following 60 days of withdrawal showed less recovery from punishment as compared to those tested following 14 days of withdrawal.

Figure. 5.

Figure. 5

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No effect of sex on recovery from histamine punishment. Percent change (±SEM) in the number of infusions obtained following histamine punishment (Post-Hist) relative to the pre-histamine baseline (Pre-Hist) for females and males in the 7- (n = 11 and 13, respectively), 14- (n = 9 and 12, respectively), or 60- (n = 12 and 10, respectively) day withdrawal groups. Significant decrease in the number of cocaine infusions obtained following histamine punishment relative to baseline (Pre-Hist) in the 60-day withdrawal group compared to the 14-day withdrawal group in males (^). Significant decrease (versus no change, 0) in the number of infusions obtained during recovery from histamine punishment (Post-Hist) relative to baseline (Pre-Hist) in 60-day withdrawal group (+).

No Associations Between ExA Intake and Development of Addiction-Like Features

Given sex differences in cocaine intake during the 10-day ExA period, we also determined whether ExA cocaine intake was predictive of the development of an enhanced motivation for cocaine or compulsive cocaine use during the histamine punishment phase (Figure 6). While ExA intake was not associated with the development of an enhanced motivation for cocaine (percent increase from Pre-ExA to Post-ExA), resistance to histamine punishment (percent decrease from Pre-Hist to Hist), or recovery from histamine punishment (percent change from Pre-Hist to Post-Hist; data not shown), it was significantly associated with levels of motivation for cocaine (average number of infusions) during each of the phases of the study including Pre-ExA PR testing (r=0.320; P<0.01), Post-ExA PR testing (r=0.389; P=0.001), Pre-Hist PR testing (r=0.320; P<0.01), Hist PR testing (r=0.342; P<0.01), and Post-Hist PR testing (r=0.349; P<0.01; data not shown). Together, these findings indicate that while average ExA intake was predictive of overall level of motivation for cocaine, it was not predictive of the development of enhanced motivation for cocaine or compulsive cocaine use.

Figure. 6.

Figure. 6

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No associations between ExA intake and development of addiction-like features. While average ExA intake was significantly correlated with motivation for cocaine (number of infusion) prior to ExA (a, Pre-ExA PR; n=37 females, n=37 males) and following ExA (b, Post-ExA PR; n=37 females, n=37 males), it was not associated with the development of an enhanced motivation for cocaine (c, percent change from Pre-ExA to Post-ExA PR; n=37 females, n=37 males). Average ExA intake was also significantly correlated with motivation for cocaine (number of infusion) prior to histamine punishment (d, Pre-Hist PR; n=32 females, n=35 males) and during histamine punishment (e, Post-Hist PR; n=32 females, n=35 males), but it was not associated with the development of compulsive use of cocaine (f, percent change from Pre-Hist to Hist PR; n=32 females, n=35 males). r, Pearson correlation; *Significant association.

Discussion

The goal of this study was to determine whether females show an accelerated time-course for the development of two key features of addiction in humans, an enhanced motivation for cocaine and compulsive use, using a rat model. As predicted, females developed an enhanced motivation for cocaine sooner during withdrawal than males (7 vs 14 days). Females also showed greater resistance to histamine punishment than males during early withdrawal (7 days); notably, males reached the female-level of resistance to histamine punishment by late withdrawal (14 days). These sex differences are unlikely to be due to higher cocaine intake in females than males given that no association was observed between intake and the development of an enhanced motivation for cocaine, resistance to histamine punishment, or recovery from histamine punishment. As with previous findings for drug-craving (Grimm et al., 2001), we found that motivation for cocaine incubated over withdrawal following ExA self-administration and was highest in female and male rats tested following 60 days of withdrawal. We also saw incubation of compulsive use, or resistance to histamine punishment, in males; whereas, in females this phenotype was already robustly observed following 7 days of withdrawal and was maintained at a similar level following late and protracted withdrawal. Overall, these findings show that features of the addiction-like phenotype develop sooner during withdrawal in females than males. This study also shows that, like drug-craving and compulsive use, motivation for cocaine incubates over a period of protracted withdrawal.

As predicted, females developed an enhanced motivation for cocaine following ExA sooner during withdrawal compared to males. These results are consistent with our previous findings showing that females develop an enhanced motivation for cocaine under conditions that do not induce this phenotype in males (e.g., following 7 days of ExA cocaine self-administration and 10 days of withdrawal; Lynch and Taylor, 2004). Also consistent with our previous findings (Roberts et al., 2007; Ramôa et al., 2013), we observed this phenotype in both females and males when the conditions were optimized by lengthening the withdrawal period (i.e. the 14-day withdrawal group). Up until now, there were no studies with females and males investigating sex differences in the time-course for the development of an enhanced motivation for cocaine; therefore, it remained unknown whether females developed an enhanced motivation for cocaine following less drug exposure and/or over a shorter time course as compared to males. These results expand on the previous studies and provide clear support for an accelerated time-course for the development of an addiction-like phenotype in females versus males.

We also expanded the investigation of sex differences in the development of an addiction-like phenotype to include a measure of compulsive use despite negative consequences. We showed that females were more resistant to histamine punishment than males during early withdrawal (7 days). Similar to the development of enhanced motivation, males developed a similar level of resistance to punishment as females following 14 days of withdrawal which was maintained at 60 days of withdrawal. The histamine punishment procedure we used has been shown to decreases cocaine use similarly in females and males under short access conditions, suggesting there is no sex difference in the effect of histamine punishment on cocaine use prior to the development of an addiction-like features (Holtz et al., 2013). To our knowledge, sex differences have not been examined for measures of compulsive use following ExA and during withdrawal when addiction-like features are known to emerge. Thus, our results are the first to show sex differences in the development of compulsive use despite negative consequences with evidence supporting a faster time-course in females.

We also observed withdrawal-dependent differences in recovery from histamine punishment with responding tending to remain decreased from pre-histamine punishment levels in the 7-day withdrawal group, but returning to pre-histamine punishment levels in the 14-day withdrawal group. However, in contrast to effects observed for motivation for cocaine and resistance to punishment, recovery from punishment was optimally observed in the 14-day group, whereas in the 60-day withdrawal group, responding continued to be significantly lower than levels observed prior to histamine punishment. Also, in contrast to effects observed for motivation for cocaine and resistance to punishment, females and males within each of the groups recovered similarly from histamine punishment. These data are consistent with previous findings showing that despite greater effects of electric shock punishment in rats given short versus ExA to cocaine, both groups showed similar recovery of responding for cocaine (Ducret et al., 2016), and together suggest that recovery from punishment may not be a measure of compulsive use. Recovery from punishment may, however, be an important measure of vulnerability to initial cocaine use based on findings under short-access conditions showing that rats with a low saccharin preference took longer to acquire cocaine self-administration and recover from histamine punishment compared to rats with a high saccharin preference. (Carroll et al., 2008; Holtz et al., 2013). Future studies are necessary to determine the significance of our current findings showing withdrawal-dependent differences in recovery from histamine punishment and to determine if similar effects occur during recovery from other forms of punishment (e.g., electric shock).

Our data also show that motivation for cocaine incubates over prolonged periods of withdrawal with the highest levels observed within the 60-day withdrawal group. These findings are similar to a large body of work on cue-induced drug craving (Grimm et al., 2001; see review, Li et al., 2015) and indicate that a similar phenomenon occurs for both the primary and secondary reinforcing effects of cocaine. As expected and described above, there was a robust sex difference observed in the 7-day withdrawal group with females (and not males) developing an enhanced motivation for cocaine following ExA, which was then maintained at a similar level during late and protracted withdrawal. In contrast, motivation for cocaine was not increased from Pre-ExA levels in males until after 14 days of withdrawal and levels of motivation progressively increased over withdrawal. While these findings seem to suggest that motivation for cocaine incubates in males, but not females, based on our previous work showing that motivation for cocaine is unchanged or even decreased in females and males tested following 1-day of withdrawal (Morgan et al., 2002; Lynch and Taylor, 2005), we argue that incubation of motivation for cocaine occurs in both sexes, but in females, the phenotype is already maximally expressed following 7 days of withdrawal.

To our surprise, motivation for cocaine was higher in females than males following ExA self-administration and withdrawal. This is surprising because we had previously showed that motivation is similar between the sexes following ExA self-administration and 14 days of withdrawal (Ramôa et al., 2013; Doyle et al., 2014). However, our previous studies focused on effects at just one withdrawal time-point (14 days) and thus, just one group of males versus females tested following ExA self-administration. In this study, the sample size was approximately three times higher than our previous studies since effects were examined at three withdrawal time-points following ExA self-administration. As such, we believe that the overall effect of sex observed during Post-ExA PR testing is fairly modest. This idea is also consistent with our current and previous findings showing that males and females tested following ExA self-administration and 14 or more days of withdrawal show a similar increase in motivation for cocaine (Ramôa et al., 2013; Doyle et al., 2014). We also observed here that females and males are similarly resistant to histamine punishment when they are tested following ExA self-administration and 14 or 60 days of withdrawal. Together, these findings suggest that once the addiction-like phenotype develops, females and males are fairly similarly motivated to obtain cocaine and show similar levels of compulsive use. Similar conclusions have also been made for cue-induced cocaine craving (Lynch et al. 2005; Doyle et al. 2014; Peterson et al. 2014; Sanchez et al. 2014, but see Reichel et al. 2012).

To our knowledge, the incubation of compulsive cocaine use following ExA has been examined in only one previous study, which established continued cocaine use despite histamine punishment as a model of compulsive drug use in rodents (Gancarz-Kausch et al., 2014). This study focused on behavior in males only and showed that they become more resistant to histamine punishment over withdrawal with rats tested following 30 days of withdrawal obtaining more cocaine/histamine infusions under a fixed-ratio schedule as compared to those tested following 1-day of withdrawal (Gancarz-Kausch et al., 2014). Here, we observed a similar effect in males with results showing that histamine was less effective at decreasing PR responding for cocaine in males tested following 60 days of withdrawal as compared to males tested following 7 days of withdrawal. In contrast, females in the 7-, 14-, and 60-day withdrawal groups showed roughly the same response to histamine. Thus, the sex difference in the time-course for incubation of compulsive use despite negative consequences appears to be similar to the sex difference observed for the incubation of motivation for cocaine. However, since no previous studies have examined sex differences in compulsive use at earlier time-points during withdrawal, it is not yet known if compulsive use increases from a lower level in females such that, like motivation for cocaine, by 7 days of withdrawal, compulsive use is already maximally expressed in females. Future research that includes an earlier time-point during withdrawal will be necessary to determine whether compulsive use incubates in females.

In summary, we showed that female rats develop key features characteristic of addiction sooner during withdrawal than male rats. These findings provide further support for the idea that the telescoping effect observed in women (Anglin et al., 1987; Brady and Randall, 1999; Griffin et al., 1989; Hernandez-Avila et al. 2004; McCance-Katz et al., 1999; Westermeyer et al., 2000) has a biological basis. These parallel findings also support the utility of our self-administration procedure as model of the telescoping effect. Future work will need to determine whether this model of the telescoping effect can be used to study other drug classes known to be associated with the telescoping effect in humans. Additionally, this model may be useful for identifying mechanisms underlying the faster time-course in females, including the role of ovarian hormones, as well as interventions to prevent its occurrence. Lastly, the incubation phenomenon appears to occur for a multitude of key features characteristic of addiction including craving, compulsive use and now motivation to obtain the drug. Future research is needed to determine the underlying molecular changes driving the incubation of these behavioral phenotypes as they could provide targets for novel sex-specific treatment methods for cocaine use disorder. This is of importance because prolonged withdrawal periods appear to be risk factor for cocaine-related overdose deaths (Binswanger et al. 2012; Binswanger et al. 2007; Seymour et al. 2000).

Acknowledgements:

This work was supported by NIDA grant R01DA024716 (Lynch).

Footnotes

Conflict of Interest:

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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