Klein LC, Popke EJ, Grunberg NE. Sex differences in effects of predictable and unpredictable footshock on fentanyl self-administration in rats. Request PDF on ResearchGate | Sex Differences in Effects of Opioid indications of fear (e.g., freezing) than males (e.g., Klein, Popke, & Grunberg, ). Exploring Gender and Sex Differences in Behavioral Dyscontrol: from Drug Addiction to Impulse Control .. Klein LC, Popke EJ, Grunberg NE.
It is less clear whether there are sex differences in the perception or Bateson, M., Popke, E. J., Chelonis, J. J., and Hinton, S. C. (). Request PDF on ResearchGate | Sex Differences in Effects of Opioid indications of fear (e.g., freezing) than males (e.g., Klein, Popke, & Grunberg, ). Exploring Gender and Sex Differences in Behavioral Dyscontrol: from Drug Addiction to Impulse Control .. Klein LC, Popke EJ, Grunberg NE.
Exploring Gender and Sex Differences in Behavioral Dyscontrol: from Drug Addiction to Impulse Control .. Klein LC, Popke EJ, Grunberg NE. Results suggest that sex plays an important role in drug-taking behavior by rats. (PsycINFO Database Laura Cousino Klein, E. Jon Popke, Neil E. Grunberg. It is less clear whether there are sex differences in the perception or Bateson, M., Popke, E. J., Chelonis, J. J., and Hinton, S. C. ().
Preventing relapse to drug abuse is one of the struggles faced by clinicians in order to treat patients with substance use disorders DSM There is a large body of clinical evidence suggesting differential characteristics of the disorder in men and women, which is in line with preclinical findings as well. The aim of this study was to assess differences in relapse-like behavior in methamphetamine METH seeking after a popke of forced abstinence, which simulates the real clinical situation very well.
Findings from such study might add new insights in gender differences in relapse mechanisms to previous studies, which employ a classical drug or cue-induced reinstatement procedure following the popke training. Active nose-poke resulted in activation of the infusion pump to deliver one intravenous infusion of METH 0. After baseline drug intake was established maintenance phasea period of forced abstinence was initiated and rats were kept singly in their home cages for 14 days.
Finally, one reinstatement session in operant boxes was conducted. Females were found to self-administer significantly lower dose of METH. The relapse rate was assessed as a number of active nose-pokes during the reinstatement session, expressed as a percentage of active nose-poking during the maintenance phase.
This indicates higher vulnerability to relapse of METH seeking behavior in female rats. This effect was detected in all females, independently of current phase of their estrous cycle.
Therefore, this paradigm using operant drug self-administration and reinstatement of drug-seeking after forced abstinence model can be used for preclinical screening for potential new anti-relapse medications specific for women. Methamphetamine METH addiction is a serious psychosocial problem, which leads to organic harm of the body as well as distortion of the normal functioning of affected people within the society and family. There is a large body of clinical evidence suggesting differential characteristics of the disorder in men and women.
Despite the absolute number of female METH abusers being lower than the male ones, women usually appear more dependent, show higher escalation rates 12 and most importantly tend to experience more frequent relapses 34. These gender specific differences require specific treatment strategies for men and women 5 — 7. This particularly applies to relapse-prevention, which represents a key treatment challenge especially for women 8.
The preclinical approach to model drug addiction with the highest validity is usually considered as the operant drug self administration. To mimic relapse in this paradigm, popke period of extinction procedure can be employed when the animal still has a regular access to the operant box popke the drug delivered by infusion pump is replaced by vehicle.
After certain number of sessions, the subject stops to respond to the active operandum e. Such studies have repeatedly shown female rats to be more vulnerable to drug-primed relapse of METH seeking behavior at conditions of time limited sessions 2 hwhich mimic rather consummatory behavior, as well as prolonged self-administration sessions.
This is considered to provide a better model for loss of control over drug taking, leading to escalation of drug consumption 9 known from a clinical situation 3. Similarly, a higher relapse-like behavior was found in female rats after priming by conditioned cue and to even higher extent by METH dose Earlier, analogous results were reported in studies with cocaine 1112 and fentanyl However, this paradigm does not mimic the human treatment very well, because the patient usually discontinues the drug abuse in the drug rehabilitation center and for some time does not have access to the drug-related environments.
Therefore, a forced abstinence model was developed where the animal does not have access to the operant box and is kept in the home cage for some time 14 — 16 ; thus, the motivation of drug response behavior is not influenced by any training procedures. Furthermore, many preclinical studies, which assess sex-dependent differences, isolate the hormonal sex either by ovariectomy and subsequent hormonal supplementation 1718 or by constant tracking of the estrous cycle phase 10 These approaches already explained extensively the role of gonadal hormones in the reward processes showing enhancement of drug intake by estradiol 171820 — 22 and attenuation of drug seeking by progesterone 4 However, the possibilities of clinical applications of these findings are limited, so far only progesterone was tested as a treatment for nicotine relapse in women 24 and such treatment would have many undesirable side effects.
Consequently, an ideal animal model with high face, construct, and predictive validity for testing new relapse-prevention treatments should not be based on hormonal levels only. The intact animals males and freely cycling females showed no sex differences to effects of amphetamines in the animal model of sex place preference CPP 25 Therefore, gender sex in the CPP paradigm might be biased by fluctuating hormonal levels in intact females.
Popke, results supporting higher vulnerability to METH in intact female rats were reported too. Female rats displayed higher increase of locomotor activity, which lasted for longer time and had higher scores of stereotypies than male rats These results indicate the sex differences may sex, besides hormonal influences, also on different pharmacokinetic processes in females Therefore, the aim of this study was to assess gender differences in all stages of operant IV self-administration of METH in male and female rats while the gonads of all animals were kept intact assuring physiological estrous cycle in females.
We expected a higher variability in the female group, especially in the reinstatement of METH seeking behavior due to different hormonal stages. However, we hypothesized that this variability may be overpowered by all other significant gender differences. Furthermore, we assessed possible sex differences in acquisition and maintenance of food self-administration in order to compare the operant behavior toward natural reward food and the drug of abuse. Eight-week-old male and female albino Sprague-Dawley rats weighing — g females and — g males at the beginning of the experiment were purchased from Charles River Germany.
The rats were housed individually in standard rat plastic cages, the experiments on males and females were performed separately, to assure the self-administration room is dedicated to one gender at a time only. Food and water were available ad libitum.
All experiments were conducted in accordance with all relevant laws and regulations of animal care and welfare. The experimental protocol was approved by the Animal Care Committee of the Masaryk University, Faculty of Medicine, Czech Popke, and carried out under the European Community guidelines for the use of experimental animals.
Methamphetamine from Sigma Chemical, Co. The solutions were prepared for specific animals depending on their body weights rounded to the closest category of, g, etc.
After adaptation period at the beginning of the study basal behavioral profile was assessed in both males and females. In brightly lit room, rats were individually tested for locomotor activity using the Actitrack system Panlab, Spain as previously described 34 Each animal was placed in the center of arena and the spontaneous behavior was tracked for 10 min. During the test, the horizontal locomotor activity the trajectory as calculated by the system from beam interruptions that occurred in the horizontal sensors and vertical activity number of rearing episodes breaking the photocell beams of the upper frame were recorded.
Animals were deeply anesthetized with i. Under aseptic conditions, a permanent intracardiac silastic catheter was implanted through the external jugular vein to the right atrium.
The outer part of the popke exited the skin in the midscapular area. After surgery, each animal was allowed for recovery, individually in its home cage with food and water freely available. Since the implantation, the catheters were flushed daily by heparinized cephazoline Vulmizolin 1. During recovery, changes in general behavior and body weight were monitored.
When a catheter was found to be blocked or damaged, the animal was excluded from the analysis. Each cage was provided with two nose-poke holes allocated on one side and programed by software Graphic State Notation 3.
Nose-pokes in the active hole led to the activation sex the infusion pump and administration of a single infusion followed by a 10 s timeout, while nose-poke stimulation was recorded but not rewarded. The cage was illuminated by a house light during the session. The light was flashing when administering infusion and off during the time-out period.
After 14 days of stable METH intake, the maintenance phase was terminated and rats were returned to their home cages for the 14 days of the forced abstinence period. On day 15, rats were placed into self-administration chambers for the last 90 min reinstatement session. The numbers of responses on the active drug-paired nose-poke and the inactive nose-poke were recorded but the drug was not delivered.
Responses on the active nose-poke are considered to reflect the reinstatement of drug-seeking behavior, while responses on inactive nose-poke reflect non-specific locomotor and exploratory activity. Under the FR-1 schedule of reinforcement 1 nose-poke lead to activation of a feeder and delivery of a single palatable pellet BioServ, sweet dustless rodent pellets, FPurified Casein Based Formula — 45 mg. The cage was illuminated by a house light during the whole session.
Self-administration sessions lasted 30 min during the dark period of the inverted light—dark cycle. Primary data were summarized using arithmetic mean and SE of the mean estimate.
Behavioral data were analyzed by t -test. Maintenance of food self-administration was analyzed at individual days by t -test.
Statistical analyses were computed using SPSS Before starting the IV self-administration protocol, basal locomotor and exploratory activity was assessed in both males and females to exclude the sex that these characteristics would lead to different drug taking behavior. Horizontal and vertical locomotor activity was measured and a proportion of each in the inner zone of the arena was calculated in order to evaluate differences in the status of anxiety in male and female rats.
Figure 1 illustrates the results on total distance traveled, vertical activity number sex rearing episodesand inner part of arena sex. There were no basal behavioral differences between the sexes, which could contribute to dissimilar behavior in the popke cage. As expected, both sexes avoided the central part of the arena, which represents normal rodent behavior and neither one shows highly anxiogenic behavior or locomotor hyper- or hypo-activity.
Figure popke. Male and female rats have the same basal behavioral profile. The acquisition and maintenance of METH taking behavior were assessed, first, in terms of mean number of infusions self-administered per session and, second, by the mean METH dose per session in milligram per kilogram.
Figure 2 A shows number of infusions obtained per daily session and mean number of infusions during the entire acquisition phase in male and female rats during the acquisition phase of METH self-administration training. ANOVA revealed no significant effects over the whole period. However, when the number of infusions was converted to a METH dose per kilogram of body weight, males were found to self-administer higher dose at the end of the acquisition phase as compared to females.
More specifically, as depicted in the Figure 2 B, mean METH intake during the last 5 days of training was significantly higher in males than in females, i. Figure 2. Acquisition and maintenance of methamphetamine intake in male and female rats. The A part shows number of infusions expressed as daily means over the 14 days of acquisition and maintenance of the METH IV self-administration. The bar graph depicts the mean number of infusions over the whole 14 days period.
After the 2-week-long period of forced abstinence one last reinstatement session was performed with no drug availability. The only measure of the drug-seeking behavior is the number of active operandum responses.
This number was converted to a percent of mean basal nose-poking 14 days of acquisition and maintenance. There popke a massive difference between the sexes recorded: male rats showed mean percent of responding Results are reported on the Figure 3.
Figure 3. Reinstatement of methamphetamine seeking behavior in male and female rats. The graphs show a percent of mean popke nose-poking 14 days of acquisition and maintenance and number of nose-pokes in the reinstatement session in male and female rats. The apparent difference between the sexes is further confirmed by behavioral activity reflected in a mean number of nose-pokes: The maintenance phase of the sex self-administration was evaluated as a mean number of self-administered pellets during the last 5 sex when the intake was stable.
Negus SS. Rapid assessment of choice between cocaine and food in rhesus monkeys: effects of environmental manipulations and treatment with d -amphetamine and flupenthixol. Choice between heroin and food in nondependent and heroin-dependent rhesus monkeys: effects of naloxone, buprenorphine, and methadone. J Pharmacol Exp Ther. Hursh SR, Silberberg A. Economic demand and essential value. Psychol Rev.
Hursh SR. Behavioral economics and the analysis of consumption and choice. The Wiley Blackwell handbook of operant and classical conditioning. Effects of environmental maniuplations and bupropion and risperidone treatments on choice between methamphetamine and food in rhesus monkeys.
Spragg SDS. Morphine addiction in chimpanzees. Discrete-trial choice procedure: effects of naloxone and methadone on choice between food and heroin. Delay discounting of food and remifentanil in rhesus monkeys. Reinforcing and subjective effects of morphine in human opioid abusers: effect of dose and alternative reinforcer. Comparison of a drug versus money and drug versus drug self-administration choice procedure with oxycodone and morphine in opioid addicts.
Extended heroin access increases heroin choices over a potent nondrug alternative. Drug versus sweet reward: greater attraction to and preference for sweet versus drug cues. Addict Biol. Drug specificity in drug versus food choice in male rats. Choosing under the influence: a drug-specific mechanism by which the setting controls drug choices in rats.
Heroin and saccharin demand and preference in rats. Choice between delayed food and immediate opioids in rats: treatment effects and individual differences. Reduction of heroin intake in baboons by an economic constraint.
Development of a translational model to screen medications for cocaine use disorder I: choice between cocaine and food in rhesus monkeys. Sex differences in selecting between food and cocaine reinforcement are mediated by estrogen. The roles of dopamine and [alpha]1-adrenergic receptors in cocaine preferences in female and male rats.
Download references. We acknowledge the expert technical assistance of Kaycee Faunce. We also acknowledge Kevin Costa for writing the original version of the behavioral program used in the choice procedure. Correspondence to Matthew L. Reprints and Permissions. Townsend, E.
Sex differences in opioid reinforcement under a fentanyl vs. Download citation. Drug and Alcohol Dependence Neuropsychopharmacology Advanced search. Skip to main content.
You are viewing this page in draft mode. Subjects Addiction Psychology Reward. Abstract Clinical evidence suggest that men are more sensitive than women to the abuse-related effects of mu-opioid agonists. Access through your institution. Buy or subscribe. Operant Conditioning. Pharmaceutical Preparations. Wistar Rats.
Appointments and Schedules. Experimental and clinical psychopharmacology , 5 2 , Klein, Laura ; Popke, E. Jon ; Grunberg, Neil E. In: Experimental and clinical psychopharmacology. In: Experimental and clinical psychopharmacology , Vol. This is consistent with the robust gender difference in the reinstatement found in this study, where the motivation of animals for the drug-seeking was not abolished by extinction training.
At this point, active responses to the operandum are the only measure to report because the session is performed without delivering the drug. We found a highly significant difference in the percent of mean basal nose-poking, as well as in the absolute number of active operant responses.
The enhancing effect of estradiol and attenuating effects of progesterone on psychostimulant d -amphetamine, METH, cocaine intake in female gender is repeatedly and consistently reported in both clinical 49 — 52 and preclinical studies 17 , 20 — Therefore, the higher variability in the reinstatement operant responding in the female group detected in this study probably originated from different hormonal stage. This conclusion can be supported by an earlier study, which employed the extinction and both drug- and cue-primed reinstatement, where females were found more vulnerable in both reinstatement procedures and also exhibited higher variability than males.
Interestingly, the numbers of lever presses in the conditioned cue-primed reinstatement session were approximately 40 in males and in females These absolute numbers are similar to those reported in the present study: 41 and , respectively.
Therefore, this effect seems to be well reproducible and strain independent Long-Evans vs. Sprague-Dawley rats. The forced abstinence model was proposed as a potentially better tool to model a spontaneous relapse in rodents 15 , To our knowledge, this is the first report of gender differences in the paradigm of reinstatement after forced abstinence. Extinction-based approach to study relapse-like behavior phase in the preclinical setting show contradictory results — females appear to meet the extinction criteria later than males 11 , but negative results have been reported as well Both studies were conducted with cocaine.
Taken together, this study reports lower consummatory METH intake during maintenance phase of the self-administration together with higher vulnerability to the reinstatement of METH seeking behavior in female rats after forced abstinence. These effects seem to be robust enough, thus relatively independent on the current hormonal level.
Therefore, we propose this paradigm for preclinical screening for potential new medications specific for women. However, the main limitation for the translation of these results to human medicine is the absence of psychosocial aspects, which are impossible to reflect in animal studies. 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.
The research is further co-financed by the South-Moravian Region. Becker JB, Hu M. Sex differences in drug abuse.
Front Neuroendocrinol 29 — Dluzen DE, Liu B. Gender differences in methamphetamine use and responses: a review. Gend Med 5 — Sex differences in the neurobiology of drug addiction. Exp Neurol — Sex differences in addictive disorders. Front Neuroendocrinol 35 — Methamphetamine use behaviors and gender differences.
Addict Behav 29 — Sex differences in striatal dopamine release in healthy adults. Biol Psychiatry 59 — Terner J, de Wit H. Menstrual cycle phase and responses to drugs of abuse in humans.
Drug Alcohol Depend 84 :1— Brecht ML, Herbeck D. Time to relapse following treatment for methamphetamine use: a long-term perspective on patterns and predictors. Drug Alcohol Depend — Sex differences in escalation of methamphetamine self-administration: cognitive and motivational consequences in rats.
Psychopharmacology Berl — Sex differences in methamphetamine seeking in rats: impact of oxytocin. Psychoneuroendocrinology 38 — Reinstatement of cocaine self-administration in rats: sex differences. Neuropsychopharmacology 29 — Sex differences in effects of predictable and unpredictable footshock on fentanyl self-administration in rats.
Exp Clin Psychopharmacol 5 — Different neural substrates mediate cocaine seeking after abstinence versus extinction training: a critical role for the dorsolateral caudate-putamen.
J Neurosci 26 —8. Forced abstinence model of relapse to study pharmacological treatments of substance use disorder. Curr Drug Abuse Rev 2 — Anti-relapse medications: preclinical models for drug addiction treatment.
Pharmacol Ther — Impact of repeated methamphetamine pretreatment on intravenous self-administration of the drug in males and estrogenized or non- estrogenized ovariectomized female rats. Neuro Endocrinol Lett 30 — PubMed Abstract Google Scholar.
Male and female rats differ in brain cannabinoid CB1 receptor density and function and in behavioural traits predisposing to drug addiction: effect of ovarian hormones.
Curr Pharm Des 20 13 — Enhancement of cue-induced reinstatement of cocaine-seeking in rats by yohimbine: sex differences and the role of the estrous cycle. Methamphetamine-induced conditioned place preference is facilitated by estradiol pretreatment in female mice.
Chin J Physiol 46 — Sex differences and ovarian hormones in animal models of drug dependence. Horm Behav 58 — Females are more vulnerable to drug abuse than males: evidence from preclinical studies and the role of ovarian hormones.
Curr Top Behav Neurosci 8 — Quinones-Jenab V, Jenab S. Progesterone attenuates cocaine-induced responses. Lynch WJ, Sofuoglu M. Role of progesterone in nicotine addiction: evidence from initiation to relapse. Exp Clin Psychopharmacol 18 — Gender differences in the behavioral effects of methamphetamine. Eur J Pharmacol —5. Female and male rats in late adolescence differ from adults in amphetamine-induced locomotor activity, but not in conditioned place preference for amphetamine.
Behav Pharmacol 18 — Evidence for the involvement of ERbeta and RGS in beta estradiol enhancement of amphetamine-induced place preference behavior. Horm Behav 52 — Pharmacol Biochem Behav 86 —9. The pharmacokinetics of methamphetamine self-administration in male and female rats. Drug Alcohol Depend —9. Tolerance to self-administration of cocaine in rats: time course and dose-response determination using a multi-dose method.
Drug Alcohol Depend 32 — Inhibition of methamphetamine self-administration in rats by cannabinoid receptor antagonist AM J Psychopharmacol 16 — The effects of methamphetamine self-administration on behavioural sensitization in the olfactory bulbectomy rat model of depression. Int J Neuropsychopharmacol 15 — Enhanced self-administration of the CB1 receptor agonist WIN55, in olfactory bulbectomized rats: evaluation of possible serotonergic and dopaminergic underlying mechanisms.
Front Pharmacol 5 Gender differences in cannabinoid and ecstasy interacting effects in mice. Homeost Health Dis 44