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. Author manuscript; available in PMC: 2023 Jan 23.
Published in final edited form as: Neuropharmacology. 2021 Sep 10;200:108786. doi: 10.1016/j.neuropharm.2021.108786

Characterization of a differential reinforcement of low rates of responding task in non-deprived male and female rats: role of Sigma-1 receptors

Valentina Sabino 1,*, Angelo Blasio 1, Ferragud Antonio 1, Sema G Quadir 1, Malliga R Iyer 2, Kenner C Rice 3, Pietro Cottone 1,*
PMCID: PMC9869339  NIHMSID: NIHMS1747212  PMID: 34516984

Abstract

Impulsive action can be defined as the inability to withhold a response and represents one of the dimensions of the broad construct impulsivity. Here, we characterized a modified differential reinforcement of low rates of responding (DRL) task developed in our laboratory, in which impulsive action is measured in ad libitum fed/watered subjects. Specifically, we first determined the effects of both sex and estrous cycle on impulsive action by systematically comparing male and estrous-synchronized female subjects. In addition, we evaluated the convergent validity of this modified DRL task by testing the effects of the D2R/5HT2AR antagonist, aripiprazole, and the noncompetitive NMDAR antagonist, MK-801. Finally, we tested the effects of the selective antagonist BD-1063 and agonist PRE-084 of Sigma-1 receptor (Sig-1R) on impulsive action using this modified DRL task. We found that female rats showed and increased inability to withhold a response when compared to males, ad this effect was driven by the metestrus/diestrus phase of the estrous cycle. In addition, aripiprazole and MK-801 fully retained their capability to reduce and increase impulsive action, respectively. Finally, the selective Sig-1R antagonist, BD-1063 dose-dependently reduced the inability to withhold a response in both sexes, though more potently in female rats. In summary, we show that impulsive action, as measured in a modified DRL task which minimizes energy-homeostatic influences, is a function of both sex and estrous cycle. Furthermore, we validate the convergent validity of the task and provide evidence that Sig-1R antagonism may represent a novel pharmacological strategy to reduce impulsive action.

Keywords: impulsivity, estrous cycle, Sigma-1 receptor, impulsive action, aripiprazole, MK-801

1. Introduction

Impulsivity is a construct that can be broadly defined as a predisposition toward rapid, unplanned reactions to internal or external stimuli without regard to the negative consequences of these reactions (Chamberlain and Sahakian, 2007; Potenza, 2007). Impulsivity cooccurs and shares biological and pharmacological substrates with numerous disorders including drug and alcohol use disorders, eating disorders, mania, personality disorders, attention deficit/hyperactivity disorder, obesity, and obsessive–compulsive disorder (Belin et al., 2008; Cassin and von Ranson, 2005; Evenden, 1999). Because of this interplay, the study of impulsivity is of paramount importance both to understand the molecular underpinning of these disorders and to potentially find novel drug treatments for them (Moeller et al., 2001).

Impulsivity is multidimensional in nature around whose conceptualization and operationalization the scientific community has been long debating (Gullo et al., 2014; Hamilton et al., 2015; Meda et al., 2009). Currently, two major dimensions, dissociable at both neuropharmacological and neuroanatomical levels, are widely recognized (Dalley et al., 2011; Evenden, 1999; Robbins et al., 2012; Winstanley et al., 2006): impulsive action, which reflects the inability to withhold a response, and impulsive choice, which reflects difficulties in delaying gratification.

At a preclinical level, numerous behavioral tasks to measure both impulsive action and impulsive choice have been developed, but the existing procedures typically involve the use of food/water restriction/deprivation in order to improve subjects’ performance. However, limiting food/water availability is known to exert profound neurobiological and metabolic effects and it therefore becomes a significant limiting/confounding factor in all those studies that involve assessment of impulsivity together with food-related variables (Bi et al., 2003; Carr et al., 2000; Cheng et al., 2004; Di Marzo and Matias, 2005; Fulton et al., 2000; Schoffelmeer et al., 2011; Skibicka et al., 2011; Wolinsky et al., 1996). Research from our laboratory has made substantial effort towards the development of tasks to assess impulse behavior in ad libitum fed/watered subjects (Blasio et al., 2012; Moore et al., 2018; Velazquez-Sanchez et al., 2014).

Therefore, the first aim of this study was to characterize a modified differential reinforcement of low rates of responding (DRL) task developed in our laboratory, which measures impulsive action in ad libitum fed/watered subjects (Velazquez-Sanchez et al., 2014). To this purpose, we systematically compared in this task male and estrous-synchronized female subjects, given that the literature has often shown inconsistent results when impulsive action was studied as a function of gender/sex and that, to such inconsistency, the estrus cycle may represent a contributing factor (Anker et al., 2008; Bayless et al., 2012; Burton and Fletcher, 2012; Colzato et al., 2010; Hasson and Fine, 2012; Jentsch and Taylor, 2003; Liu et al., 2013; Nederkoorn et al., 2009; Papaleo et al., 2012; Reynolds et al., 2007; Reynolds, 2006; Saunders et al., 2008; Townshend and Duka, 2005; van der Plas et al., 2009; Weafer and de Wit, 2014).

The second aim of this study was to evaluate the convergent validity of this modified DRL task, defined as the degree to which a test correlates with other tests when attempting to measure the same construct (Geyer, 1995). To this aim we tested the effects of the dopamine 2 receptor (D2R)/serotonin 2A receptor (5HT2AR) antagonist, aripiprazole, and the noncompetitive antagonist of the N-Methyl-D-aspartate receptor (NMDAR), MK-801, two pharmacological agents shown to decrease and increase impulsive action, respectively, in other impulsive action tasks (Barlow et al., 2018; Besson et al., 2010; Higgins et al., 2016).

The third aim of this study was to determine whether the selective antagonist BD-1063 and agonist PRE-084 of the Sigma-1 receptor (Sig-1R) were able to modulate bidirectionally the inability to withhold a response, using the modified DRL task. Sig-1R is a non-opioid, non-PCP binding site working as a ligand-operated molecular chaperone; Sig-1R is expressed in the endoplasmic reticulum and, when activated, it translocates to the plasma membrane where it modulates multiple neurotransmitter systems (Delprat et al., 2020; Schmidt and Kruse, 2019). Based on the evidence that Sig-1R ligands bidirectionally modulate the reinforcing and rewarding properties of drugs of abuse, alcohol and highly palatable food (Cottone et al., 2012; Quadir et al., 2019; Sabino et al., 2017) and that drug/alcohol use disorder and eating disorders share neurobiological and pharmacological substrates with impulsivity (Belin et al., 2008; Cassin and von Ranson, 2005; Evenden, 1999; Moeller et al., 2001), we hypothesized that BD-1063 and PRE-084 would reduce and increase impulsive action, respectively.

2. Materials and Methods

2.1. Subjects

Male (n = 41) and Female (n = 27) Wistar rats 41–47 days old at arrival (Charles River, Wilmington, MA, USA), were single housed in wire-topped, plastic cages (27 × 48 × 20 cm) on a 12-hour reverse light cycle (lights off at 11:00 am), in an Association for Assessment and Accreditation of Laboratory Animal Care International-approved humidity- (60%) and temperature-controlled (22°C) vivarium. Rats had access to corn-based chow (Harlan Teklad LM-485 Diet 7012 [65% (kcal) carbohydrate, 13% fat, 21% protein, metabolizable energy 310 cal/100 g; Harlan, Indianapolis, IN, USA]) and water ad libitum at all times unless otherwise specified. Procedures adhered to the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH publication number 85–23, revised 1996) and the Principles of Laboratory Animal Care (http://www.nap.edu/readingroom/bookslabrats), and were approved by the Institutional Animal Care and Use Committees (IACUC) of Boston University.

2.2. Drugs

The gonadotropin-releasing hormone (GnRH) superagonist [D-Try6, Pro9-NEt]-GnRH was synthesized by solid-phase methodology (Rivier et al., 1974) and kindly gifted by Jean Rivier (The Clayton Foundation Laboratories for Peptide Biology, The Salk Institute, La Jolla, CA, USA). The peptide was freshly dissolved in 0.1 N acetic acid (0.5 μg/μl), then diluted to the concentration of 10 mg/l in 1 × PBS and administered subcutaneously (see section 2.5 Estrous cycle synchronization) (Cottone et al., 2007; Parylak et al., 2012; Richardson et al., 2006; Rivier and Vale, 1990). Aripiprazole (AK Scientific, Inc., CA, USA) was first dissolved in a 2% glacial acetic acid/30% dimethyl formamide in water; the pH was then adjusted to 5.5; aripiprazole was administered intraperitoneally (vehicle, 0.3, 1 and 3 mg/kg, 1 ml/kg) 30 min before testing (Besson et al., 2010). MK-801 (Dizocilpine or [5R,10S]-[+]-5-methyl-10,11- dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine) (Cayman Chemicals Company, MI, USA) was dissolved in isotonic saline, and administered intraperitoneally (vehicle, 0.001, 0.003, 0.01, and 0.03 mg/kg, 1 ml/kg) 30 min before testing (Barlow et al., 2018; Yates et al., 2018). BD-1063 × 2HBr salt (1-[2-(3,4-dichlorophenyl)ethyl]-4-methylpiperazine dihydrobromide]) was synthesized as reported previously (de Costa et al., 1993) and dissolved in isotonic saline; BD-1063 was administered subcutaneously (vehicle, 3.75, 7.5, 15, and 30 mg/kg, calculated on the base weight, 2 ml/kg) 15 min before testing (Cottone et al., 2012). PRE-084 (2-(4-Morpholinethyl) 1-phenylcyclohexanecarboxylate hydrochloride) was dissolved in isotonic saline and administered intraperitoneally (vehicle, 3, and 10 mg/kg, 1 ml/kg) 30 min before testing (Maurice et al., 2003). Aripiprazole, MK-801, BD-1063, and PRE-084 treatments were given in full Latin square designs with one to three intervening treatment-free test days, in which dependent variables returned to baseline. Rats were given 3 days of acclimation to daily vehicle injections before starting drug treatments. In female rats drugs were administered during metestrus, when the influence of ovarian hormones is minimal (Andersson et al., 2013; Cottone et al., 2007).

2.3. Apparatus

Operant chambers (30×24×29 cm, Med Associates Inc., St. Albans, VT, USA), previously described (Blasio et al., 2013; Cottone et al., 2012), had grid floors and were located in sound-attenuating and ventilated environmental cubicles (Blasio et al., 2012; Cottone et al., 2009; Cottone et al., 2007; Fekete et al., 2011). Two syringe pumps dispensed solutions into two stainless steel drinking cups mounted 2 cm above the grid floor in the middle of an aluminum panel (Sabino et al., 2006b). Two retractable levers were located 3.2 cm to either side of the drinking cups and two 28-V stimulus cue-lights were located above each lever. All responses were recorded automatically by a microcomputer with 10-ms resolution.

2.4. Modified differential reinforcement of low rates of responding (DRL) task in ad libitum fed rats

Performance on the modified DRL task has been used to provide a measure of impulsive action, defined as the inability to withhold a response (Dalley et al., 2008; Neill, 1976; Uslaner and Robinson, 2006). The DRL procedure used here was originally modified (Velazquez-Sanchez et al., 2014) from previous reports (Simon et al., 2013; Sokolowski and Salamone, 1994; Wiley et al., 2000) to be used in ad libitum fed rats. To increase subjects’ motivation towards reinforcers without using food restriction/deprivation, a glucose/saccharin (“supersaccharin”) solution was used, which consisted of 1.5% w/v glucose and 0.4% w/v saccharin (Blasio et al., 2012; Valenstein et al., 1967), whose highly rewarding and reinforcing properties are well-known (Blasio et al., 2012; Sabino et al., 2006a; Sabino et al., 2009a; Valenstein et al., 1967). Rats were first trained to lever press for the supersaccharin solution in an overnight session and then in 1 to 4 30-minute fixed ratio 1 (FR1) self-administration sessions (Blasio et al., 2012; Valenstein et al., 1967). Rats were then trained on a DRL-5 schedule for 4–8 sessions, during which a lever press resulted in the delivery of the supersaccharin solution if at least 5 seconds had elapsed since the previous lever press. If the rat made a premature lever press, the 5 second time period was reset; thus, rats obtained the reinforcement if they withheld a response for longer than 5 seconds. Rats were then trained on a DRL-10 schedule for 4–8 sessions and then a DRL-15 schedule until stabilization of responding, during which the response had to be withheld for 10 seconds and 15 seconds, respectively, in order to obtain the reinforcement. Operant sessions were performed daily. Therefore, the microcomputer recorded reinforced (correct), and premature (incorrect) responses on the active lever and inactive responses on the inactive lever. Impulsive action was defined as Efficiency % [100 * ratio between the reinforced responses and the total (reinforced + incorrect) responses], with higher efficiency reflecting more accurate performance, indicative of less impulsive action.

2.5. Estrous cycle synchronization

To synchronize the estrous cycle, female rats were administered, 3 and 8 h into their dark cycle, the potent GnRH receptor superagonist (D-Try6, Pro9-NEt)-GnRH (2 μg/200 μl). This procedure has been extensively used to simulate the proestrous GnRH surge (Sisk et al., 2001), which is followed by a synchronized 4-day period (estrus, metestrus, diestrus, proestrus etc.) (Cottone et al., 2007; Mandyam et al., 2008; Parylak et al., 2012; Richardson et al., 2006; Rivier and Vale, 1990). Therefore, on the second day after GnRH injections, all rats were synchronized in metestrus. The use of pharmacological synchronization provides multiple advantages over other methodologies. First, using this approach, >80% of rats reproducibly show cornified cells in vaginal lavage the following morning, and thereafter share entrained cycles (Richardson et al., 2006; Rivier and Vale, 1990). Therefore, by using pharmacological synchronization, subjects can be studied simultaneously on a defined day of the estrus cycle. Subsequently, synchronization allows the measure of a dependent variable on a defined day of experimentation. Hence, this approach results in a significant reduction of day-to-day and experimental error variance. Furthermore, the small minority of rats not entrained by this procedure would not differ systematically across treatment conditions and thereby constitute (reduced) noise, rather than bias. Finally, pharmacological synchronization does not represent a stressful procedure like the more traditional vaginal lavage/smears procedure (Sharp et al., 2003), which, for this reason, was not performed in any of the experiments of this study.

As previously done (Jaini et al., 2015; Kiani et al., 2018; Rodriguez-Landa et al., 2021), dependent variables collected during proestrus and estrus days were averaged (P-E). Analogously, dependent variables collected during metestrus and diestrus days (M-D) were averaged (M-D).

2.6. Statistical analysis

Unpaired Student’s t-tests were used to evaluate the effects of Sex on efficiency (%), number of correct responses, number of incorrect responses, and number of inactive responses. For female rats, these variables were averaged across the 4 days of the estrous cycle. To evaluate the effects estrous cycle on efficiency (%), number of correct responses, number of incorrect responses, and number of inactive responses, paired Student’s t-tests were used. To evaluate differences between the different phases of the estrous cycle vs males on efficiency (%), number of correct responses, number of incorrect responses, and number of inactive responses, Bonferroni corrected unpaired Student’s t-tests were used. To evaluate the effects of aripiprazole, MK-801, BD-1063 and PRE-084 on efficiency (%), number of correct responses, number of incorrect responses, and number of inactive responses, two-way split plot ANOVAs withs Sex as between-subject factor and Dose as within-subject factor were used. Pairwise post-hoc comparisons were made using Dunnett’s tests. Significance was set at p≤0.05. The software/graphic packages used were InStat 3.0, Statistica 12.0, and Prism 8.0.

3. Results

3.1. Effects of Sex and Estrous cycle on impulsive action, measured using the modified DRL task

As shown in the left panel of Figure 1A, female rats were overall more impulsive than males as revealed by a lower DRL efficiency % (t(66)=2.75, p≤0.01). When females’ inability to withhold a response was studied as a function of the estrous cycle, we found that the smaller efficiency % was mostly driven by the M-D phase (t(26)=3.53, p≤0.01, P-E vs. M-D; Figure 1A, right panel). Accordingly, female rats were more impulsive during the M-D phase of the estrous cycle compared to males (t(66)=2.02, p≤0.01), but not the P-E phase (t(66)=1.97, n.s.).

9.1 Figure 1.

9.1 Figure 1

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Effects of Sex (left panels) and Estrous cycle (right panels) on (A) Efficiency %, (B) Correct responses, (C) Incorrect responses, and (D) Inactive lever responses in male (n=41) and female (n=27) Wistar rats. Panels show M±SEM. Symbols denote significant differences from males: **p≤0.01; ***p≤0.001 and from P-E ##p≤0.01; ###p≤0.001 (uncorrected and Bonferroni corrected Student’s t-tests).

We then determined whether the increased impulsive behavior observed in female rats as compared to males was due to changes in either correct or incorrect responding. We found that, while reinforced responding never differed between sexes (males vs. females: t(66)=0.45, n.s.; Males vs. P-E: t(66)=0.31, n.s.; Males vs. M-D: t(66)=1.22, n.s.; Figure 1B), the decreased efficiency % in female rats was driven by increased premature responding, irrespective of the phase of the estrous cycle (Males vs. Females: t(66)=3.62, p≤0.001; Males vs. P-E: t(66)=2.77, p≤0.05; Males vs. M-D: t(66)=4.28, p≤0.001; Figure 1C). Nonetheless, both reinforced and nonreinforced responding was affected by the estrous cycle, with female rats in M-D phase emitting less correct and more premature responses than in E-P phase (Correct responses: t(26)=4.04, p≤0.001, P-E vs. M-D; Figure 1B, right panel; Incorrect responses: t(26)=3.57, p≤0.01, P-E vs. M-D; Figure 1C, right panel).

Inactive lever responding did not differ between sexes (Males vs. Females: t(66)=0.64, n.s.; Males vs. P-E: t(66)=0.35, n.s.; Males vs. M-D: t(66)=0.87, n.s.; Figure 1D) or between phases of the estrous cycle (t(26)=1.52, n.s., P-E vs. M-D; Figure 1D, right panel).

3.2. Effects of Aripiprazole on impulsive action measured using the modified DRL task

The D2R/5HT2AR antagonist aripiprazole dose-dependently decreased impulsive action in the modified DRL task irrespective of sex, as revealed by an increased efficiency % (Dose: F(3,57)=6.56, p≤0.001; Sex: F(1,19)=5.77, p≤0.05; Dose*Sex: F(3,57)=0.44, n.s.; Figure 2A). Aripiprazole increased the efficiency % in both male and female rats at the highest dose administered (3 mg/kg), as compared to vehicle conditions.

9.2 Figure 2.

9.2 Figure 2

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Effects of pretreatment with the D2R/5HT2AR antagonist, aripiprazole (vehicle, 0.3, 1 and 3 mg/kg, 1 ml/kg, i.p., −30 min) on (A) Efficiency %, (B) Correct responses, (C) Incorrect responses, and (D) Inactive lever responses in male (n=11, left panels) and female (n=10, right panels) Wistar rats. Panels show M±SEM. Symbols denote significant differences from vehicle: *p≤0.05; **p≤0.01 (Dunnett’s test).*p≤0.05; **p≤0.01 (Dunnett’s test).

The improved performance of male and female rats following aripiprazole administration was due to both a reduction of premature responding (Dose: F(3,57)=6.48, p≤0.001; Sex: F(1,19)=5.85, p≤0.05; Dose*Sex: F(3,57)=0.19, n.s.; Figure 2C), and an increase of correct responding (Dose: F(3,57)=4.35, p≤0.01; Sex: F(1,19)=0.68, n.s.; Dose*Sex: F(3,57)=1.80, n.s.; Figure 2B). However, post-hoc analyses revealed that incorrect responding decreased following administration of the highest dose (3 mg/kg) in both sexes, whereas no dose of aripiprazole significantly affected correct responding on the modified DRL task.

Aripiprazole treatment did not affect inactive lever responding (Dose: F(3,57)=6.56, n.s.; Sex: F(1,19)=4.66, p≤0.05; Dose*Sex: F(3,57)=0.78, n.s.; Figure 2D).

3.3. Effects of MK-801 on impulsive action measured using the modified DRL task

The noncompetitive NMDAR antagonist, MK-801, dose-dependently worsened the ability to withhold a response both in male and female rats in the modified DRL task, as shown by a reduced efficiency % (Dose: F(4,68)=15.76, p≤0.001; Sex: F(1,17)=5.07, p≤0.05; Dose*Sex: F(4,68)=0.40, n.s.; Figure 3A). Efficiency % decreased following administration of the 0.01 and the 0.03 mg/kg doses of MK-801 in both sexes.

9.3 Figure 3.

9.3 Figure 3

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Effects of pretreatment with the noncompetitive NMDAR antagonist, MK-801 (vehicle, 0.001, 0.003, 0.01, and 0.03 mg/kg, 1 ml/kg, i.p., −30 min) on (A) Efficiency %, (B) Correct responses, (C) Incorrect responses, and (D) Inactive lever responses in male (n=11, left panels) and female (n=8, right panels) Wistar rats. Panels show M±SEM. Symbols denote significant differences from vehicle: *p≤0.05; **p≤0.01; ***p≤0.001 (Dunnett’s test).

The analysis of responding revealed that the increased impulsive action following MK-801 was due to the contribution of both a decreased number of correct, reinforced responses (Dose: F(4,68)=17.68, p≤0.001; Sex: F(1,17)=6.07, p≤0.05; Dose*Sex: F(4,68)=0.84, n.s.; Figure 3B) and an increased number of incorrect, premature responses (Dose: F(4,68)=8.59, p≤0.001; Sex: F(1,17)=4.41, p≤0.05; Dose*Sex: F(4,68)=0.66, n.s.; Figure 3C). Post-hoc analyses revealed that both the 0.01 and the 0.03 mg/kg doses of MK-801 decreased reinforced responding in both sexes, while only the highest dose (0.03 mg/kg) increased premature responding, and only in male rats.

MK-801 treatment did not affect inactive lever responding (Dose: F(3,57)=2.17, n.s.; Sex: F(1,19)=1.23, n.s.; Dose*Sex: F(3,57)=1.33, n.s.; Figure 3D).

3.4. Effects of BD-1063 on impulsive action measured using the modified DRL task

As shown in Figure 4A, the selective Sig-1R antagonist, BD-1063, dose-dependently decreased impulsive behavior in both sexes, as revealed by an increased efficiency % (Dose: F(4,72)=11.96, p≤0.001; Sex: F(1,18)=8.71, p≤0.01; Figure 4A). The 2-way ANOVA revealed a significant interaction Dose*Sex suggesting that drug treatment affected efficiency % differently in male and female rats (F(4,72)=3.13, p≤0.02; Figure 4A). Hence, post-hoc comparisons showed that BD-1063 increased efficiency % more potently in female rats than in males. Indeed, drug treatment significantly decreased efficiency % in female rats following administration of the 7.5, 15, and 30 mg/kg doses as compared to vehicle condition, while in male rats only the last two doses were effective in decreasing efficiency (15 and 30 mg/kg).

9.4 Figure 4.

9.4 Figure 4

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Effects of pretreatment with the selective Sig-1R antagonist, BD-1063 (vehicle, 3.75, 7.5, 15, and 30 mg/kg, 2 ml/kg, s.c., −15 min) on (A) Efficiency %, (B) Correct responses, (C) Incorrect responses, and (D) Inactive lever responses in male (n=9, left panels) and female (n=11, right panels) Wistar rats. Panels show M±SEM. Symbols denote significant differences from vehicle: *p≤0.05; **p≤0.01; ***p≤0.001 (Dunnett’s test).

Analysis on correct responding revealed that BD-1063 treatment increased the number of reinforced lever presses selectively in female rats at the highest dose administered (30 mg/kg) as compared to male rats (Dose: F(4,72)=2.39, n.s.; Sex: F(1,18)=0.13, n.s.; Dose*Sex: F(4,72)=3.87, p≤0.01; Figure 4B). On the other hand, drug treatment decreased premature responding in both sexes (Dose: F(4,72)=10.27, p≤0.001; Sex: F(1,18)=7.50, p≤0.02; Dose*Sex: F(4,72)=1.90, n.s.; Figure 4C), but once again more potently in females with the 7.5, 15, and 30 mg/kg doses being significantly different compared to vehicle condition, as compared to males, in which only the last dose (30 mg/kg) significantly differed from vehicle.

BD-1063 treatment did not affect inactive lever responding (Dose: F(3,57)=1.91, n.s.; Sex: F(1,19)=0.91, n.s.; Dose*Sex: F(3,57)=0.13, n.s.; Figure 4D).

3.5. Effects of PRE-084 on impulsive action measured using the modified DRL task

Pretreatment with the selective Sig-1R agonist, PRE-084, had no effect on efficiency % (Dose: F(2,32)=0.25, n.s.; Sex: F(1,16)=3.28, n.s.; Dose*Sex: F(2,32)=1.92, n.s.; Figure 5A), number of correct responses (Dose: F(2,32)=0.79, n.s.; Sex: F(1,16)=0.19, n.s.; Dose*Sex: F(2,32)=1.98, n.s.; Figure 5B), number of incorrect responses (Dose: F(2,32)=0.66, n.s.; Sex: F(1,16)=5.85, p≤0.05; Dose*Sex: F(2,32)=1.49, n.s.; Figure 5C), or the number of inactive lever responses (Dose: F(2,32)=2.64, n.s.; Sex: F(1,16)=0.80, n.s.; Dose*Sex: F(2,32)=1.29, n.s.; Figure 5D).

9.5 Figure 5.

9.5 Figure 5

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Effects of pretreatment with the selective Sig-1R agonist, PRE-084 (vehicle, 3, and 10 mg/kg, 1 ml/kg, i.p., −30 min) on (A) Efficiency %, (B) Correct responses, (C) Incorrect responses, and (D) Inactive lever responses in male (n=9, left panels) and female (n=9, right panels) Wistar rats. Panels show M±SEM.

4. Discussion

The modified DRL task used in this study did not use food/water restriction/deprivation. The rationale behind the use ad libitum fed and watered subjects was based on the major limitations associated with reducing the availability of food/water. In fact, the use of food/water restriction/deprivation is known to exert significant neurobiological and metabolic effects (Bi et al., 2003; Carr et al., 2000; Cheng et al., 2004; Di Marzo and Matias, 2005; Fulton et al., 2000; Schoffelmeer et al., 2011; Skibicka et al., 2011; Wolinsky et al., 1996) and it therefore represents an important confounding variable in all those feeding/obesity-related studies which involve also the assessment of impulsivity (Blasio et al., 2012; Moore et al., 2018; Velazquez-Sanchez et al., 2014). We accomplished this by using a “supersaccharin” solution (1.5% w/v glucose and 0.4% w/v saccharin), which is highly rewarding and reinforcing (Blasio et al., 2012; Sabino et al., 2006a; Sabino et al., 2009a; Valenstein et al., 1967) and, therefore, sufficient to increase subjects’ motivation without the need to employ any other experimental manipulation. In addition, another advantage of using this solution is that, compared to other models which are based on the critical limitation of using food as reinforcer, the caloric content of each delivery here is negligible (0.006 kcal), resulting in only ~0.3% of rat daily caloric intake after completion of a session (Blasio et al., 2012; Cottone et al., 2013; Velazquez-Sanchez et al., 2014); this greatly reduces possible influences of energy-homeostatic variables on impulsivity.

In this study, we systematically compared male and estrous-synchronized female rats using this modified DRL task in ad libitum fed and watered subjects. Female rats were administered the potent GnRH receptor superagonist (D-Try6, Pro9-NEt)-GnRH which has been shown to synchronize estrous cycles in more than 80% of rats, while the remaining ~20% of the potentially unsynchronized female subjects would not differ systematically across treatment conditions and thereby constitute noise (Cottone et al., 2007; Richardson et al., 2006; Rivier and Vale, 1990). Our results showed that female rats present a worsened inability to withhold a response than male rats. The increased impulsive action was due to a higher level of premature responding as compared to male rats, while reinforced responding did not significantly differ between sexes. Our results are, therefore, in agreement with a number of clinical and preclinical studies, showing that women/females are more impulsive than males (Anker et al., 2008; Burton and Fletcher, 2012; Colzato et al., 2010; Crosbie et al., 2013; Nederkoorn et al., 2009; Townshend and Duka, 2005). However, existing literature has often given inconclusive and even contradictory results, so that in some studies females have been found to be less impulsive (Bayless et al., 2012; Hasson and Fine, 2012; Jentsch and Taylor, 2003; Liu et al., 2013; Papaleo et al., 2012; Saunders et al., 2008) or equally impulsive (Fernie et al., 2010; Reynolds et al., 2007; Reynolds, 2006; van der Plas et al., 2009) than males.

We have observed that female’s impulsive behavior changed as a function of the estrous cycle with higher impulsive action during the metestrus/diestrus phase, consistent with studies that have shown that females are less impulsive and show better cognitive performance during fertile phases (Carroll et al., 2013; Chavanne and Gallup, 1998; Kaighobadi and Stevens, 2013; Pine and Fletcher, 2011; Slade and Jenner, 1980; Solis-Ortiz et al., 2004; Souza et al., 2012). This behavioral pattern has been interpreted as resulting from an evolutionarily adaptive mechanism through which females employ a more self-controlled and less impulsive behavioral strategy for mate selection during potentially reproductive periods (Hosseini-Kamkar and Morton, 2014).

One of the aims of this study was to evaluate the convergent validity of this modified DRL task, by testing whether the D2R/5HT2AR antagonist, aripiprazole, and the noncompetitive NMDAR antagonist, MK-801, would retain their capability to decrease and increase impulsive action, respectively, as shown using other impulsive action tasks (Barlow et al., 2018; Besson et al., 2010; Higgins et al., 2016). For this purpose estrous synchronized female rats were administered the experimental drugs during metestrus, when the influence of ovarian hormones is minimal (Andersson et al., 2013; Cottone et al., 2007). We found that aripiprazole dose-dependently reduced impulsive action in both male and female rats, and this effect resulted from a decrease in premature responding, consistent with studies that found aripiprazole administration decreased impulsive behavior in rats by reducing the number of premature responding in a 5choice serial reaction time task (5-CSRTT) (Besson et al., 2010). The administration of MK-801 in rats tested in this modified DRL task resulted in a dose-dependent increase in impulsive action in males and females due to both a decrease in number of correct responding and an increase in premature responding. Once again, our results are in agreement with 5-CSRTT studies demonstrating increased impulsive action resulting from both a decreased correct responding and increased premature responding (Barlow et al., 2018; Higgins et al., 2016). Following treatments with both aripiprazole and MK-801, the number of inactive lever responses was unchanged, suggesting specificity of the effects. Therefore, our results support the convergent validity of this modified DRL task.

The third aim of this study was to test whether the selective Sig-1R antagonist BD-1063 and agonist PRE-084 were able to respectively decrease and increase the inability to withhold a response in the modified DRL task. We observed that BD-1063 dose-dependently reduced impulsive action in both sexes, but more potently in female rats as compared to males. Further analysis of lever responding revealed that the nature of this effect was substantially different in the two sexes: indeed, BD-1063 treatment decreased premature responding in both sexes, but once again more potently in female than male rats; in addition, drug treatment selectively increased correct, reinforced responding in female but not in male rats. BD-1063 did not affect responding on the inactive lever, suggesting specificity of the effects. These results extend the role of Sig-1R antagonism as a promising pharmacological tool for the treatment of a variety of neuropsychiatric disorders, including drug and alcohol use disorder as well as eating disorders (Quadir et al., 2019; Sabino et al., 2017), disorders with strong components of impulsivity and inhibitory control deficits. Indeed, antagonism of Sig-1R has been shown to reduce both the locomotor and reinforcing/rewarding effects of psychostimulants like cocaine (Kaushal et al., 2011; Matsumoto et al., 2001; Matsumoto et al., 2002; Romieu et al., 2000; Romieu et al., 2004; Romieu et al., 2002; Sage et al., 2013; Xu et al., 2010; Xu et al., 2012) and methamphetamine (Nguyen et al., 2005; Rodvelt et al., 2011; Takahashi et al., 2000). In addition, blockade of Sig-1R has been successful in blunting a variety of alcohol-related excessive behaviors. Specifically, the selective Sig-1R antagonist, BD-1047, was shown to dose-dependently reduce both the locomotor-stimulating effects of ethanol as well as the rewarding properties of alcohol, as shown by a reduction in the acquisition and the expression of alcohol-induced place preference (Bhutada et al., 2012; Maurice et al., 2003). In addition, the selective Sig-1R antagonists BD-1063 and NE-100 reduced the acquisition, the excessive intake and the preference for alcohol in Sardinian alcohol-preferring rats, a specific strain selectively bred to prefer alcohol (Blasio et al., 2015; Sabino et al., 2009b). Moreover, pretreatment with NE-100 fully prevented the alcohol deprivation effect (Sabino et al., 2009b). Furthermore, BD-1063 was shown to reduce alcohol-seeking behavior in a second-order schedule of reinforcement (Blasio et al., 2015). Finally, Sig-1R antagonism has been successfully used to block binge and compulsive eating (Cifani et al., 2020; Cottone et al., 2012; Del Bello et al., 2019). To the best of our knowledge, this is the first observation that Sig-1R plays a role in impulsive choice behavior, and it may suggest that Sig-1R antagonism may improve addictionrelated behaviors by reducing impulsive behavior.

BD-1063 more potently reduced impulsive behavior in females than in males. These results are consistent with previous finding showing that Sig-1R antagonism exerts greater effects in females compared to males when reducing ethanol binge drinking (Ruiz-Leyva et al., 2020) or the number of earned food responses in a food deprivation status (Tapia et al., 2019). Although this series of studies was not designed to determine the molecular mechanism underlying the increased basal impulsive action and responsiveness to BD-1063 in females compared to males, we can speculate that such differences may be due to differential expression of the Sig-1R protein in the striatum, a brain area involved in decision making and impulsivity (Eagle and Baunez, 2010). Indeed, previous literature has shown that female rats show an increased Sig-1R density in both dorsal and ventral striatum compared to males (Silvers et al., 2006), and such differences may be consistent with a facilitating role of this class of receptors for motivated and impulsive behavior (Quadir et al., 2019; Sabino et al., 2017).

Our results showed that the Sig-1R agonist PRE-084 did not affect the ability to withhold a response in the modified DRL task. Although these results are against our original hypothesis, they are not necessarily unexpected, as scientific literature show that the bidirectional modulatory effects of Sigma receptor ligands not always occur and that, when acutely administered, agonists are often ineffective (Cottone et al., 2012; Romieu et al., 2002; Sabino et al., 2011).

5. Conclusions

In conclusion, the major findings of this series of experiments are as follows: i) in a modified DRL task, in which subjects do not undergo food/water restriction/deprivation, female rats showed an increased inability to withhold a response when compared to males; ii) the increased impulsive action observed in female rats was driven by the metestrus/diestrus phase of the estrous cycle; iii) supporting the convergent validity of the task, the D2R/5HT2AR antagonist, aripiprazole, and the noncompetitive NMDAR antagonist, MK-801, fully retained their capability to reduce and increase impulsive action, respectively; iv) the selective Sig-1R antagonist, BD1063, dose-dependently reduced the inability to withhold a response in both sexes, but more potently in female rats; v) the Sig-1R agonist PRE-084 did not affect impulsive action.

Highlights.

  • A task to measure impulsive action in ad libitum fed/watered subjects was used

  • In this task, female rats show higher impulsive action compared to males

  • Females’ impulsivity is driven by the diestrus phase of the estrous cycle

  • Aripiprazole and MK-801 retain their ability to block and increase impulsivity

  • The Sig-1R antagonist, BD-1063, reduces impulsive action in both sexes

6. Acknowledgements

We thank Lauren Lepeak and Sophia Miracle for the technical assistance.

7. Formatting of funding sources

This publication was made possible thanks to grant numbers AA024439 (VS), AA025038 (VS), and AA026051 (PC), all from the National Institute on Alcohol and Alcoholism (NIAAA), and the Boston University’s Undergraduate Research Opportunities Program (UROP). The work of the Drug Design and Synthesis Section, MTMDB, NIDA, and NIAAA was supported by the NIH Intramural Research Programs of the National Institute on Drug Abuse (NIDA) and the National Institute of Alcohol Abuse and Alcoholism (NIAAA). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.

Footnotes

The authors declare no conflict of interest and no biomedical financial interests.

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8. References

  1. Andersson H, Rehm S, Stanislaus D, Wood CE, 2013. Scientific and regulatory policy committee (SRPC) paper: assessment of circulating hormones in nonclinical toxicity studies III. female reproductive hormones. Toxicol Pathol 41, 921–934. [DOI] [PubMed] [Google Scholar]
  2. Anker JJ, Gliddon LA, Carroll ME, 2008. Impulsivity on a Go/No-go task for intravenous cocaine or food in male and female rats selectively bred for high and low saccharin intake. Behav Pharmacol 19, 615–629. [DOI] [PubMed] [Google Scholar]
  3. Barlow RL, Dalley JW, Pekcec A, 2018. Differences in trait impulsivity do not bias the response to pharmacological drug challenge in the rat five-choice serial reaction time task. Psychopharmacology (Berl) 235, 1199–1209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Bayless DW, Darling JS, Stout WJ, Daniel JM, 2012. Sex differences in attentional processes in adult rats as measured by performance on the 5-choice serial reaction time task. Behav Brain Res 235, 48–54. [DOI] [PubMed] [Google Scholar]
  5. Belin D, Mar AC, Dalley JW, Robbins TW, Everitt BJ, 2008. High impulsivity predicts the switch to compulsive cocaine-taking. Science 320, 1352–1355. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Besson M, Belin D, McNamara R, Theobald DE, Castel A, Beckett VL, Crittenden BM, Newman AH, Everitt BJ, Robbins TW, Dalley JW, 2010. Dissociable control of impulsivity in rats by dopamine d2/3 receptors in the core and shell subregions of the nucleus accumbens. Neuropsychopharmacology 35, 560–569. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Bhutada PS, Mundhada YR, Ghodki YR, Chaware P, Dixit PV, Jain KS, Umathe SN, 2012. Influence of sigma-1 receptor modulators on ethanol-induced conditioned place preference in the extinction-reinstatement model. Behav Pharmacol 23, 25–33. [DOI] [PubMed] [Google Scholar]
  8. Bi S, Robinson BM, Moran TH, 2003. Acute food deprivation and chronic food restriction differentially affect hypothalamic NPY mRNA expression. American journal of physiology. Regulatory, integrative and comparative physiology 285, R1030–1036. [DOI] [PubMed] [Google Scholar]
  9. Blasio A, Narayan AR, Kaminski BJ, Steardo L, Sabino V, Cottone P, 2012. A modified adjusting delay task to assess impulsive choice between isocaloric reinforcers in non-deprived male rats: effects of 5-HT(2)A/C and 5-HT(1)A receptor agonists. Psychopharmacology (Berl) 219, 377–386. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Blasio A, Steardo L, Sabino V, Cottone P, 2013. Opioid system in the medial prefrontal cortex mediates binge-like eating. Addict Biol. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Blasio A, Valenza M, Iyer MR, Rice KC, Steardo L, Hayashi T, Cottone P, Sabino V, 2015. Sigma-1 receptor mediates acquisition of alcohol drinking and seeking behavior in alcohol-preferring rats. Behav Brain Res 287, 315–322. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Burton CL, Fletcher PJ, 2012. Age and sex differences in impulsive action in rats: the role of dopamine and glutamate. Behav Brain Res 230, 21–33. [DOI] [PubMed] [Google Scholar]
  13. Carr KD, Kim G, Cabeza de Vaca S, 2000. Hypoinsulinemia may mediate the lowering of selfstimulation thresholds by food restriction and streptozotocin-induced diabetes. Brain research 863, 160168. [DOI] [PubMed] [Google Scholar]
  14. Carroll ME, Kohl EA, Johnson KM, LaNasa RM, 2013. Increased impulsive choice for saccharin during PCP withdrawal in female monkeys: influence of menstrual cycle phase. Psychopharmacology (Berl) 227, 413–424. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Cassin SE, von Ranson KM, 2005. Personality and eating disorders: a decade in review. Clin Psychol Rev 25, 895–916. [DOI] [PubMed] [Google Scholar]
  16. Chamberlain SR, Sahakian BJ, 2007. The neuropsychiatry of impulsivity. Curr Opin Psychiatry 20, 255–261. [DOI] [PubMed] [Google Scholar]
  17. Chavanne TJ, Gallup GG, 1998. Variation in risk taking behavior among female college students as a function of the menstrual cycle. Evolution and Human Behavior 19, 27–32. [Google Scholar]
  18. Cheng CM, Hicks K, Wang J, Eagles DA, Bondy CA, 2004. Caloric restriction augments brain glutamic acid decarboxylase-65 and −67 expression. Journal of neuroscience research 77, 270–276. [DOI] [PubMed] [Google Scholar]
  19. Cifani C, Micioni Di Bonaventura E, Botticelli L, Del Bello F, Giorgioni G, Pavletic P, Piergentili A, Quaglia W, Bonifazi A, Schepmann D, Wunsch B, Vistoli G, Micioni Di Bonaventura MV, 2020. Novel Highly Potent and Selective Sigma1 Receptor Antagonists Effectively Block the Binge Eating Episode in Female Rats. ACS Chem Neurosci 11, 3107–3116. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Colzato LS, Hertsig G, van den Wildenberg WP, Hommel B, 2010. Estrogen modulates inhibitory control in healthy human females: evidence from the stop-signal paradigm. Neuroscience 167, 709–715. [DOI] [PubMed] [Google Scholar]
  21. Cottone P, Iemolo A, Narayan AR, Kwak J, Momaney D, Sabino V, 2013. The uncompetitive NMDA receptor antagonists ketamine and memantine preferentially increase the choice for a small, immediate reward in low-impulsive rats. Psychopharmacology (Berl) 226, 127–138. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Cottone P, Sabino V, Roberto M, Bajo M, Pockros L, Frihauf JB, Fekete EM, Steardo L, Rice KC, Grigoriadis DE, Conti B, Koob GF, Zorrilla EP, 2009. CRF system recruitment mediates dark side of compulsive eating. Proc Natl Acad Sci U S A 106, 20016–20020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Cottone P, Sabino V, Steardo L, Zorrilla EP, 2007. FG 7142 specifically reduces meal size and the rate and regularity of sustained feeding in female rats: evidence that benzodiazepine inverse agonists reduce food palatability. Neuropsychopharmacology 32, 1069–1081. [DOI] [PubMed] [Google Scholar]
  24. Cottone P, Wang X, Park JW, Valenza M, Blasio A, Kwak J, Iyer MR, Steardo L, Rice KC, Hayashi T, Sabino V, 2012. Antagonism of sigma-1 receptors blocks compulsive-like eating. Neuropsychopharmacology 37, 2593–2604. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Crosbie J, Arnold P, Paterson A, Swanson J, Dupuis A, Li X, Shan J, Goodale T, Tam C, Strug LJ, Schachar RJ, 2013. Response inhibition and ADHD traits: correlates and heritability in a community sample. J Abnorm Child Psychol 41, 497–507. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Dalley JW, Everitt BJ, Robbins TW, 2011. Impulsivity, compulsivity, and top-down cognitive control. Neuron 69, 680–694. [DOI] [PubMed] [Google Scholar]
  27. Dalley JW, Mar AC, Economidou D, Robbins TW, 2008. Neurobehavioral mechanisms of impulsivity: fronto-striatal systems and functional neurochemistry. Pharmacol Biochem Behav 90, 250–260. [DOI] [PubMed] [Google Scholar]
  28. de Costa BR, He XS, Linders JT, Dominguez C, Gu ZQ, Williams W, Bowen WD, 1993. Synthesis and evaluation of conformationally restricted N-[2-(3,4-dichlorophenyl)ethyl]-N-methyl-2-(1-pyrrolidinyl)ethylamines at sigma receptors. 2. Piperazines, bicyclic amines, bridged bicyclic amines, and miscellaneous compounds. J Med Chem 36, 2311–2320. [DOI] [PubMed] [Google Scholar]
  29. Del Bello F, Micioni Di Bonaventura MV, Bonifazi A, Wunsch B, Schepmann D, Giancola JB, Micioni Di Bonaventura E, Vistoli G, Giorgioni G, Quaglia W, Piergentili A, Cifani C, 2019. Investigation of the Role of Chirality in the Interaction with sigma Receptors and Effect on Binge Eating Episode of a Potent sigma1 Antagonist Analogue of Spipethiane. ACS Chem Neurosci 10, 3391–3397. [DOI] [PubMed] [Google Scholar]
  30. Delprat B, Crouzier L, Su TP, Maurice T, 2020. At the Crossing of ER Stress and MAMs: A Key Role of Sigma-1 Receptor? Adv Exp Med Biol 1131, 699–718. [DOI] [PubMed] [Google Scholar]
  31. Di Marzo V, Matias I, 2005. Endocannabinoid control of food intake and energy balance. Nature neuroscience 8, 585–589. [DOI] [PubMed] [Google Scholar]
  32. Eagle DM, Baunez C, 2010. Is there an inhibitory-response-control system in the rat? Evidence from anatomical and pharmacological studies of behavioral inhibition. Neurosci Biobehav Rev 34, 50–72. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Evenden JL, 1999. Varieties of impulsivity. Psychopharmacology (Berl) 146, 348–361. [DOI] [PubMed] [Google Scholar]
  34. Fekete EM, Zhao Y, Szucs A, Sabino V, Cottone P, Rivier J, Vale WW, Koob GF, Zorrilla EP, 2011. Systemic urocortin 2, but not urocortin 1 or stressin 1-A, suppresses feeding via CRF2 receptors without malaise and stress. Br J Pharmacol 164, 1959–1975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Fernie G, Cole JC, Goudie AJ, Field M, 2010. Risk-taking but not response inhibition or delay discounting predict alcohol consumption in social drinkers. Drug Alcohol Depend 112, 54–61. [DOI] [PubMed] [Google Scholar]
  36. Fulton S, Woodside B, Shizgal P, 2000. Modulation of brain reward circuitry by leptin. Science 287, 125–128. [DOI] [PubMed] [Google Scholar]
  37. Geyer M. A. a. M., A., 1995. Animal models of psychiatric disorders., Psychopharmacology: The Fourth Generation of Progress Raven Press: New York. [Google Scholar]
  38. Gullo MJ, Loxton NJ, Dawe S, 2014. Impulsivity: four ways five factors are not basic to addiction. Addict Behav 39, 1547–1556. [DOI] [PubMed] [Google Scholar]
  39. Hamilton KR, Mitchell MR, Wing VC, Balodis IM, Bickel WK, Fillmore M, Lane SD, Lejuez CW, Littlefield AK, Luijten M, Mathias CW, Mitchell SH, Napier TC, Reynolds B, Schutz CG, Setlow B, Sher KJ, Swann AC, Tedford SE, White MJ, Winstanley CA, Yi R, Potenza MN, Moeller FG, 2015. Choice impulsivity: Definitions, measurement issues, and clinical implications. Personal Disord 6, 182–198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Hasson R, Fine JG, 2012. Gender differences among children with ADHD on continuous performance tests: a meta-analytic review. J Atten Disord 16, 190–198. [DOI] [PubMed] [Google Scholar]
  41. Higgins GA, Silenieks LB, MacMillan C, Sevo J, Zeeb FD, Thevarkunnel S, 2016. Enhanced attention and impulsive action following NMDA receptor GluN2B-selective antagonist pretreatment. Behav Brain Res 311, 1–14. [DOI] [PubMed] [Google Scholar]
  42. Hosseini-Kamkar N, Morton JB, 2014. Sex differences in self-regulation: an evolutionary perspective. Front Neurosci 8, 233. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Jaini R, Altuntas CZ, Loya MG, Tuohy VK, 2015. Disruption of estrous cycle homeostasis in mice with experimental autoimmune encephalomyelitis. J Neuroimmunol 279, 71–74. [DOI] [PubMed] [Google Scholar]
  44. Jentsch JD, Taylor JR, 2003. Sex-related differences in spatial divided attention and motor impulsivity in rats. Behav Neurosci 117, 76–83. [DOI] [PubMed] [Google Scholar]
  45. Kaighobadi F, Stevens JR, 2013. Does fertility status influence impulsivity and risk taking in human females? Adaptive influences on intertemporal choice and risky decision making. Evol Psychol 11, 700717. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Kaushal N, Robson MJ, Vinnakota H, Narayanan S, Avery BA, McCurdy CR, Matsumoto RR, 2011. Synthesis and pharmacological evaluation of 6-acetyl-3-(4-(4-(4-fluorophenyl)piperazin-1-yl)butyl)benzo[d]oxazol-2(3H)-one (SN79), a cocaine antagonist, in rodents. AAPS J 13, 336–346. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Kiani K, Movahedin M, Malekafzali H, Mirfasihi F, Sadati SN, Moini A, Ostad S, Aflatoonian R, 2018. Effect of the estrus cycle stage on the establishment of murine endometriosis lesions. Int J Reprod Biomed 16, 305–314. [PMC free article] [PubMed] [Google Scholar]
  48. Liu T, Xiao T, Shi J, 2013. Response inhibition, preattentive processing, and sex difference in young children: an event-related potential study. Neuroreport 24, 126–130. [DOI] [PubMed] [Google Scholar]
  49. Mandyam CD, Crawford EF, Eisch AJ, Rivier CL, Richardson HN, 2008. Stress experienced in utero reduces sexual dichotomies in neurogenesis, microenvironment, and cell death in the adult rat hippocampus. Dev Neurobiol 68, 575–589. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Matsumoto RR, McCracken KA, Friedman MJ, Pouw B, De Costa BR, Bowen WD, 2001. Conformationally restricted analogs of BD1008 and an antisense oligodeoxynucleotide targeting sigma1 receptors produce anti-cocaine effects in mice. Eur J Pharmacol 419, 163–174. [DOI] [PubMed] [Google Scholar]
  51. Matsumoto RR, McCracken KA, Pouw B, Zhang Y, Bowen WD, 2002. Involvement of sigma receptors in the behavioral effects of cocaine: evidence from novel ligands and antisense oligodeoxynucleotides. Neuropharmacology 42, 1043–1055. [DOI] [PubMed] [Google Scholar]
  52. Maurice T, Casalino M, Lacroix M, Romieu P, 2003. Involvement of the sigma 1 receptor in the motivational effects of ethanol in mice. Pharmacol Biochem Behav 74, 869–876. [DOI] [PubMed] [Google Scholar]
  53. Meda SA, Stevens MC, Potenza MN, Pittman B, Gueorguieva R, Andrews MM, Thomas AD, Muska C, Hylton JL, Pearlson GD, 2009. Investigating the behavioral and self-report constructs of impulsivity domains using principal component analysis. Behav Pharmacol 20, 390–399. [DOI] [PMC free article] [PubMed] [Google Scholar]
  54. Moeller FG, Barratt ES, Dougherty DM, Schmitz JM, Swann AC, 2001. Psychiatric aspects of impulsivity. Am J Psychiatry 158, 1783–1793. [DOI] [PubMed] [Google Scholar]
  55. Moore CF, Blasio A, Sabino V, Cottone P, 2018. Impulsive choice does not predict binge-like eating in rats. Behav Pharmacol 29, 726–731. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Nederkoorn C, Baltus M, Guerrieri R, Wiers RW, 2009. Heavy drinking is associated with deficient response inhibition in women but not in men. Pharmacol Biochem Behav 93, 331–336. [DOI] [PubMed] [Google Scholar]
  57. Neill DB, 1976. Frontal-striatal control of behavioral inhibition in the rat. Brain Res 105, 89–103. [DOI] [PubMed] [Google Scholar]
  58. Nguyen EC, McCracken KA, Liu Y, Pouw B, Matsumoto RR, 2005. Involvement of sigma (σ) receptors in the acute actions of methamphetamine: receptor binding and behavioral studies. Neuropharmacology 49, 638–645. [DOI] [PubMed] [Google Scholar]
  59. Papaleo F, Erickson L, Liu G, Chen J, Weinberger DR, 2012. Effects of sex and COMT genotype on environmentally modulated cognitive control in mice. Proc Natl Acad Sci U S A 109, 20160–20165. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Parylak SL, Cottone P, Sabino V, Rice KC, Zorrilla EP, 2012. Effects of CB1 and CRF1 receptor antagonists on binge-like eating in rats with limited access to a sweet fat diet: lack of withdrawal-like responses. Physiol Behav 107, 231–242. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Pine KJ, Fletcher B, 2011. Women’s spending behaviour is menstrual-cycle sensitive. Personality and Individual Differences 50, 74–78. [Google Scholar]
  62. Potenza MN, 2007. To do or not to do? The complexities of addiction, motivation, self-control, and impulsivity. Am J Psychiatry 164, 4–6. [DOI] [PubMed] [Google Scholar]
  63. Quadir SG, Cottone P, Sabino V, 2019. Role of Sigma Receptors in Alcohol Addiction. Front Pharmacol 10, 687. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Reynolds B, Patak M, Shroff P, Penfold RB, Melanko S, Duhig AM, 2007. Laboratory and self-report assessments of impulsive behavior in adolescent daily smokers and nonsmokers. Exp Clin Psychopharmacol 15, 264–271. [DOI] [PubMed] [Google Scholar]
  65. Reynolds BO,A; Richards JB; de Wit H, 2006. Dimensions of impulsive behavior: personality and behavioral measures. Personality and Individual Differences 40, 305–315. [Google Scholar]
  66. Richardson HN, Zorrilla EP, Mandyam CD, Rivier CL, 2006. Exposure to repetitive versus varied stress during prenatal development generates two distinct anxiogenic and neuroendocrine profiles in adulthood. Endocrinology 147, 2506–2517. [DOI] [PubMed] [Google Scholar]
  67. Rivier C, Vale W, 1990. Cytokines act within the brain to inhibit luteinizing hormone secretion and ovulation in the rat. Endocrinology 127, 849–856. [DOI] [PubMed] [Google Scholar]
  68. Rivier J, Amoss M, Rivier C, Vale W, 1974. Synthetic luteinizing hormone releasing factor. Short chain analogs. J Med Chem 17, 230–233. [DOI] [PubMed] [Google Scholar]
  69. Robbins TW, Gillan CM, Smith DG, de Wit S, Ersche KD, 2012. Neurocognitive endophenotypes of impulsivity and compulsivity: towards dimensional psychiatry. Trends Cogn Sci 16, 81–91. [DOI] [PubMed] [Google Scholar]
  70. Rodriguez-Landa JF, Guillen-Ruiz G, Hernandez-Lopez F, Cueto-Escobedo J, Rivadeneyra-Dominguez E, Bernal-Morales B, Herrera-Huerta EV, 2021. Chrysin reduces anxiety-like behavior through actions on GABAA receptors during metestrus-diestrus in the rat. Behav Brain Res 397, 112952. [DOI] [PubMed] [Google Scholar]
  71. Rodvelt KR, Oelrichs CE, Blount LR, Fan K-H, Lever SZ, Lever JR, Miller DK, 2011. The sigma receptor agonist SA4503 both attenuates and enhances the effects of methamphetamine. Drug Alcohol Depend 116, 203–210. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Romieu P, Martin-Fardon R, Maurice T, 2000. Involvement of the sigma1 receptor in the cocaineinduced conditioned place preference. Neuroreport 11, 2885–2888. [DOI] [PubMed] [Google Scholar]
  73. Romieu P, Meunier J, Garcia D, Zozime N, Martin-Fardon R, Bowen WD, Maurice T, 2004. The sigma1 (sigma1) receptor activation is a key step for the reactivation of cocaine conditioned place preference by drug priming. Psychopharmacology (Berl) 175, 154–162. [DOI] [PubMed] [Google Scholar]
  74. Romieu P, Phan VL, Martin-Fardon R, Maurice T, 2002. Involvement of the sigma(1) receptor in cocaine-induced conditioned place preference: possible dependence on dopamine uptake blockade. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 26, 444–455. [DOI] [PubMed] [Google Scholar]
  75. Ruiz-Leyva L, Salguero A, Moron I, Portillo-Salido E, Cendan CM, Pautassi RM, 2020. Sigma-1 antagonism inhibits binge ethanol drinking at adolescence. Drug Alcohol Depend 215, 108214. [DOI] [PubMed] [Google Scholar]
  76. Sabino V, Cottone P, Blasio A, Iyer MR, Steardo L, Rice KC, Conti B, Koob GF, Zorrilla EP, 2011. Activation of sigma-receptors induces binge-like drinking in Sardinian alcohol-preferring rats. Neuropsychopharmacology 36, 1207–1218. [DOI] [PMC free article] [PubMed] [Google Scholar]
  77. Sabino V, Cottone P, Koob GF, Steardo L, Lee MJ, Rice KC, Zorrilla EP, 2006a. Dissociation between opioid and CRF1 antagonist sensitive drinking in Sardinian alcohol-preferring rats. Psychopharmacology 189, 175–186. [DOI] [PubMed] [Google Scholar]
  78. Sabino V, Cottone P, Koob GF, Steardo L, Lee MJ, Rice KC, Zorrilla EP, 2006b. Dissociation between opioid and CRF1 antagonist sensitive drinking in Sardinian alcohol-preferring rats. Psychopharmacology (Berl) 189, 175–186. [DOI] [PubMed] [Google Scholar]
  79. Sabino V, Cottone P, Zhao Y, Iyer MR, Steardo L Jr., Steardo L, Rice KC, Conti B, Koob GF, Zorrilla EP, 2009a. The sigma-receptor antagonist BD-1063 decreases ethanol intake and reinforcement in animal models of excessive drinking. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 34, 1482–1493. [DOI] [PMC free article] [PubMed] [Google Scholar]
  80. Sabino V, Cottone P, Zhao Y, Steardo L, Koob GF, Zorrilla EP, 2009b. Selective reduction of alcohol drinking in Sardinian alcohol-preferring rats by a sigma-1 receptor antagonist. Psychopharmacology (Berl) 205, 327–335. [DOI] [PMC free article] [PubMed] [Google Scholar]
  81. Sabino V, Hicks C, Cottone P, 2017. Sigma Receptors and Substance Use Disorders. Adv Exp Med Biol 964, 177–199. [DOI] [PMC free article] [PubMed] [Google Scholar]
  82. Sage AS, Vannest SC, Fan KH, Will MJ, Lever SZ, Lever JR, Miller DK, 2013. N-Phenylpropyl-N’-(3-methoxyphenethyl)piperazine (YZ-185) Attenuates the Conditioned-Rewarding Properties of Cocaine in Mice. ISRN Pharmacol 2013, 546314. [DOI] [PMC free article] [PubMed] [Google Scholar]
  83. Saunders B, Farag N, Vincent AS, Collins FL Jr., Sorocco KH, Lovallo WR, 2008. Impulsive errors on a Go-NoGo reaction time task: disinhibitory traits in relation to a family history of alcoholism. Alcohol Clin Exp Res 32, 888–894. [DOI] [PMC free article] [PubMed] [Google Scholar]
  84. Schmidt HR, Kruse AC, 2019. The Molecular Function of sigma Receptors: Past, Present, and Future. Trends Pharmacol Sci 40, 636–654. [DOI] [PMC free article] [PubMed] [Google Scholar]
  85. Schoffelmeer AN, Drukarch B, De Vries TJ, Hogenboom F, Schetters D, Pattij T, 2011. Insulin modulates cocaine-sensitive monoamine transporter function and impulsive behavior. The Journal of neuroscience : the official journal of the Society for Neuroscience 31, 1284–1291. [DOI] [PMC free article] [PubMed] [Google Scholar]
  86. Sharp J, Zammit T, Azar T, Lawson D, 2003. Stress-like responses to common procedures in individually and group-housed female rats. Contemp Top Lab Anim Sci 42, 9–18. [PubMed] [Google Scholar]
  87. Silvers JM, Wallace DR, Harrod SB, Mactutus CF, Booze RM, 2006. Prenatal cocaine alters dopamine and sigma receptor binding in nucleus accumbens and striatum in dams and adolescent offspring. Neurotoxicol Teratol 28, 173–180. [DOI] [PubMed] [Google Scholar]
  88. Simon NW, Beas BS, Montgomery KS, Haberman RP, Bizon JL, Setlow B, 2013. Prefrontal cortical-striatal dopamine receptor mRNA expression predicts distinct forms of impulsivity. Eur J Neurosci 37, 1779–1788. [DOI] [PMC free article] [PubMed] [Google Scholar]
  89. Sisk CL, Richardson HN, Chappell PE, Levine JE, 2001. In vivo gonadotropin-releasing hormone secretion in female rats during peripubertal development and on proestrus. Endocrinology 142, 2929–2936. [DOI] [PubMed] [Google Scholar]
  90. Skibicka KP, Hansson C, Alvarez-Crespo M, Friberg PA, Dickson SL, 2011. Ghrelin directly targets the ventral tegmental area to increase food motivation. Neuroscience 180, 129–137. [DOI] [PubMed] [Google Scholar]
  91. Slade P, Jenner FA, 1980. Performance tests in different phases of the menstrual cycle. J Psychosom Res 24, 5–8. [DOI] [PubMed] [Google Scholar]
  92. Sokolowski JD, Salamone JD, 1994. Effects of dopamine depletions in the medial prefrontal cortex on DRL performance and motor activity in the rat. Brain Res 642, 20–28. [DOI] [PubMed] [Google Scholar]
  93. Solis-Ortiz S, Guevara MA, Corsi-Cabrera M, 2004. Performance in a test demanding prefrontal functions is favored by early luteal phase progesterone: an electroencephalographic study. Psychoneuroendocrinology 29, 1047–1057. [DOI] [PubMed] [Google Scholar]
  94. Souza EG, Ramos MG, Hara C, Stumpf BP, Rocha FL, 2012. Neuropsychological performance and menstrual cycle: a literature review. Trends Psychiatry Psychother 34, 5–12. [DOI] [PubMed] [Google Scholar]
  95. Takahashi S, Miwa T, Horikomi K, 2000. Involvement of sigma 1 receptors in methamphetamineinduced behavioral sensitization in rats. Neurosci.Lett. 289, 21–24. [DOI] [PubMed] [Google Scholar]
  96. Tapia MA, Lee JR, Bathe EL, Rivera LL, Mason KL, Cessac ME, Bodeen JL, Miller DK, Will MJ, 2019. Sigma-1 receptor antagonist, PD144418, selectively reduces female motivation for food during negative energy balance. Behav Brain Res 373, 112087. [DOI] [PubMed] [Google Scholar]
  97. Townshend JM, Duka T, 2005. Binge drinking, cognitive performance and mood in a population of young social drinkers. Alcohol Clin Exp Res 29, 317–325. [DOI] [PubMed] [Google Scholar]
  98. Uslaner JM, Robinson TE, 2006. Subthalamic nucleus lesions increase impulsive action and decrease impulsive choice - mediation by enhanced incentive motivation? Eur J Neurosci 24, 2345–2354. [DOI] [PubMed] [Google Scholar]
  99. Valenstein ES, Cox VC, Kakolewski JW, 1967. Polydipsia elicited by the synergistic action of a saccharin and glucose solution. Science 157, 552–554. [DOI] [PubMed] [Google Scholar]
  100. van der Plas EA, Crone EA, van den Wildenberg WP, Tranel D, Bechara A, 2009. Executive control deficits in substance-dependent individuals: a comparison of alcohol, cocaine, and methamphetamine and of men and women. J Clin Exp Neuropsychol 31, 706–719. [DOI] [PMC free article] [PubMed] [Google Scholar]
  101. Velazquez-Sanchez C, Ferragud A, Moore CF, Everitt BJ, Sabino V, Cottone P, 2014. High trait impulsivity predicts food addiction-like behavior in the rat. Neuropsychopharmacology 39, 2463–2472. [DOI] [PMC free article] [PubMed] [Google Scholar]
  102. Weafer J, de Wit H, 2014. Sex differences in impulsive action and impulsive choice. Addict Behav 39, 1573–1579. [DOI] [PMC free article] [PubMed] [Google Scholar]
  103. Wiley JL, Compton AD, Golden KM, 2000. Separation of drug effects on timing and behavioral inhibition by increased stimulus control. Exp Clin Psychopharmacol 8, 451–461. [DOI] [PubMed] [Google Scholar]
  104. Winstanley CA, Eagle DM, Robbins TW, 2006. Behavioral models of impulsivity in relation to ADHD: translation between clinical and preclinical studies. Clin Psychol Rev 26, 379–395. [DOI] [PMC free article] [PubMed] [Google Scholar]
  105. Wolinsky TD, Carr KD, Hiller JM, Simon EJ, 1996. Chronic food restriction alters mu and kappa opioid receptor binding in the parabrachial nucleus of the rat: a quantitative autoradiographic study. Brain research 706, 333–336. [DOI] [PubMed] [Google Scholar]
  106. Xu YT, Kaushal N, Shaikh J, Wilson LL, Mesangeau C, McCurdy CR, Matsumoto RR, 2010. A novel substituted piperazine, CM156, attenuates the stimulant and toxic effects of cocaine in mice. The Journal of pharmacology and experimental therapeutics 333, 491–500. [DOI] [PMC free article] [PubMed] [Google Scholar]
  107. Xu YT, Robson MJ, Szeszel-Fedorowicz W, Patel D, Rooney R, McCurdy CR, Matsumoto RR, 2012. CM156, a sigma receptor ligand, reverses cocaine-induced place conditioning and transcriptional responses in the brain. Pharmacol Biochem Behav 101, 174–180. [DOI] [PMC free article] [PubMed] [Google Scholar]
  108. Yates JR, Gunkel BT, Rogers KK, Breitenstein KA, Hughes MN, Johnson AB, Sharpe SM, 2018. Effects of N-methyl-d-aspartate receptor (NMDAr) uncompetitive antagonists in a delay discounting paradigm using a concurrent-chains procedure. Behav Brain Res 349, 125–129. [DOI] [PMC free article] [PubMed] [Google Scholar]

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