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

• Published in: Neuropharmacology Vol. 200; p. 108786
• Main Authors: Sabino, Valentina, Blasio, Angelo, Ferragud, Antonio, Quadir, Sema G., Iyer, Malliga R., Rice, Kenner C., Cottone, Pietro
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.12.2021
• Subjects: Animals; Aripiprazole; Aripiprazole - pharmacology; Behavior, Animal - drug effects; Choice Behavior - drug effects; Dizocilpine Maleate - pharmacology; Dopamine D2 Receptor Antagonists - pharmacology; Estrous cycle; Estrous Cycle - drug effects; Female; Impulsive action; Impulsive Behavior - drug effects; Impulsivity; Male; MK-801; Piperazines - pharmacology; Rats; Rats, Wistar; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, sigma - drug effects; Serotonin 5-HT2 Receptor Agonists - pharmacology; Sigma-1 Receptor; MK-801; Impulsivity; Impulsive action; Estrous cycle; Aripiprazole; Sigma-1 receptor
• ISSN: 0028-3908; 1873-7064; 1873-7064
• DOI: 10.1016/j.neuropharm.2021.108786

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, and 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. •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.