Pharmacological characterization of sex differences in the effects of dopaminergic drugs on effort-based decision making in rats

• Published in: Psychopharmacology 2024-10, Vol.241 (10), p.2033-2044
• Main Authors: Ecevitoglu, Alev, Beard, Kathryn R., Srynath, Sonia, Edelstein, Gayle A., Olivares-Garcia, Regulo, Martinez-Verdu, Andrea, Meka, Nicolette, Correa, Merce, Salamone, John D.
• Format: Article
• Language: English
• Subjects: Antagonists; Biomedical and Life Sciences; Biomedicine; c-Fos protein; Decision making; Dopamine; Dopamine receptors; Dopamine transporter; Females; Gender differences; Haloperidol; Immunoreactivity; Males; Mental disorders; Neurosciences; Nucleus accumbens; Original Investigation; Pharmacology/Toxicology; Psychiatry; Psychopathology; Sex differences; Tetrabenazine
• ISSN: 0033-3158; 1432-2072; 1432-2072
• DOI: 10.1007/s00213-024-06615-8

Rationale Motivational dysfunctions related to effort exertion are common in psychiatric disorders. Dopamine systems regulate exertion of effort and effort-based choice in humans and rodents. Objectives Previous rodent studies mainly employed male rats, and it is imperative to conduct studies in male and female rats. Methods The present studies compared the effort-related effects of IP injections of the dopamine antagonists ecopipam and haloperidol, and the vesicular monoamine transport-2 inhibitor tetrabenazine (TBZ), in male and female rats using the fixed ratio 5/chow feeding choice task. Results Ecopipam (0.05–0.2 mg/kg) and haloperidol (0.05–0.15 mg/kg) induced a low-effort bias, decreasing lever pressing and increasing chow intake in males and females in the same dose range. With lever pressing, there was a modest but significant dose x sex interaction after ecopipam injection, but there was no significant interaction after administration of haloperidol. In the first study with TBZ (0.25-1.0 mg/kg), there was a robust sex difference. TBZ shifted choice from lever pressing to chow intake in male rats, but was ineffective in females. In a second experiment, 2.0 mg/kg affected choice behavior in both males and females. TBZ increased accumbens c-Fos immunoreactivity in a sex-dependent manner, with males significantly increasing at 1.0 mg/kg, while females showed augmented immunoreactivity at 2.0 mg/kg. Conclusions The neural and behavioral effects of TBZ differed across sexes, emphasizing the importance of conducting studies in male and female rats. This research has implications for understanding the effort-related motivational dysfunctions seen in psychopathology.