The D1/D2-like receptor antagonist flupentixol and the D2-like receptor antagonist L-741626 decrease operant responding for nicotine and food and locomotor activity in male and female rats

Abstract

Background: The reinforcing properties of nicotine play a critical role in smoking and vaping. There is a need for treatments that decrease the reinforcing properties of nicotine and thereby improve smoking and vaping rates. Dopamine plays a role in the reinforcing properties of nicotine, but little is known about the role of dopamine D2-like receptors in nicotine intake and whether there are sex differences in the effects of dopaminergic drugs on nicotine intake. Aim: The goal of the present studies was to investigate the effects of the D1/D2-like receptor antagonist flupentixol and the D2-like receptor antagonist L-741626 on nicotine self-administration in male and female rats. Methods: The effects of flupentixol and L-741626 on operant responding for nicotine and food and locomotor activity in a small open field were investigated. Results: There were no sex differences in baseline nicotine intake. The D1/D2-like receptor antagonist flupentixol and the D2-like receptor antagonist L-741626 decreased operant responding for nicotine. Blockade of D1/D2-like receptors and blockade of D2-like receptors also decreased operant responding for food and decreased locomotor activity. Flupentixol induced a greater decrease in operant responding for food in males than females. However, in the other tests, there were no sex differences in the effects of the dopamine receptor antagonists. Conclusions: Blockade of D1/D2-like receptors with flupentixol and D2-like receptors with L-741626 decreases nicotine and food intake in rats of both sexes. These compounds also decrease locomotor activity which might be indicative of a sedative effect.

VTA dopamine neurons are hyperexcitable in 3xTg-AD mice due to casein kinase 2-dependent SK channel dysfunction

“…AD patients suffer from deficits in motivation-based appetitive behaviors that could indicate a central role for VTA DA neurons 16 . To assess whether 3xTg mice display behavioral impairment in operant reward learning, we assessed acquisition of an operant task to gain access to palatable pellets in non-food restricted 6- and 12-month-old 3xTg and wildtype (WT) mice (Figure 1a), a task previously shown to rely on NAc DA 22 . All WT mice tested at both ages successfully acquired the operant task.…”

Sex Differences in E-Cigarette Use and Related Health Effects

“…In almost all cases, particularly in central nervous system responses, the presence of nicotine in vaping fluids exacerbated the effects [94,95,[103][104][105]108]. Not surprisingly, sexdependent effects were found, whereby female adolescent rats displayed lower anxiolytic effects and were more sensitive to the rewarding effect of nicotine than their male counterparts [93,139,140], although others did not find sex differences [107]. Interestingly, the gut microbiome was found to mediate sex-dependent effects related to nicotine metabolism in chronic e-cigarette exposure, and nicotine exposure was found to decrease alpha diversity in females and beta diversity in both sexes [92].…”

Mifepristone decreases nicotine intake in dependent and non-dependent adult rats

“…2A). The rats were fed 90%-95% of their baseline food intake in the home cage after operant responding for food (Chellian et al, 2022(Chellian et al, , 2023. The rats were mildly food deprived to enhance their motivation for operant responding for food pellets.…”