Chemogenetic inhibition of dopaminergic projections to the nucleus accumbens has sexually dimorphic effects in the rat gambling task.

Abstract

Women and men can differ in their propensity to take risks and develop impulse control and addiction disorders. Sexual dimorphisms in behavioral control by the mesolimbic dopaminergic reward system may underlie these phenomena, given its sensitivity to gonadal hormones. However, this is hard to test experimentally using humans. Using the rat gambling task (rGT), we investigated what impact acute inhibition of accumbal dopamine had on decision-making and impulsivity in animals of both sexes. We expressed an inhibitory designer receptor exclusively activated by designer drugs (hM4D[Gi]) in the accumbal dopaminergic efferents of female and male transgenic (Tg) rats, engineered to selectively express cre recombinase in neurons synthesizing tyrosine hydroxylase. We then trained the rats to perform the rGT and assessed the effect of an acute clozapine-n-oxide (0–3 mg/kg) challenge. Chemogenetic inhibition of dopaminergic projections to the accumbens did not affect choice in females, perhaps due to low levels of risky choice in Tg+ animals at baseline, but induced a switch from risky to optimal decision-making in males performing the cued rGT. This manipulation also decreased motor impulsivity but only in females. These data support the hypothesis that cue-driven risky choice is mediated, at least in males, by activity of accumbal dopaminergic neurons. However, motor impulsivity is more sensitive to inhibition of accumbal dopamine neurons in female rats. These data may help explain differences in the manifestation of addictions across gender and reinforce the importance of examining both sexes when seeking to attribute control of behavior to specific monoaminergic pathways.

Dopamine neurons gate the intersection of cocaine use, decision making, and impulsivity

“…Concordant with our hypotheses, TG+ males showed reduced premature responding throughout testing (Figure 5B; TG: F 1,29 = 9.581, p = 0.004); these differences emerged on the fifth session of crGT training and continued throughout (TG− vs. TG+; s1–s4: all t s < 0.967, all p s > 0.171; s5: t 29 = 2.218, p = 0.018; s35: t 29 = 0.699, p = 0.050). The main effect of sex reported above appears to be driven by TG− males, perhaps suggesting baseline differences in impulsivity across the sexes, although this was not seen in a previous investigation 17 …”

“…A score of 100 indicates a perfectly optimal choice profile, while a score of −100 indicates a perfectly risky one. Females and males did not initially (i.e., in first five sessions) differ in decision making score (session × sex: F 4,220 = 0.482, p = 0.749; session × sex × TG: F 4,220 = 0.647, p = 0.579), yet in light of our recent report that females and males respond differently to manipulations of the DA system in the crGT, we analysed the decision making profile of females and males separately 17 . In stark contrast to our initial hypothesis, TG+ females developed a significantly lower score over time than TG− females, indicative of greater risky choice (Figure 3A, session × TG: F 34,884 = 1.728, p = 0.006).…”

“…Sections were then cover‐slipped under HARLECO® Krystalon™ mounting medium (Thermo Fischer Scientific; Burnaby, BC, Canada) and visualized using a SP8 WLL confocal microscope (Leica Microsystems, Germany). For quantification of DREADDs expression, we adopted a method similar to previous published methods 17,24,25 . We defined the anterior and posterior bounds of DREADD expression (i.e., <1 mCherry+ cell) in coronal sections and counted cells from one to three sections within these bounds immediately anterior or posterior to the DREADD infusion site.…”

“…We therefore anticipated that chemogenetic inhibition of VTA DA neurons would reduce such premature responding. Regarding predicted sex differences, females are thought to have more sensitive dopamine systems, but recent data suggest dopamine antagonists are less effective at modulating decision making on the rGT in female rats 16,17 . Drug addiction also takes a different trajectory in females 18,19 .…”

Pharmacological evidence of a cholinergic contribution to elevated impulsivity and risky decision-making caused by adding win-paired cues to a rat gambling task

“…Sex differences are also apparent in muscarinic receptor densities and their age-related decline (Yoshida et al, 2000), as well as in the effects of ACh on memory (Capettini et al, 2011). With regards to rGT performance, males and females appear differentially sensitive to both pharmacological and chemogenetic manipulations of the dopamine system (Georgiou et al, 2018; Hynes et al, 2020). It would therefore be beneficial for future studies to investigate cholinergic modulation of decision making on the rGT using female subjects.…”