Differential effects of glutamate N-methyl-d-aspartate receptor antagonists on risky choice as assessed in the risky decision task

Yates, Justin R.; Horchar, Matthew J.; Ellis, Alexis L.; Kappesser, Joy L.; Mbambu, Prodiges; Sutphin, Tanner G.; Dehner, Destiny S.; Igwe, Hephzibah O.; Wright, Makayla R.

doi:10.1007/s00213-020-05664-z

Cited by 9 publications

(3 citation statements)

References 60 publications

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“…It is possible that this sex-specificity was caused by a ceiling effect in males, as both strains approached near complete preference for the risky reward (Figure 2c). This may be a result of the relatively low shock intensity used for this experiment (0.15 mA), which is lower than the amplitude used in other experiments (Glover et al, 2020;Mitchell et al, 2014;Orsini et al, 2018;Yates et al, 2021). As this was the first experiment (to our knowledge) to use the RDT in inbred strains, this measure was selected based on a pilot experiment that observed that higher shock amplitude evoked excessive trial omissions in female subjects.…”

Section: Risky Decision-making and Impulsivity Between Strainsmentioning

confidence: 99%

Divergent risky decision-making and impulsivity behaviors in Lewis rat substrains with low genetic difference.

Gabriel¹,

Liley²,

Franks³

et al. 2023

Behavioral Neuroscience

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Substance use disorder (SUD) is associated with a cluster of cognitive disturbances that engender vulnerability to ongoing drug seeking and relapse. Two of these endophenotypes—risky decision-making and impulsivity—are amplified in individuals with SUD and are augmented by repeated exposure to illicit drugs. Identifying genetic factors underlying variability in these behavioral patterns is critical for early identification, prevention, and treatment of SUD-vulnerable individuals. Here, we compared risky decision-making and different facets of impulsivity between two fully inbred substrains of Lewis rats—LEW/NCrl and LEW/NHsd. We performed whole genome sequencing of both substrains to identify almost all relevant variants. We observed substantial differences in risky decision-making and impulsive behaviors. Relative to LEW/NHsd, the LEW/NCrl substrain accepts higher risk options in a decision-making task and higher rates of premature responses in the differential reinforcement of low rates of responding task. These phenotypic differences were more pronounced in females than males. We defined a total of ∼9,000 polymorphisms between these substrains at 40× whole genome short-read coverage. Roughly half of variants are located within a single 1.5 Mb region of Chromosome 8, but none impact protein-coding regions. In contrast, other variants are widely distributed, and of these, 38 are predicted to cause protein-coding variants. In conclusion, Lewis rat substrains differ significantly in risk-taking and impulsivity and only a small number of easily mapped variants are likely to be causal. Sequencing combined with a reduced complexity cross should enable identification of one or more variants underlying multiple complex addiction-relevant behaviors.

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Section: Risky Decision-making and Impulsivity Between Strainsmentioning

confidence: 99%

Divergent risky decision-making and impulsivity behaviors in Lewis rat substrains with low genetic difference.

Gabriel¹,

Liley²,

Franks³

et al. 2023

Behavioral Neuroscience

View full text Add to dashboard Cite

show abstract

“…It is possible that this sexspecificity was caused by a ceiling effect in males, as both strains approached near complete preference for the risky reward (Figure 2c). This may be a result of the relatively low shock intensity used for this experiment (0.15 mA), which is lower than the amplitude used in other experiments 7,[56][57][58] . As this was the first experiment (to our knowledge) to use the RDT in inbred strains, this measure was selected based on a pilot experiment which observed that higher shock amplitude evoked excessive trial omissions in female subjects.…”

Section: Risky Decision-making and Impulsivity Between Strainsmentioning

confidence: 81%

Divergent risky decision-making and impulsivity behaviors in Lewis rat substrains with low genetic difference

Gabriel

Liley

Franks

et al. 2022

Preprint

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Substance use disorder (SUD) is associated with a cluster of cognitive disturbances that engender vulnerability to ongoing drug seeking and relapse. Two of these endophenotypes, risky decision-making and impulsivity, are amplified in individuals with substance use disorder and are augmented by repeated exposure to illicit drugs. Thus, identifying the genetic factors underlying variability in these traits is critical for early identification and ongoing treatment of SUD-vulnerable individuals. Here, we compared risky decision-making and different facets of impulsivity between two commercially available substrains of inbred Lewis rats (Charles River vs. Envigo). We also performed whole genome sequencing (WGS) to identify genetic variants between strains. We observed differences in risky decision-making and impulsive action, with Lewis rats from Charles River demonstrating both increased preference for risky options in the risky decision-making task and increased premature responses in the Differential Reinforcement of Low Rates of Responding (DRL) task. Interestingly, these phenotypic differences were more pronounced in females than males. Our WGS at ~40X coverage detected a total of ~9,000 polymorphisms between these substrain. Roughly half are located within a single 1.5 Mb region of Chromosome 8, but do not impact any protein coding genes. In contrast the other widely distributed variants are predicted to have moderate or high impact on the function of 38 protein-coding genes. In conclusion, Lewis rat substrains differ significantly in risk-taking and impulsivity but only a small number of easily mapped variants are likely to be causal. Sequencing combined with a reduced complexity cross (RCC) should enable identification of one or more variants underlying multiple complex addiction-relevant traits.

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“…When animals are presented with diminishing rewards upon the choice to stay in a patch, not only are they being reinforced, but they are also gaining new information about the quality of the reward, an important component of the economics of choice behavior 1 , 2 . Finally, females may tend to choose safer options, which is supported by studies in rats 71 – 74 .…”

Section: Discussionmentioning

confidence: 94%

Reward maximization assessed using a sequential patch depletion task in a large sample of heterogeneous stock rats

Gancarz

Mitchell

George

et al. 2023

Sci Rep

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Choice behavior requires animals to evaluate both short- and long-term advantages and disadvantages of all potential alternatives. Impulsive choice is traditionally measured in laboratory tasks by utilizing delay discounting (DD), a paradigm that offers a choice between a smaller immediate reward, or a larger more delayed reward. This study tested a large sample of Heterogeneous Stock (HS) male (n = 896) and female (n = 898) rats, part of a larger genetic study, to investigate whether measures of reward maximization overlapped with traditional models of delay discounting via the patch depletion model using a Sequential Patch Depletion procedure. In this task, rats were offered a concurrent choice between two water “patches” and could elect to “stay” in the current patch or “leave” for an alternative patch. Staying in the current patch resulted in decreasing subsequent reward magnitudes, whereas the choice to leave a patch was followed by a delay and a resetting to the maximum reward magnitude. Based on the delay in a given session, different visit durations were necessary to obtain the maximum number of rewards. Visit duration may be analogous to an indifference point in traditional DD tasks. Males and females did not significantly differ on traditional measures of DD (e.g. delay gradient; AUC). When examining measures of patch utilization, females made fewer patch changes at all delays and spent more time in the patch before leaving for the alternative patch compared to males. Consistent with this, there was some evidence that females deviated from reward maximization more than males. However, when controlling for body weight, females had a higher normalized rate of reinforcement than males. Measures of reward maximization were only weakly associated with traditional DD measures and may represent distinctive underlying processes. Taken together, females performance differed from males with regard to reward maximization that were not observed utilizing traditional measures of DD, suggesting that the patch depletion model was more sensitive to modest sex differences when compared to traditional DD measures in a large sample of HS rats.

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Differential effects of glutamate N-methyl-d-aspartate receptor antagonists on risky choice as assessed in the risky decision task

Cited by 9 publications

References 60 publications

Divergent risky decision-making and impulsivity behaviors in Lewis rat substrains with low genetic difference.

Divergent risky decision-making and impulsivity behaviors in Lewis rat substrains with low genetic difference.

Divergent risky decision-making and impulsivity behaviors in Lewis rat substrains with low genetic difference

Reward maximization assessed using a sequential patch depletion task in a large sample of heterogeneous stock rats

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