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Research ArticleResearch Article: New Research, Cognition and Behavior

Serotonin 2C Antagonism in the Lateral Orbitofrontal Cortex Ameliorates Cue-Enhanced Risk Preference and Restores Sensitivity to Reinforcer Devaluation in Male Rats

Brett A. Hathaway, Jackson D. Schumacher, Kelly M. Hrelja and Catharine A. Winstanley
eNeuro 23 November 2021, 8 (6) ENEURO.0341-21.2021; https://doi.org/10.1523/ENEURO.0341-21.2021
Brett A. Hathaway
Department of Psychology, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada
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Jackson D. Schumacher
Department of Psychology, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada
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Kelly M. Hrelja
Department of Psychology, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada
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Catharine A. Winstanley
Department of Psychology, Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada
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Figures

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  • Figure 1.
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    Figure 1.

    Task schematic of the crGT. A nose poke response in the food tray extinguished the traylight and initiated a new trial. After an ITI of 5 s, four stimulus lights were turned on in holes 1, 2, 4, and 5, each of which was associated with a different number of sugar pellets. The order of the options from left to right was counter-balanced within each cohort to avoid development of a simple side bias [version A (shown): P1, P4, P3, P2; version B: P4, P1, P3, P2]. The animal was required to respond at a hole within 10 s. This response was then rewarded or punished depending on the reinforcement schedule for that option. Reward delivery was accompanied by a 2-s audiovisual cue that increased in complexity with reward magnitude. If the animal lost, the stimulus light in the chosen hole flashed at a frequency of 0.5 Hz for the duration of the punishing time out, and all other lights were extinguished. The maximum number of pellets available per 30-min session shows that P1 and P2 are better than P3 and P4. The percent choice of the different options is one of the primary dependent variables. A score variable is also calculated, as for the IGT, to determine the overall level of risky choice as follows: [(P1 + P2) – (P3 + P4)]. Figure is modified from Barrus and Winstanley (2016).

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    Figure 2.

    Histologic analysis of cannulae implantation. Location of all acceptable lOFC (A) and PrL region (B) infusions and an example microscopy image for each region in C, D are shown. Coordinates are relative to bregma. Plates modified from Paxinos and Watson (1998).

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    Figure 3.

    Baseline preferences for each option in the lOFC and PrL cohorts in risk-preferring rats (A) and optimal decision-makers (B). Optimal rats in the PrL cohort selected P2 at a significantly higher rate than optimal rats in the lOFC cohort. Data are expressed as mean ± SEM; *p < 0.05 according to an independent-groups t test.

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    Figure 4.

    Effects of intra-lOFC infusions of the 5-HT2C receptor agonist RS 102221 in (A) risk-preferring animals (n = 9) and (B) optimal decision-makers (n = 9) on P1–P4 choice. Antagonism of the 5-HT2C receptor in the lOFC decreased P3 choice and increased P1 choice on the crGT in risk-preferring rats. Data are expressed as mean ± SEM; *p < 0.05 compared with vehicle.

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    Figure 5.

    Effects of sucrose pellet devaluation on choice preference and other task variables. Only rats receiving intra-lOFC RS 102221 shifted their choice profile (A) and completed significantly fewer trials (B) in response to devaluation. Animals in all groups exhibited a significant reduction in premature responding (C) and increased choice latencies (D). No shift in latencies to collect reward were observed in any group (E). In panel A, data are expressed as the mean change in % choice from baseline ± SEM to illustrate effects independent of differences in preference for each option between cohorts. Data are expressed as mean ± SEM in all other panels; *p < 0.05, **p < 0.01, ****p < 0.0001, #p = 0.07 compared with each group’s own baseline.

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    Figure 6.

    Effects of intra-PrL infusions of the 5-HT2C receptor agonist RS 102221 in (A) risk-preferring animals (n = 5) and (B) optimal decision-makers (n = 6) on P1–P4 choice. Antagonism of the 5-HT2C receptor in the PrL did not significantly increase or decrease choice of any particular option in either risk-preferring (A) or optimal (B) rats. Data are expressed as mean ± SEM.

Tables

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    Table 1

    Mean values of all other task variables (% premature response, choice latency, collect latency, omissions, trials completed) at each dose of RS 102221 delivered into either the lOFC or PrL

    RegionDose% Premature responsesChoice latencyCollect latencyOmissionsTrials completed
    lOFC028.62 ± 4.051.28 ± 0.191.32 ± 0.071.50 ± 0.5375.38 ± 5.28
    0.129.66 ± 3.651.20 ± 0.121.19 ± 0.040.94 ± 0.2277.56 ± 5.11
    1.031.90 ± 4.711.22 ± 0.121.24 ± 0.030.39 ± 0.1875.63 ± 5.05
    3.025.92 ± 3.721.30 ± 0.132.01 ± 0.420.94 ± 0.5183.63 ± 6.41
    PrL034.05 ± 5.351.13 ± 0.121.42 ± 0.161.36 ± 0.7269.98 ± 7.94
    0.131.94 ± 6.591.14 ± 0.121.29 ± 0.050.91 ± 0.4473.37 ± 9.67
    1.028.64 ± 6.301.31 ± 0.171.21 ± 0.071.18 ± 0.4675.41 ± 10.12
    3.024.19 ± 5.001.34 ± 0.151.24 ± 0.120.91 ± 0.4478.66 ± 10.78
    • Data are mean ± SEM.

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    Table 2

    Percent choice of the different options in response to acute sucrose pellet devaluation in surgically-naive rats, rats who received intra-lOFC RS 102221 in addition to devaluation, and rats who received intra-lOFC vehicle and devaluation

    GroupConditionP1P2P3P4
    Surgically naiveBaseline4.82 ± 1.3351.72 ± 9.1724.93 ± 8.6818.53 ± 7.18
    Devaluation3.62 ± 1.3353.50 ± 9.2522.09 ± 8.1220.79 ± 6.66
    Drug + devaluationVehicle1.59 ± 0.7956.57 ± 7.9325.91 ± 11.5515.93 ± 8.51
    Drug7.13 ± 1.6758.16 ± 5.4418.67 ± 8.1216.04 ± 6.56
    Devaluation9.29 ± 1.7337.67 ± 10.0618.94 ± 8.3434.10 ± 12.09
    Vehicle + devaluationVehicle4.83 ± 2.4641.01 ± 13.1240.03 ± 19.2314.13 ± 5.56
    Devaluation4.92 ± 1.7239.91 ± 10.9231.19 ± 17.1723.98 ± 9.85
    • Data are mean ± SEM.

    • View popup
    Table 3

    Mean values of all other task variables (% premature response, choice latency, collect latency, omissions, trials completed) in response to acute sucrose pellet devaluation in surgically-naive rats, rats who received intra-lOFC RS 102221 in addition to devaluation, and rats who received intra-lOFC vehicle and devaluation

    GroupCondition% Premature responsesChoice latencyCollect latencyOmissionsTrials completed
    Surgically naiveBaseline27.96 ± 3.000.93 ± 0.081.12 ± 0.110.25 ± 0.1179.89 ± 7.63
    Devaluation8.82 ± 2.091.71 ± 0.211.38 ± 0.151.31 ± 0.5563.14 ± 9.87
    Drug + devaluationVehicle26.72 ± 5.721.35 ± 1.201.57 ± 0.351.50 ± 1.1180.87 ± 11.71
    Drug19.96 ± 6.941.26 ± 0.251.23 ± 0.080.50 ± 0.3492.18 ± 9.46
    Devaluation6.61 ± 2.812.40 ± 0.521.51 ± 0.061.33 ± 0.4932.00 ± 7.93
    Vehicle + devaluationVehicle37.74 ± 5.721.10 ± 0.211.33 ± 0.191.20 ± 0.9771.06 ± 7.63
    Devaluation14.00 ± 6.682.04 ± 0.431.31 ± 0.140.80 ± 0.3751.62 ± 5.40
    • Data are mean ± SEM.

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Serotonin 2C Antagonism in the Lateral Orbitofrontal Cortex Ameliorates Cue-Enhanced Risk Preference and Restores Sensitivity to Reinforcer Devaluation in Male Rats
Brett A. Hathaway, Jackson D. Schumacher, Kelly M. Hrelja, Catharine A. Winstanley
eNeuro 23 November 2021, 8 (6) ENEURO.0341-21.2021; DOI: 10.1523/ENEURO.0341-21.2021

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Serotonin 2C Antagonism in the Lateral Orbitofrontal Cortex Ameliorates Cue-Enhanced Risk Preference and Restores Sensitivity to Reinforcer Devaluation in Male Rats
Brett A. Hathaway, Jackson D. Schumacher, Kelly M. Hrelja, Catharine A. Winstanley
eNeuro 23 November 2021, 8 (6) ENEURO.0341-21.2021; DOI: 10.1523/ENEURO.0341-21.2021
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Keywords

  • decision making
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  • orbitofrontal cortex
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