Abstract
Risky decision making involves the ability to weigh risks and rewards associated with different options to make adaptive choices. Previous work has established a necessary role for the basolateral amygdala (BLA) in mediating effective decision making under risk of punishment, but the mechanisms by which the BLA mediates this process are less clear. Because this form of decision making is profoundly sensitive to dopaminergic (DA) manipulations, we hypothesized that DA receptors in the BLA may be involved in risk-taking behavior. To test this hypothesis, male and female Long-Evans rats were trained in a decision-making task in which rats chose between a small, safe food reward and a larger food reward that was associated with a variable risk of footshock punishment. Once behavioral stability emerged, rats received intra-BLA infusions of ligands targeting distinct dopamine receptor subtypes prior to behavioral testing. Intra-BLA infusions of the dopamine D2 receptor (D2R) agonist quinpirole decreased risk taking in females at all doses, and this reduction in risk taking was accompanied by an increase in sensitivity to punishment. In males, decreased risk taking was only observed at the highest dose of quinpirole. In contrast, intra-BLA manipulations of dopamine D1 or D3 receptors (D1R and D3R, respectively) had no effect on risk taking. Considered together, these data suggest that differential D2R sensitivity in the BLA may contribute to the well-established sex differences in risk taking. Neither D1Rs nor D3Rs, however, appear to contribute to risky decision making in either sex.
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References
Brand M, Grabenhorst F, Starcke K, Vandekerckhove MM, Markowitsch HJ. Role of the amygdala in decisions under ambiguity and decisions under risk: evidence from patients with Urbach-Wiethe disease. Neuropsychologia. 2007;45:1305–17.
Bechara A, Damasio H, Damasio AR, Lee GP. Different contributions of the human amygdala and ventromedial prefrontal cortex to decision-making. J Neurosci. 1999;19:5473–81.
Fein G, Landman B, Tran H, McGillivray S, Finn P, Barakos J, et al. Brain atrophy in long-term abstinent alcoholics who demonstrate impairment on a simulated gambling task. NeuroImage. 2006;32:1465–71.
De Martino B, Camerer CF, Adolphs R. Amygdala damage eliminates monetary loss aversion. Proc Natl Acad Sci USA. 2010;107:3788–92.
van Honk J, Eisenegger C, Terburg D, Stein DJ, Morgan B. Generous economic investments after basolateral amygdala damage. Proc Natl Acad Sci USA. 2013;110:2506–10.
Kahn I, Yeshurun Y, Rotshtein P, Fried I, Ben-Bashat D, Hendler T. The role of the amygdala in signaling prospective outcome of choice. Neuron. 2002;33:983–94.
Jung WH, Lee S, Lerman C, Kable JW. Amygdala functional and structural connectivity predicts individual risk tolerance. Neuron. 2018;98:394–404 e4.
Ferland JN, Adams WK, Murch S, Wei L, Clark L, Winstanley CA. Investigating the influence of ‘losses disguised as wins’ on decision making and motivation in rats. Behav Pharmacol. 2018;29:732–44.
Tremblay M, Cocker PJ, Hosking JG, Zeeb FD, Rogers RD, Winstanley CA. Dissociable effects of basolateral amygdala lesions on decision making biases in rats when loss or gain is emphasized. Cogn Affect Behav Neurosci. 2014;14:1184–95.
Zeeb FD, Winstanley CA. Lesions of the basolateral amygdala and orbitofrontal cortex differentially affect acquisition and performance of a rodent gambling task. J Neurosci. 2011;31:2197–204.
Orsini CA, Trotta RT, Bizon JL, Setlow B. Dissociable roles for the basolateral amygdala and orbitofrontal cortex in decision-making under risk of punishment. J Neurosci. 2015;35:1368–79.
Ghods-Sharifi S, St Onge JR, Floresco SB. Fundamental contribution by the basolateral amygdala to different forms of decision making. J Neurosci. 2009;29:5251–9.
van Holstein M, MacLeod PE, Floresco SB. Basolateral amygdala - nucleus accumbens circuitry regulates optimal cue-guided risk/reward decision making. Prog Neuro Psychopharmacol Biol Psychiatry. 2020;98:109830.
Orsini CA, Hernandez CM, Singhal S, Kelly KB, Frazier CJ, Bizon JL, et al. Optogenetic inhibition reveals distinct roles for basolateral amygdala activity at discrete time points during risky decision making. J Neurosci. 2017;37:11537–48.
Simon NW, Montgomery KS, Beas BS, Mitchell MR, LaSarge CL, Mendez IA, et al. Dopaminergic modulation of risky decision-making. J Neurosci. 2011;31:17460–70.
Blaes SL, Orsini CA, Mitchell MR, Spurrell MS, Betzhold SM, Vera K, et al. Monoaminergic modulation of decision-making under risk of punishment in a rat model. Behav Pharmacol. 2018;29:745–61.
Orsini CA, Willis ML, Gilbert RJ, Bizon JL, Setlow B. Sex differences in a rat model of risky decision making. Behav Neurosci. 2016;130:50–61.
Simon NW, Gilbert RJ, Mayse JD, Bizon JL, Setlow B. Balancing risk and reward: a rat model of risky decision making. Neuropsychopharmacology. 2009;34:2208–17.
Mitchell MR, Weiss VG, Beas BS, Morgan D, Bizon JL, Setlow B. Adolescent risk taking, cocaine self-administration, and striatal dopamine signaling. Neuropsychopharmacology. 2014;39:955–62.
Asan E. The catecholaminergic innervation of the rat amygdala. Adv Anat Embryol Cell Biol 1998;142:1–118.
Brinley-Reed M, McDonald AJ. Evidence that dopaminergic axons provide a dense innervation of specific neuronal subpopulations in the rat basolateral amygdala. Brain Res. 1999;850:127–35.
Asan E. Ultrastructural features of tyrosine-hydroxylase-immunoreactive afferents and their targets in the rat amygdala. Cell Tissue Res. 1997;288:449–69.
Chu HY, Ito W, Li J, Morozov A. Target-specific suppression of GABA release from parvalbumin interneurons in the basolateral amygdala by dopamine. J Neurosci. 2012;32:14815–20.
Bissiere S, Humeau Y, Luthi A. Dopamine gates LTP induction in lateral amygdala by suppressing feedforward inhibition. Nat Neurosci. 2003;6:587–92.
Inglis FM, Moghaddam B. Dopaminergic innervation of the amygdala is highly responsive to stress. J Neurochem. 1999;72:1088–94.
Harmer CJ, Phillips GD. Enhanced dopamine efflux in the amygdala by a predictive, but not a non-predictive, stimulus: facilitation by prior repeated D-amphetamine. Neuroscience. 1999;90:119–30.
Hori K, Tanaka J, Nomura M. Effects of discrimination learning on the rat amygdala dopamine release: a microdialysis study. Brain Res. 1993;621:296–300.
Young AM, Rees KR. Dopamine release in the amygdaloid complex of the rat, studied by brain microdialysis. Neurosci Lett. 1998;249:49–52.
de Oliveira AR, Reimer AE, de Macedo CE, de Carvalho MC, Silva MA, Brandao ML. Conditioned fear is modulated by D2 receptor pathway connecting the ventral tegmental area and basolateral amygdala. Neurobiol Learn Mem. 2011;95:37–45.
Lintas A, Chi N, Lauzon NM, Bishop SF, Gholizadeh S, Sun N, et al. Identification of a dopamine receptor-mediated opiate reward memory switch in the basolateral amygdala-nucleus accumbens circuit. J Neurosci. 2011;31:11172–83.
Antunes GF, Gouveia FV, Rezende FS, Seno MDJ, de Carvalho MC, de Oliveira CC, et al. Dopamine modulates individual differences in avoidance behavior: A pharmacological, immunohistochemical, neurochemical and volumetric investigation. Neurobiol Stress. 2020;12:100219.
Larkin JD, Jenni NL, Floresco SB. Modulation of risk/reward decision making by dopaminergic transmission within the basolateral amygdala. Psychopharmacology. 2016;233:121–36.
Orsini CA, Moorman DE, Young JW, Setlow B, Floresco SB. Neural mechanisms regulating different forms of risk-related decision-making: Insights from animal models. Neurosci Biobehav Rev. 2015;58:14–67.
Winstanley CA, Floresco SB. Deciphering decision making: variation in animal models of effort- and uncertainty-based choice reveals distinct neural circuitries underlying core cognitive processes. J Neurosci. 2016;36:12069–79.
Wassum KM, Izquierdo A. The basolateral amygdala in reward learning and addiction. Neurosci Biobehav Rev. 2015;57:271–83.
Piantadosi PT, Halladay LR, Radke AK, Holmes A. Advances in understanding meso-cortico-limbic-striatal systems mediating risky reward seeking. J Neurochem. 2021;157:1547–71.
Farrell MR, Ruiz CM, Castillo E, Faget L, Khanbijian C, Liu S, et al. Ventral pallidum is essential for cocaine relapse after voluntary abstinence in rats. Neuropsychopharmacology. 2019;44:2174–85.
Halladay LR, Kocharian A, Piantadosi PT, Authement ME, Lieberman AG, Spitz NA, et al. Prefrontal regulation of punished ethanol self-administration. Biol psychiatry. 2020;87:967–78.
Blanchard DC, Griebel G, Pobbe R, Blanchard RJ. Risk assessment as an evolved threat detection and analysis process. Neurosci Biobehav Rev. 2011;35:991–8.
Hunt HF, Brady JV. Some effects of punishment and intercurrent anxiety on a simple operant. J Comp Physiol Psychol. 1955;48:305–10.
Orsini CA, Maren S. Neural and cellular mechanisms of fear and extinction memory formation. Neurosci Biobehav Rev. 2012;36:1773–802.
Liley AE, Gabriel DBK, Simon NW. Lateral orbitofrontal cortex and basolateral amygdala regulate sensitivity to delayed punishment during decision-making. eNeuro. 2022;9:ENEURO.0170-22.2022.
Liley AE, Gabriel DBK, Sable HJ, Simon NW. Sex differences and effects of predictive cues on delayed punishment discounting. eNeuro. 2019;6:ENEURO.0225-19.2019.
Chowdhury TG, Wallin-Miller KG, Rear AA, Park J, Diaz V, Simon NW, et al. Sex differences in reward- and punishment-guided actions. Cogn Affect Behav Neurosci. 2019;19:1404–17.
Islas-Preciado D, Wainwright SR, Sniegocki J, Lieblich SE, Yagi S, Floresco SB, et al. Risk-based decision making in rats: modulation by sex and amphetamine. Horm Behav. 2020;125:104815.
Truckenbrod LM, Cooper EM, Orsini CA. Cognitive mechanisms underlying decision making involving risk of explicit punishment in male and female rats. Cogn Affect Behav Neurosci. 2022;23:248–75.
Orsini CA, Blaes SL, Hernandez CM, Betzhold SM, Perera H, Wheeler AR, et al. Regulation of risky decision making by gonadal hormones in males and females. Neuropsychopharmacology. 2021;46:603–13.
Levant B, Grigoriadis DE, DeSouza EB. [3H]quinpirole binding to putative D2 and D3 dopamine receptors in rat brain and pituitary gland: a quantitative autoradiographic study. J Pharmacol Exp Ther. 1993;264:991–1001.
Malmberg A, Mohell N. Characterization of [3H]quinpirole binding to human dopamine D2A and D3 receptors: effects of ions and guanine nucleotides. J Pharmacol Exp Ther. 1995;274:790–7.
Bouthenet ML, Souil E, Martres MP, Sokoloff P, Giros B, Schwartz JC. Localization of dopamine D3 receptor mRNA in the rat brain using in situ hybridization histochemistry: comparison with dopamine D2 receptor mRNA. Brain Res. 1991;564:203–19.
Lintas A, Chi N, Lauzon NM, Bishop SF, Sun N, Tan H, et al. Inputs from the basolateral amygdala to the nucleus accumbens shell control opiate reward magnitude via differential dopamine D1 or D2 receptor transmission. Eur J Neurosci. 2012;35:279–90.
Beaulieu JM, Gainetdinov RR. The physiology, signaling, and pharmacology of dopamine receptors. Pharmacol Rev. 2011;63:182–217.
Georgiou P, Zanos P, Bhat S, Tracy JK, Merchenthaler IJ, McCarthy MM, et al. Dopamine and stress system modulation of sex differences in decision making. Neuropsychopharmacology. 2018;43:313–24.
Pinard CR, Muller JF, Mascagni F, McDonald AJ. Dopaminergic innervation of interneurons in the rat basolateral amygdala. Neuroscience. 2008;157:850–63.
Blume SR, Freedberg M, Vantrease JE, Chan R, Padival M, Record MJ, et al. Sex- and estrus-dependent differences in rat basolateral amygdala. J Neurosci. 2017;37:10567–86.
Philpot BD, Lim JH, Brunjes PC. Activity-dependent regulation of calcium-binding proteins in the developing rat olfactory bulb. J Comp Neurol. 1997;387:12–26.
Jiao Y, Zhang C, Yanagawa Y, Sun QQ. Major effects of sensory experiences on the neocortical inhibitory circuits. J Neurosci. 2006;26:8691–701.
Carder RK, Leclerc SS, Hendry SH. Regulation of calcium-binding protein immunoreactivity in GABA neurons of macaque primary visual cortex. Cereb Cortex. 1996;6:271–87.
Blurton-Jones M, Tuszynski MH. Estrogen receptor-beta colocalizes extensively with parvalbumin-labeled inhibitory neurons in the cortex, amygdala, basal forebrain, and hippocampal formation of intact and ovariectomized adult rats. J Comp Neurol. 2002;452:276–87.
Lebron-Milad K, Abbs B, Milad MR, Linnman C, Rougemount-Bucking A, Zeidan MA, et al. Sex differences in the neurobiology of fear conditioning and extinction: a preliminary fMRI study of shared sex differences with stress-arousal circuitry. Biol Mood Anxiety Disord. 2012;2:7.
Blume SR, Padival M, Urban JH, Rosenkranz JA. Disruptive effects of repeated stress on basolateral amygdala neurons and fear behavior across the estrous cycle in rats. Sci Rep. 2019;9:12292.
Zeidan MA, Igoe SA, Linnman C, Vitalo A, Levine JB, Klibanski A, et al. Estradiol modulates medial prefrontal cortex and amygdala activity during fear extinction in women and female rats. Biol Psychiatry. 2011;70:920–7.
Macoveanu J, Henningsson S, Pinborg A, Jensen P, Knudsen GM, Frokjaer VG, et al. Sex-steroid hormone manipulation reduces brain response to reward. Neuropsychopharmacology. 2016;41:1057–65.
van Wingen GA, Ossewaarde L, Backstrom T, Hermans EJ, Fernandez G. Gonadal hormone regulation of the emotion circuitry in humans. Neuroscience. 2011;191:38–45.
Minnes GL, Wiener AJ, Liley AE, Simon NW. Dopaminergic modulation of sensitivity to immediate and delayed punishment during decision-making. Cogn Affect Behav Neurosci. 2023;24:304–21.
Orsini CA, Setlow B. Sex differences in animal models of decision making. J Neurosci Res. 2017;95:260–69.
Grissom NM, Reyes TM. Let’s call the whole thing off: evaluating gender and sex differences in executive function. Neuropsychopharmacology. 2019;44:86–96.
Chen CS, Ebitz RB, Bindas SR, Redish AD, Hayden BY, Grissom NM. Divergent strategies for learning in males and females. Curr Biol. 2021;31:39–50 e4.
Kutlu MG, Zachry JE, Brady LJ, Melugin PR, Kelly SJ, Sanders C, et al. A novel multidimensional reinforcement task in mice elucidates sex-specific behavioral strategies. Neuropsychopharmacology. 2020;45:1463–72.
Mitchell MR, Weiss VG, Beas BS, Morgan D, Bizon JL, Setlow B. Adolescent risk taking, cocaine self-administration, and striatal dopamine signaling. Neuropsychopharmacology. 2014;39:955–62.
Freels TG, Gabriel DBK, Lester DB, Simon NW. Risky decision-making predicts dopamine release dynamics in nucleus accumbens shell. Neuropsychopharmacology. 2020;45:266–75.
Krettek JE, Price JL. A description of the amygdaloid complex in the rat and cat with observations on intra-amygdaloid axonal connections. J Comp Neurol. 1978;178:255–80.
Scibilia RJ, Lachowicz JE, Kilts CD. Topographic nonoverlapping distribution of D1 and D2 dopamine receptors in the amygdaloid nuclear complex of the rat brain. Synapse. 1992;11:146–54.
Sias AC, Jafar Y, Goodpaster CM, Ramirez-Armenta K, Wrenn TM, Griffin NK, et al. Dopamine projections to the basolateral amygdala drive the encoding of identity-specific reward memories. Nat Neurosci. 2024;27:728–36.
Tang W, Kochubey O, Kintscher M, Schneggenburger R. A VTA to basal amygdala dopamine projection contributes to signal salient somatosensory events during fear learning. J Neurosci. 2020;40:3969–80.
Funding
This research was generously supported by R00DA41493 (CAO), R01DA55676 (CAO)Â and T32DA018926 (ARW) from the National Institute on Drug Abuse.
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AW designed the work, conducted the experiments, analyzed the data, and drafted the manuscript. LMT and AB conducted the experiments. PK contributed to collection of additional data for resubmission and histological procedures. CAO conceptualized the experiments, aided in their design, analyzed the data, revised the manuscript, and approved the final version. CAO is accountable for all aspects of the work presented in the manuscript.
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Wheeler, AR., Truckenbrod, L.M., Boehnke, A. et al. Sex differences in sensitivity to dopamine receptor manipulations of risk-based decision making in rats. Neuropsychopharmacol. 49, 1978–1988 (2024). https://doi.org/10.1038/s41386-024-01925-z
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DOI: https://doi.org/10.1038/s41386-024-01925-z
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