Abstract
Rationale
Several studies have examined the role of different neurotransmitter systems in modulating risk-taking behavior.
Objective
This investigation was aimed to determine whether the benzodiazepine lorazepam dose-dependently alters risk-taking behavior and underlying neural substrates.
Materials and methods
Fifteen healthy, nonsmoking, individuals (six women, nine men), aged 18–39 years (mean 27.6 ± 1.4 years) with 12–18 years of education (mean 15.6 ± 0.3 years) underwent functional magnetic resonance imaging while performing a risk-taking decision-making task.
Results
Our results show that lorazepam did not affect risky behavior at 0.25 and 1 mg, but dose-dependently attenuated activation in (a) the amygdala and medial prefrontal cortex during the response selection phase, and in (b) the bilateral insular cortex and amygdala during the outcome (i.e., rewarded or punished) phase. Furthermore, a lorazepam-induced increase in insular cortex activation was associated with less risky responses.
Conclusions
Taken together, our findings support the idea that GABAergic modulation in limbic and paralimbic structures is important during both the response selection and outcome phase of risk-taking decision-making.
Similar content being viewed by others
References
Arana FS, Parkinson JA, Hinton E, Holland AJ, Owen AM, Roberts AC (2003) Dissociable contributions of the human amygdala and orbitofrontal cortex to incentive motivation and goal selection. J Neurosci 23:9632–9638
Baas JM, Grillon C, Bocker KB, Brack AA, Morgan CA, III, Kenemans JL, Verbaten MN (2002) Benzodiazepines have no effect on fear-potentiated startle in humans. Psychopharmacology (Berl) 161:233–247
Bechara A (2001) Neurobiology of decision-making: risk and reward. Semin Clin Neuropsychiatry 6:205–216
Bechara A, Damasio H (2002) Decision-making and addiction (part I): impaired activation of somatic states in substance dependent individuals when pondering decisions with negative future consequences. Neuropsychologia 40:1675–1689
Botvinick M, Nystrom LE, Fissell K, Carter CS, Cohen JD (1999) Conflict monitoring versus selection-for-action in anterior cingulate cortex. Nature 402:179–181
Boynton GM, Engel SA, Glover GH, Heeger DJ (1996) Linear systems analysis of functional magnetic resonance imaging in human V1. J Neurosci 16:4207–4221
Burian SE, Liguori A, Robinson JH (2002) Effects of alcohol on risk-taking during simulated driving. Hum Psychopharmacol 17:141–150
Carter CS, Macdonald AM, Botvinick M, Ross LL, Stenger VA, Noll D, Cohen JD (2000) Parsing executive processes: strategic vs. evaluative functions of the anterior cingulate cortex. Proc Natl Acad Sci U S A 97:1944–1948
Cohen MX, Heller A, Ranganath C (2005) Functional connectivity with anterior cingulate and orbitofrontal cortices during decision-making. Brain Res Cogn Brain Res 23:61–70
Coricelli G, Critchley HD, Joffily M, O’Doherty JP, Sirigu A, Dolan RJ (2005) Regret and its avoidance: a neuroimaging study of choice behavior. Nat Neurosci 8:1255–1262
Coull JT, Frith CD, Dolan RJ (1999) Dissociating neuromodulatory effects of diazepam on episodic memory encoding and executive function. Psychopharmacology (Berl) 145:213–222
Cox RW (1996) AFNI: software for analysis and visualization of functional magnetic resonance neuroimages. Comput Biomed Res 29:162–173
Craig AD (2002) How do you feel? Interoception: the sense of the physiological condition of the body. Nat Rev Neurosci 3:655–666
Craig AD (2003) A new view of pain as a homeostatic emotion. Trends Neurosci 26:303–307
Damasio AR (1996) The somatic marker hypothesis and the possible functions of the prefrontal cortex. Philos Trans R Soc Lond B Biol Sci 351:1413–1420
Ernst M, Bolla K, Mouratidis M, Contoreggi C, Matochik JA, Kurian V, Cadet JL, Kimes AS, London ED (2002) Decision-making in a risk-taking task. A PET Study. Neuropsychopharmacology 26:682–691
Ernst M, Dickstein DP, Munson S, Eshel N, Pradella A, Jazbec S, Pine DS, Leibenluft E (2004a) Reward-related processes in pediatric bipolar disorder: a pilot study. J Affect Disord 82(Suppl 1):S89–S101
Ernst M, Nelson EE, McClure EB, Monk CS, Munson S, Eshel N, Zarahn E, Leibenluft E, Zametkin A, Towbin K, Blair J, Charney D, Pine DS (2004b) Choice selection and reward anticipation: an fMRI study. Neuropsychologia 42:1585–1597
Ernst M, Nelson EE, Jazbec S, McClure EB, Monk CS, Leibenluft E, Blair J, Pine DS (2005) Amygdala and nucleus accumbens in responses to receipt and omission of gains in adults and adolescents. Neuroimage 25:1279–1291
Forman SD, Cohen JD, Fitzgerald M, Eddy WF, Mintun MA, Noll DC (1995) Improved assessment of significant activation in functional magnetic resonance imaging (fMRI): use of a cluster-size threshold. Magn Reson Med 33:636–647
Frith CD, Done DJ (1988) Towards a neuropsychology of schizophrenia. Br J Psychiatry 153:437–443
Fukui H, Murai T, Fukuyama H, Hayashi T, Hanakawa T (2005) Functional activity related to risk anticipation during performance of the Iowa Gambling Task. Neuroimage 24:253–259
Gehring WJ, Willoughby AR (2002) The medial frontal cortex and the rapid processing of monetary gains and losses. Science 295:2279–2282
George S, Rogers RD, Duka T (2005) The acute effect of alcohol on decision making in social drinkers. Psychopharmacology (Berl) 182(1):160–169
Grant S, Contoreggi C, London ED (2000) Drug abusers show impaired performance in a laboratory test of decision making. Neuropsychologia 38:1180–1187
Greenblatt DJ, Harmatz JS, Dorsey C, Shader RI (1988) Comparative single-dose kinetics and dynamics of lorazepam, alprazolam, prazepam, and placebo. Clin Pharmacol Ther 44:326–334
Harmer CJ, Rogers RD, Tunbridge E, Cowen PJ, Goodwin GM (2003) Tryptophan depletion decreases the recognition of fear in female volunteers. Psychopharmacology (Berl) 167:411–417
Hsu M, Bhatt M, Adolphs R, Tranel D, Camerer CF (2005) Neural systems responding to degrees of uncertainty in human decision-making. Science 310:1680–1683
Huettel SA, Stowe CJ, Gordon EM, Warner BT, Platt ML (2006) Neural signatures of economic preferences for risk and ambiguity. Neuron 49:765–775
Kahn I, Yeshurun Y, Rotshtein P, Fried I, Ben Bashat D, Hendler T (2002) The role of the amygdala in signaling prospective outcome of choice. Neuron 33:983–994
Kahneman D, Tversky A (1979) Prospect theory: an analysis of decision under risk. Econometrica 47:263–291
Kahneman D, Tversky A (1984) Choices, values, and frames. Am Psychol 39:341–350
Kahneman D, Tversky A (2000) Choices, values and frames. Cambridge University Press, Cambridge, UK
Knutson B, Cooper JC (2005) Functional magnetic resonance imaging of reward prediction. Curr Opin Neurol 18:411–417
Knutson B, Fong GW, Adams CM, Varner JL, Hommer D (2001) Dissociation of reward anticipation and outcome with event-related fMRI. Neuroreport 12:3683–3687
Kyriakopoulos AA, Greenblatt DJ, Shader RI (1978) Clinical pharmacokinetics of lorazepam—review. J Clin Psychiatry 39:16–23
Lancaster JL, Woldorff MG, Parsons LM, Liotti M, Freitas CS, Rainey L, Kochunov PV, Nickerson D, Mikiten SA, Fox PT (2000) Automated Talairach atlas labels for functional brain mapping. Hum Brain Mapp 10:120–131
Lane SD, Cherek DR (2000) Analysis of risk taking in adults with a history of high risk behavior. Drug Alcohol Depend 60:179–187
Lane SD, Cherek DR, Pietras CJ, Tcheremissine OV (2004) Alcohol effects on human risk taking. Psychopharmacology (Berl) 172:68–77
Lane SD, Cherek DR, Tcheremissine OV, Lieving LM, Pietras CJ (2005a) Acute marijuana effects on human risk taking. Neuropsychopharmacology 30:800–809
Lane SD, Tcheremissine OV, Lieving LM, Nouvion S, Cherek DR (2005b) Acute effects of alprazolam on risky decision making in humans. Psychopharmacology (Berl) 181(2):364–373
Leland DS, Paulus MP (2005) Increased risk-taking decision-making but not altered response to punishment in stimulant-using young adults. Drug Alcohol Depend 78:83–90
Loewenstein GF, Weber EU, Hsee CK, Welch N (2001) Risk as feelings. Psychol Bull 127:267–286
Madden GJ, Bickel WK, Jacobs EA (1999) Discounting of delayed rewards in opioid-dependent outpatients: exponential or hyperbolic discounting functions? Exp Clin Psychopharmacol 7:284–293
Marowsky A, Fritschy JM, Vogt KE (2004) Functional mapping of GABA A receptor subtypes in the amygdala. Eur J Neurosci 20:1281–1289
Millan MJ (2003) The neurobiology and control of anxious states. Prog Neurobiol 70:83–244
Monterosso J, Ehrman R, Napier KL, O’Brien CP, Childress AR (2001) Three decision-making tasks in cocaine-dependent patients: do they measure the same construct? Addiction 96:1825–1837
Norusis MJ (1990) SPSS base system user’s guide. SPSS Inc, Chicago, IL
Paulus MP, Rogalsky C, Simmons A, Feinstein JS, Stein MB (2003) Increased activation in the right insula during risk-taking decision making is related to harm avoidance and neuroticism. Neuroimage 19:1439–1448
Paulus MP, Feinstein JS, Castillo G, Simmons AN, Stein MB (2005) Dose-dependent decrease of activation in bilateral amygdala and insula by lorazepam during emotion processing. Arch Gen Psychiatry 62:282–288
Petersson KM, Nichols TE, Poline JB, Holmes AP (1999) Statistical limitations in functional neuroimaging. II. Signal detection and statistical inference. Philos Trans R Soc Lond B Biol Sci 354:1261–1281
Petry NM, Bickel WK, Arnett M (1998) Shortened time horizons and insensitivity to future consequences in heroin addicts. Addiction 93:729–738
Quirk GJ, Gehlert DR (2003) Inhibition of the amygdala: key to pathological states? Ann N Y Acad Sci 985:263–272
Riba J, Rodriguez-Fornells A, Urbano G, Morte A, Antonijoan R, Barbanoj MJ (2001) Differential effects of alprazolam on the baseline and fear-potentiated startle reflex in humans: a dose-response study. Psychopharmacology (Berl) 157:358–367
Richmond BJ, Liu Z, Shidara M (2003) Neuroscience. Predicting future rewards. Science 301:179–180
Ridderinkhof KR, Ullsperger M, Crone EA, Nieuwenhuis S (2004) The role of the medial frontal cortex in cognitive control. Science 306:443–447
Roache JD, Griffiths RR (1987) Lorazepam and meprobamate dose effects in humans: behavioral effects and abuse liability. J Pharmacol Exp Ther 243:978–988
Rogers RD, Ramnani N, Mackay C, Wilson JL, Jezzard P, Carter CS, Smith SM (2004) Distinct portions of anterior cingulate cortex and medial prefrontal cortex are activated by reward processing in separable phases of decision-making cognition. Biol Psychiatry 55:594–602
Rush CR, Higgins ST, Bickel WK, Hughes JR (1993) Acute effects of triazolam and lorazepam on human learning, performance and subject ratings. J Pharmacol Exp Ther 264:1218–1226
Rush CR, Higgins ST, Bickel WK, Hughes JR (1994) Acute behavioral effects of lorazepam and caffeine, alone and in combination, in humans. Behav Pharmacol 5:245–254
Rushworth MF, Walton ME, Kennerley SW, Bannerman DM (2004) Action sets and decisions in the medial frontal cortex. Trends Cogn Sci 8:410–417
Slovic P (1987) Perception of risk. Science 236:280–285
Slovic P (2000) Perception of risk. Earthscan Publications, London
Sperling R, Greve D, Dale A, Killiany R, Holmes J, Rosas HD, Cocchiarella A, Firth P, Rosen B, Lake S, Lange N, Routledge C, Albert M (2002) Functional MRI detection of pharmacologically induced memory impairment. Proc Natl Acad Sci U S A 99:455–460
Spielberger CD (1983) Manual for the state-trait anxiety inventory (Form Y). Consulting Psychologists Press, Palo Alto, CA
Stein EA, Pankiewicz J, Harsch HH, Cho JK, Fuller SA, Hoffmann RG, Hawkins M, Rao SM, Bandettini PA, Bloom AS (1998) Nicotine-induced limbic cortical activation in the human brain: a functional MRI study. Am J Psychiatry 155:1009–1015
Zezula J, Cortes R, Probst A, Palacios JM (1988) Benzodiazepine receptor sites in the human brain: autoradiographic mapping. Neuroscience 25:771–795
Acknowledgements
We would like to acknowledge the invaluable help of Thuy Le. This work was supported by grants from NIH (DA13186, MPP; MH65413, MBS).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Arce, E., Miller, D.A., Feinstein, J.S. et al. Lorazepam dose-dependently decreases risk-taking related activation in limbic areas. Psychopharmacology 189, 105–116 (2006). https://doi.org/10.1007/s00213-006-0519-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-006-0519-8