Psychopharmacology

, Volume 189, Issue 1, pp 105–116

Lorazepam dose-dependently decreases risk-taking related activation in limbic areas

  • Estibaliz Arce
  • Daniel A. Miller
  • Justin S. Feinstein
  • Murray B. Stein
  • Martin P. Paulus
Original Investigation

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.

Keywords

Risk-taking Decision-making fMRI Insula Amygdala Medial prefrontal cortex GABAergic Lorazepam 

References

  1. 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 23:9632–9638PubMedGoogle Scholar
  2. 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) 161:233–247CrossRefGoogle Scholar
  3. Bechara A (2001) Neurobiology of decision-making: risk and reward. Semin Clin Neuropsychiatry 6:205–216PubMedCrossRefGoogle Scholar
  4. 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 40:1675–1689PubMedCrossRefGoogle Scholar
  5. Botvinick M, Nystrom LE, Fissell K, Carter CS, Cohen JD (1999) Conflict monitoring versus selection-for-action in anterior cingulate cortex. Nature 402:179–181PubMedCrossRefGoogle Scholar
  6. Boynton GM, Engel SA, Glover GH, Heeger DJ (1996) Linear systems analysis of functional magnetic resonance imaging in human V1. J Neurosci 16:4207–4221PubMedGoogle Scholar
  7. Burian SE, Liguori A, Robinson JH (2002) Effects of alcohol on risk-taking during simulated driving. Hum Psychopharmacol 17:141–150PubMedCrossRefGoogle Scholar
  8. 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 97:1944–1948PubMedCrossRefGoogle Scholar
  9. Cohen MX, Heller A, Ranganath C (2005) Functional connectivity with anterior cingulate and orbitofrontal cortices during decision-making. Brain Res Cogn Brain Res 23:61–70PubMedCrossRefGoogle Scholar
  10. 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 8:1255–1262PubMedCrossRefGoogle Scholar
  11. Coull JT, Frith CD, Dolan RJ (1999) Dissociating neuromodulatory effects of diazepam on episodic memory encoding and executive function. Psychopharmacology (Berl) 145:213–222CrossRefGoogle Scholar
  12. Cox RW (1996) AFNI: software for analysis and visualization of functional magnetic resonance neuroimages. Comput Biomed Res 29:162–173PubMedCrossRefGoogle Scholar
  13. Craig AD (2002) How do you feel? Interoception: the sense of the physiological condition of the body. Nat Rev Neurosci 3:655–666PubMedGoogle Scholar
  14. Craig AD (2003) A new view of pain as a homeostatic emotion. Trends Neurosci 26:303–307PubMedCrossRefGoogle Scholar
  15. Damasio AR (1996) The somatic marker hypothesis and the possible functions of the prefrontal cortex. Philos Trans R Soc Lond B Biol Sci 351:1413–1420PubMedGoogle Scholar
  16. 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 26:682–691PubMedCrossRefGoogle Scholar
  17. 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–S101PubMedCrossRefGoogle Scholar
  18. 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 42:1585–1597PubMedCrossRefGoogle Scholar
  19. 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 25:1279–1291PubMedCrossRefGoogle Scholar
  20. 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 33:636–647PubMedGoogle Scholar
  21. Frith CD, Done DJ (1988) Towards a neuropsychology of schizophrenia. Br J Psychiatry 153:437–443PubMedCrossRefGoogle Scholar
  22. 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 24:253–259PubMedCrossRefGoogle Scholar
  23. Gehring WJ, Willoughby AR (2002) The medial frontal cortex and the rapid processing of monetary gains and losses. Science 295:2279–2282PubMedCrossRefGoogle Scholar
  24. George S, Rogers RD, Duka T (2005) The acute effect of alcohol on decision making in social drinkers. Psychopharmacology (Berl) 182(1):160–169CrossRefGoogle Scholar
  25. Grant S, Contoreggi C, London ED (2000) Drug abusers show impaired performance in a laboratory test of decision making. Neuropsychologia 38:1180–1187PubMedCrossRefGoogle Scholar
  26. Greenblatt DJ, Harmatz JS, Dorsey C, Shader RI (1988) Comparative single-dose kinetics and dynamics of lorazepam, alprazolam, prazepam, and placebo. Clin Pharmacol Ther 44:326–334PubMedCrossRefGoogle Scholar
  27. Harmer CJ, Rogers RD, Tunbridge E, Cowen PJ, Goodwin GM (2003) Tryptophan depletion decreases the recognition of fear in female volunteers. Psychopharmacology (Berl) 167:411–417Google Scholar
  28. Hsu M, Bhatt M, Adolphs R, Tranel D, Camerer CF (2005) Neural systems responding to degrees of uncertainty in human decision-making. Science 310:1680–1683PubMedCrossRefGoogle Scholar
  29. Huettel SA, Stowe CJ, Gordon EM, Warner BT, Platt ML (2006) Neural signatures of economic preferences for risk and ambiguity. Neuron 49:765–775PubMedCrossRefGoogle Scholar
  30. 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 33:983–994PubMedCrossRefGoogle Scholar
  31. Kahneman D, Tversky A (1979) Prospect theory: an analysis of decision under risk. Econometrica 47:263–291CrossRefGoogle Scholar
  32. Kahneman D, Tversky A (1984) Choices, values, and frames. Am Psychol 39:341–350CrossRefGoogle Scholar
  33. Kahneman D, Tversky A (2000) Choices, values and frames. Cambridge University Press, Cambridge, UKGoogle Scholar
  34. Knutson B, Cooper JC (2005) Functional magnetic resonance imaging of reward prediction. Curr Opin Neurol 18:411–417PubMedCrossRefGoogle Scholar
  35. Knutson B, Fong GW, Adams CM, Varner JL, Hommer D (2001) Dissociation of reward anticipation and outcome with event-related fMRI. Neuroreport 12:3683–3687PubMedCrossRefGoogle Scholar
  36. Kyriakopoulos AA, Greenblatt DJ, Shader RI (1978) Clinical pharmacokinetics of lorazepam—review. J Clin Psychiatry 39:16–23PubMedGoogle Scholar
  37. 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 10:120–131PubMedCrossRefGoogle Scholar
  38. Lane SD, Cherek DR (2000) Analysis of risk taking in adults with a history of high risk behavior. Drug Alcohol Depend 60:179–187PubMedCrossRefGoogle Scholar
  39. Lane SD, Cherek DR, Pietras CJ, Tcheremissine OV (2004) Alcohol effects on human risk taking. Psychopharmacology (Berl) 172:68–77CrossRefGoogle Scholar
  40. Lane SD, Cherek DR, Tcheremissine OV, Lieving LM, Pietras CJ (2005a) Acute marijuana effects on human risk taking. Neuropsychopharmacology 30:800–809PubMedCrossRefGoogle Scholar
  41. 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):364–373CrossRefGoogle Scholar
  42. Leland DS, Paulus MP (2005) Increased risk-taking decision-making but not altered response to punishment in stimulant-using young adults. Drug Alcohol Depend 78:83–90PubMedCrossRefGoogle Scholar
  43. Loewenstein GF, Weber EU, Hsee CK, Welch N (2001) Risk as feelings. Psychol Bull 127:267–286PubMedCrossRefGoogle Scholar
  44. Madden GJ, Bickel WK, Jacobs EA (1999) Discounting of delayed rewards in opioid-dependent outpatients: exponential or hyperbolic discounting functions? Exp Clin Psychopharmacol 7:284–293PubMedCrossRefGoogle Scholar
  45. Marowsky A, Fritschy JM, Vogt KE (2004) Functional mapping of GABA A receptor subtypes in the amygdala. Eur J Neurosci 20:1281–1289PubMedCrossRefGoogle Scholar
  46. Millan MJ (2003) The neurobiology and control of anxious states. Prog Neurobiol 70:83–244PubMedCrossRefGoogle Scholar
  47. 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 96:1825–1837PubMedCrossRefGoogle Scholar
  48. Norusis MJ (1990) SPSS base system user’s guide. SPSS Inc, Chicago, ILGoogle Scholar
  49. 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 19:1439–1448PubMedCrossRefGoogle Scholar
  50. 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 62:282–288PubMedCrossRefGoogle Scholar
  51. 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 354:1261–1281PubMedCrossRefGoogle Scholar
  52. Petry NM, Bickel WK, Arnett M (1998) Shortened time horizons and insensitivity to future consequences in heroin addicts. Addiction 93:729–738PubMedCrossRefGoogle Scholar
  53. Quirk GJ, Gehlert DR (2003) Inhibition of the amygdala: key to pathological states? Ann N Y Acad Sci 985:263–272PubMedCrossRefGoogle Scholar
  54. 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) 157:358–367CrossRefGoogle Scholar
  55. Richmond BJ, Liu Z, Shidara M (2003) Neuroscience. Predicting future rewards. Science 301:179–180PubMedCrossRefGoogle Scholar
  56. Ridderinkhof KR, Ullsperger M, Crone EA, Nieuwenhuis S (2004) The role of the medial frontal cortex in cognitive control. Science 306:443–447PubMedCrossRefGoogle Scholar
  57. Roache JD, Griffiths RR (1987) Lorazepam and meprobamate dose effects in humans: behavioral effects and abuse liability. J Pharmacol Exp Ther 243:978–988PubMedGoogle Scholar
  58. 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 55:594–602PubMedCrossRefGoogle Scholar
  59. 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 264:1218–1226PubMedGoogle Scholar
  60. Rush CR, Higgins ST, Bickel WK, Hughes JR (1994) Acute behavioral effects of lorazepam and caffeine, alone and in combination, in humans. Behav Pharmacol 5:245–254PubMedGoogle Scholar
  61. Rushworth MF, Walton ME, Kennerley SW, Bannerman DM (2004) Action sets and decisions in the medial frontal cortex. Trends Cogn Sci 8:410–417PubMedCrossRefGoogle Scholar
  62. Slovic P (1987) Perception of risk. Science 236:280–285PubMedCrossRefGoogle Scholar
  63. Slovic P (2000) Perception of risk. Earthscan Publications, LondonGoogle Scholar
  64. 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 99:455–460PubMedCrossRefGoogle Scholar
  65. Spielberger CD (1983) Manual for the state-trait anxiety inventory (Form Y). Consulting Psychologists Press, Palo Alto, CAGoogle Scholar
  66. 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 155:1009–1015PubMedGoogle Scholar
  67. Zezula J, Cortes R, Probst A, Palacios JM (1988) Benzodiazepine receptor sites in the human brain: autoradiographic mapping. Neuroscience 25:771–795PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Estibaliz Arce
    • 1
  • Daniel A. Miller
    • 1
  • Justin S. Feinstein
    • 1
  • Murray B. Stein
    • 1
    • 2
  • Martin P. Paulus
    • 1
    • 2
  1. 1.Department of Psychiatry, Laboratory of Biological Dynamics and Theoretical MedicineUniversity of California San DiegoLa JollaUSA
  2. 2.Psychiatry ServiceSan Diego Veterans Affairs Medical CenterSan DiegoUSA

Personalised recommendations