Abstract
Rationale
Norepinephrine plays a critical role in the stress response. Clarifying the psychopharmacological effects of norepinephrine manipulation on stress reactivity in humans has important implications for basic neuroscience and treatment of stress-related psychiatric disorders, such as posttraumatic stress disorder and alcohol use disorders. Preclinical research implicates the norepinephrine alpha-1 receptor in responses to stressors. The No Shock, Predictable Shock, Unpredictable Shock (NPU) task is a human laboratory paradigm that is well positioned to test cross-species neurobiological stress mechanisms and advance experimental therapeutic approaches to clinical trials testing novel treatments for psychiatric disorders.
Objectives
We hypothesized that acute administration of prazosin, a noradrenergic alpha-1 antagonist, would have a larger effect on reducing stress reactivity during unpredictable, compared to predictable, stressors in the NPU task.
Methods
We conducted a double-blind, placebo-controlled, crossover randomized controlled trial in which 64 healthy adults (32 female) completed the NPU task at two visits (2 mg prazosin vs. placebo).
Results
A single acute dose of 2 mg prazosin did not reduce stress reactivity in a healthy adult sample. Neither NPU startle potentiation nor self-reported anxiety was reduced by prazosin (vs. placebo) during unpredictable (vs. predictable) stressors.
Conclusions
Further research is needed to determine whether this failure to translate preclinical neuroscience to human laboratory models is due to methodological factors (e.g., acute vs. chronic drug administration, brain penetration, study population) and/or suggests limited clinical utility of noradrenergic alpha-1 antagonists for treating stress-related psychiatric disorders.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Notes
We preregistered a sequential recruitment plan to enroll an equal number of participants with AUD in early recover if we confirmed our hypothesis that prazosin reduced stress reactivity to unpredictable (vs. predictable) stressors in health adults (https://clinicaltrials.gov/ct2/show/NCT02966340).
The University of Iowa Pharmaceuticals prepared and over-encapsulated study drug and matching placebos. The University of Wisconsin Pharmaceutical Research Center implemented and maintained the randomization and blind. At visit 1, participants were randomized 1:1 to Drug Order (A: visit 1 prazosin and visit 2 placebo; B: visit 1 placebo and visit 2 prazosin) and NPU Task Order (four condition and startle probe counterbalancing orders), stratified by Sex.
In accordance with our pre-registration, we excluded and replaced two participants with general startle reactivity at their first study visit of < 5 μV (non-responders).
We analyze raw startle potentiation consistent with our preregistered analysis plan and numerous previous studies with this and related tasks (Moberg and Curtin 2009; Bradford et al. 2013, 2014; Kaye et al. 2016; Moberg et al. 2017). We report analyses of startle response during the no-shock blocks to confirm that observed effects result from shock threat rather than control condition (no-shock block) differences (see footnote 6 and 8). We do not standardize startle potentiation as it yields lower internal consistency and temporal stability than raw startle potentiation in the NPU task (Bradford et al. 2015; Kaye et al. 2016). Consistent with our previous studies, we also limit analyses to the cue period in predictable and unpredictable blocks to control for (i.e., match) the attentional demands associated with the visual foreground across these blocks (Lang et al. 1990).
We collected a battery of other measures that were available to be used as either covariates or moderators in the analysis of the primary and secondary dependent variables (see Supplement). We utilize covariates to increase power to detect the focal effect in our analytic models. We preregistered to select covariates if we confirmed that the specific covariate (e.g., general startle reactivity, drug order, intolerance of uncertainty) significantly predicted the test of the primary hypothesis (i.e., two-way interaction between drug and NPU task condition). Any categorical between-subject factors were coded as unit-weighted, centered, orthogonal regressors (e.g., sex: male = − 0.5, female = 0.5). Any continuous/quantitative individual difference covariates were mean-centered. We conducted analyses separately for each dependent variable (e.g., startle potentiation, self-reported fear/anxiety potentiation) with only one covariate in the model at a time to determine covariate selection. We only used the covariate if it was a significant predictor of the drug X NPU condition interaction for each dependent variable separately (e.g., startle potentiation or self-reported fear/anxiety potentiation).
We did not include any covariates in models predicting the two-way interaction on startle potentiation (primary outcome) or self-reported anxiety (secondary outcome) as none met our preregistered decision threshold. We did not identify or remove any model outliers (i.e., Bonferroni-corrected studentized residuals, p < .05).
There was not a significant effect of drug on startle response only during the No Shock condition, ηp2 = .039, b = 4.2 μV, t(61) = 1.57, p = .121, suggesting that the main effect of prazosin on startle potentiation (i.e., shock cues minus no-shock cues) was not driven by a reduction in startle during No Shock.
In the unadjusted model, there was not a significant main effect of drug on overall startle potentiation, ηp2 = .107, b = − 6.8 μV, t(63) = − 1.97, p = .053, with no covariates included or outliers removed.
We removed one model outlier, but there was still not a significant main effect of drug on overall self-reported anxiety/fear, ηp2 = .008, b = 0.09, t(63) = 0.70, p = .484, with no outliers removed. We did not include any covariates in either model predicting the drug main effect on self-reported anxiety as none met our preregistered decision threshold. We also confirmed that was not a significant effect of drug on startle response during the No Shock condition, ηp2 = .013, b = 0.06, t(62) = 0.89, p = 0.375.
Previous literature suggests that prazosin’s peak effects on peripheral physiology and plasma concentration occur 1–4 h post-administration (Jaillon 1980). Unfortunately, there is limited research in humans to confirm the time course of effects in the brain (but see Rutland et al. 1980). Although prazosin is still widely used in rodent behavioral neuroscience research today to study the central nervous system, human studies have primarily examined peripheral physiology as prazosin was originally developed as an antihypertensive agent. Indeed, very few studies have examined basic acute effects of prazosin in humans since the 1970s.
Considerable preclinical research supports our study hypothesis that acute prazosin would selectively reduce startle potentiation during unpredictable (relative to predictable) shock. However, the most direct translational design of our current study in humans (i.e., acute prazosin effects on startle potentiation to unpredictable vs predictable shock) has not been performed in rodent models to date. We believe reverse-translation of our current study design in rodents, using parallel pharmacological manipulation (acute prazosin), stressor manipulation (unpredictable vs. predictable shock), and measurement (startle potentiation) is essential to clarify convergent or divergent results across species. Furthermore, additional psychopharmacology studies in both human and rodent models should address differences in acute vs chronic prazosin administration. Only recently have preclinical labs begun to examine the effects of chronic prazosin on relevant anxiety-like behaviors and alcohol use/seeking behaviors (Froehlich et al. 2013; Skelly and Weiner 2014; Rasmussen et al. 2017). However, no studies have examined chronic prazosin administration effects on startle response as the primary outcome measure.
References
Arnsten AFT (2009) Stress signalling pathways that impair prefrontal cortex structure and function. Nat Rev Neurosci 10:410–422. https://doi.org/10.1038/nrn2648
Berridge CW (2008) Noradrenergic modulation of arousal. Brain Res Rev 58:1–17. https://doi.org/10.1016/j.brainresrev.2007.10.013
Berridge CW, Dunn AJ (1989) Restraint-stress-induced changes in exploratory behavior appear to be mediated by norepinephrine-stimulated release of CRF. J Neurosci 9:3513–3521
Berridge CW, Waterhouse BD (2003) The locus coeruleus-noradrenergic system: modulation of behavioral state and state-dependent cognitive processes. Brain Res Brain Res Rev 42:33–84
Blumenthal TD, Cuthbert BN, Filion DL, Hackley S, Lipp OV, van Boxtel A (2005) Committee report: guidelines for human startle eyeblink electromyographic studies. Psychophysiology 42:1–15. https://doi.org/10.1111/j.1469-8986.2005.00271.x
Bradford DE, Kaye JT, Curtin JJ (2014) Not just noise: individual differences in general startle reactivity predict startle response to uncertain and certain threat. Psychophysiology 51:407–411. https://doi.org/10.1111/psyp.12193
Bradford DE, Shapiro BL, Curtin JJ (2013) How bad could it be? Alcohol dampens stress responses to threat of uncertain intensity. Psychol Sci 24:2541–2549. https://doi.org/10.1177/0956797613499923
Bradford DE, Starr MJ, Shackman AJ, Curtin JJ (2015) Empirically based comparisons of the reliability and validity of common quantification approaches for eyeblink startle potentiation in humans. Psychophysiology 52:1669–1681. https://doi.org/10.1111/psyp.12545
Darracq L, Blanc G, Glowinski J, Tassin JP (1998) Importance of the noradrenaline-dopamine coupling in the locomotor activating effects of D-amphetamine. J Neurosci 18:2729–2739
Davis M, Walker DL, Miles L, Grillon C (2010) Phasic vs sustained fear in rats and humans: role of the extended amygdala in fear vs anxiety. Neuropsychopharmacol Rev 35:105–135. https://doi.org/10.1037/npp.2009
Dunlop BW, Binder EB, Iosifescu D, Mathew SJ, Neylan TC, Pape JC, Carrillo-Roa T, Green C, Kinkead B, Grigoriadis D, Rothbaum BO, Nemeroff CB, Mayberg HS (2017) Corticotropin-releasing factor receptor 1 antagonism is ineffective for women with posttraumatic stress disorder. Biol Psychiatry 82:866–874. https://doi.org/10.1016/j.biopsych.2017.06.024
Fox HC, Anderson GM, Tuit K, Hansen J, Kimmerling A, Siedlarz KM, Morgan PT, Sinha R (2012) Prazosin effects on stress- and cue-induced craving and stress response in alcohol-dependent individuals: preliminary findings. Alcohol Clin Exp Res 36:351–360. https://doi.org/10.1111/j.1530-0277.2011.01628.x
Froehlich JC, Hausauer BJ, Federoff DL, Fischer SM, Rasmussen DD (2013) Prazosin reduces alcohol drinking throughout prolonged treatment and blocks the initiation of drinking in rats selectively bred for high alcohol intake. Alcohol Clin Exp Res 37:1552–1560. https://doi.org/10.1111/acer.12116
Funk D, Coen K, Tamadon S, Li Z, Loughlin A, Lê AD (2016) Effects of prazosin and doxazosin on yohimbine-induced reinstatement of alcohol seeking in rats. Psychopharmacology 233:2197–2207. https://doi.org/10.1007/s00213-016-4273-2
Galvez R, Mesches MH, McGaugh JL (1996) Norepinephrine release in the amygdala in response to footshock stimulation. Neurobiol Learn Mem 66:253–257. https://doi.org/10.1006/nlme.1996.0067
Gilpin NW, Weiner JL (2017) Neurobiology of comorbid post-traumatic stress disorder and alcohol-use disorder. Genes Brain Behav 16:15–43. https://doi.org/10.1111/gbb.12349
Gorka SM, Nelson BD, Shankman SA (2013) Startle response to unpredictable threat in comorbid panic disorder and alcohol dependence. Drug Alcohol Depend 132:216–222. https://doi.org/10.1016/j.drugalcdep.2013.02.003
Gresack J, Risbrough V (2011) Corticotropin-releasing factor and noradrenergic signalling exert reciprocal control over startle reactivity. Int J Neuropsychopharmacol 14:1179–1194. https://doi.org/10.1017/S1461145710001409
Grillon C, Baas JM, Pine DS et al (2006) The benzodiazepine alprazolam dissociates contextual fear from cued fear in humans as assessed by fear-potentiated startle. Biol Psychiatry 60:760–766. https://doi.org/10.1016/j.biopsych.2005.11.027
Grillon C, Chavis C, Covington MF, Pine DS (2009a) Two-week treatment with the selective serotonin reuptake inhibitor citalopram reduces contextual anxiety but not cued fear in healthy volunteers: a fear-potentiated startle study. Neuropsychopharmacology 34:964–971. https://doi.org/10.1038/npp.2008.141
Grillon C, Hale E, Lieberman L, Davis A, Pine DS, Ernst M (2015) The CRH1 antagonist GSK561679 increases human fear but not anxiety as assessed by startle. Neuropsychopharmacology 40:1064–1071. https://doi.org/10.1038/npp.2014.316
Grillon C, Levenson J, Pine DS (2007) A single dose of the selective serotonin reuptake inhibitor citalopram exacerbates anxiety in humans: a fear-potentiated startle study. Neuropsychopharmacology 32:225–231. https://doi.org/10.1038/sj.npp.1301204
Grillon C, Lissek S, Rabin S et al (2008) Increased anxiety during anticipation of unpredictable but not predictable aversive stimuli as a psychophysiologic marker of panic disorder. Am J Psychiatr 165:898–904. https://doi.org/10.1176/appi.ajp.2007.07101581
Grillon C, Pine DS, Lissek S, Rabin S, Bonne O, Vythilingam M (2009b) Increased anxiety during anticipation of unpredictable aversive stimuli in posttraumatic stress disorder but not in generalized anxiety disorder. Biol Psychiatry 66:47–53. https://doi.org/10.1016/j.biopsych.2008.12.028
Haass-Koffler CL, Swift RM, Leggio L (2018) Noradrenergic targets for the treatment of alcohol use disorder. Psychopharmacology 235:1625–1634. https://doi.org/10.1007/s00213-018-4843-6
Hendrickson R, Raskind M (2016) Noradrenergic dysregulation in the pathophysiology of PTSD. Exp Neurol 284:181–195. https://doi.org/10.1016/j.expneurol.2016.05.014
Homan P, Lin Q, Murrough JW et al (2017) Prazosin during threat discrimination boosts memory of the safe stimulus. Learn Mem. Cold Spring Harbor Laboratory Press 24:597–601. https://doi.org/10.1101/lm.045898.117
Jaillon P (1980) Clinical pharmacokinetics of prazosin. Clin Pharmacokinet 5:365–376
Kaye JT, Bradford DE, Curtin JJ (2016) Psychometric properties of startle and corrugator response in NPU, affective picture viewing, and resting state tasks. Psychophysiology 53:1241–1255. https://doi.org/10.1111/psyp.12663
Kaye JT, Bradford DE, Magruder KP, Curtin JJ (2017) Probing for neuroadaptations to unpredictable stressors in addiction: translational methods and emerging evidence. J Stud Alcohol Drugs 78:353–371. https://doi.org/10.15288/jsad.2017.78.353
Kleiner M, Brainard D, Pelli D et al (2007) What’s new in Psychtoolbox-3. Perception 36:1
Kleinman RA, Ostacher MJ (2019) Prazosin and alcohol use disorder. Am J Psychiatry 176:165. https://doi.org/10.1176/appi.ajp.2018.18101143
Koob GF (2009) Brain stress systems in the amygdala and addiction. Brain Res 1293:61–75. https://doi.org/10.1016/j.brainres.2009.03.038
Krystal JH, Davis LL, Neylan TC, A. Raskind M, Schnurr PP, Stein MB, Vessicchio J, Shiner B, Gleason TD, Huang GD (2017) It is time to address the crisis in the pharmacotherapy of posttraumatic stress disorder: a consensus statement of the PTSD psychopharmacology working group. Biol Psychiatry 82:e51–e59. https://doi.org/10.1016/j.biopsych.2017.03.007
Lang PJ, Bradley MM, Cuthbert BN (1990) Emotion, attention, and the startle reflex. Psychol Rev 97:377–395. https://doi.org/10.1037/0033-295X.97.3.377
Lê AD, Funk D, Juzytsch W, Coen K, Navarre BM, Cifani C, Shaham Y (2011) Effect of prazosin and guanfacine on stress-induced reinstatement of alcohol and food seeking in rats. Psychopharmacology 218:89–99. https://doi.org/10.1007/s00213-011-2178-7
Manion S, Gamble E, Li H (2007) Prazosin administered prior to inescapable stressor blocks subsequent exaggeration of acoustic startle response in rats. Pharmacol Biochem Behav 86:559–565. https://doi.org/10.1016/j.pbb.2007.01.019
Mantsch JR, Baker DA, Funk D, Lê AD, Shaham Y (2016) Stress-induced reinstatement of drug seeking: 20 years of progress. Neuropsychopharmacology 41:335–356. https://doi.org/10.1038/npp.2015.142
McCarthy E, Petrakis I (2010) Epidemiology and management of alcohol dependence in individuals with post-traumatic stress disorder. CNS Drugs 24:997–1007. https://doi.org/10.2165/11539710-000000000-00000
Moberg CA, Bradford DE, Kaye JT, Curtin JJ (2017) Increased startle potentiation to unpredictable stressors in alcohol dependence: possible stress neuroadaptation in humans. J Abnorm Psychol 126:441–453. https://doi.org/10.1037/abn0000265
Moberg CA, Curtin JJ (2009) Alcohol selectively reduces anxiety but not fear: startle response during unpredictable vs. predictable threat. J Abnorm Psychol 118:335–347. https://doi.org/10.1037/a0015636
Morgan C, Grillon C, Southwick S et al (1995) Yohimbine facilitated acoustic startle in combat veterans with post-traumatic stress disorder. Psychopharmacology 117:466–471
Morgan C, Southwick S, Grillon C et al (1993) Yohimbine-facilitated acoustic startle reflex in humans. Psychopharmacology 110:342–346
Pacák K, McCarty R, Palkovits M et al (1995) Effects of immobilization on in vivo release of norepinephrine in the bed nucleus of the stria terminalis in conscious rats. Brain Res 688:242–246
Petrakis IL, Desai N, Gueorguieva R, Arias A, O'Brien E, Jane JS, Sevarino K, Southwick S, Ralevski E (2016) Prazosin for veterans with posttraumatic stress disorder and comorbid alcohol dependence: a clinical trial. Alcohol Clin Exp Res 40:178–186. https://doi.org/10.1111/acer.12926
Rajbhandari AK, Baldo BA, Bakshi VP (2015) Predator stress-induced CRF release causes enduring sensitization of basolateral amygdala norepinephrine sstems that promote PTSD-like startle abnormalities. J Neurosci 35:14270–14285. https://doi.org/10.1523/JNEUROSCI.5080-14.2015
Raskind M, Peskind ER, Chow B et al (2018) Trial of prazosin for post-traumatic stress disorder in military veterans. N Engl J Med 378:507–517. https://doi.org/10.1056/NEJMoa1507598
Raskind M, Peskind ER, Hoff DJ et al (2007) A parallel group placebo controlled study of prazosin for trauma nightmares and sleep disturbance in combat veterans with post-traumatic stress disorder. Biol Psychiatry 61:928–934. https://doi.org/10.1016/j.biopsych.2006.06.032
Raskind M, Peskind ER, Kanter ED et al (2003) Reduction of nightmares and other PTSD symptoms in combat veterans by prazosin: a placebo-controlled study. Am J Psychiatry 160:371–373. https://doi.org/10.1176/appi.ajp.160.2.371
Raskind M, Peterson K, Williams T et al (2013) A trial of prazosin for combat trauma PTSD with nightmares in active-duty soldiers returned from Iraq and Afghanistan. Am J Psychiatry 170:1003–1010. https://doi.org/10.1176/appi.ajp.2013.12081133
Rasmussen DD, Kincaid CL, Froehlich JC (2017) Prazosin prevents increased anxiety behavior that occurs in response to stress during alcohol deprivations. Alcohol Alcohol 52:5–11. https://doi.org/10.1093/alcalc/agw082
Rutland MD, Lee TY, Nimmon CC, Granowska M, Britton KE (1980) Measurement of the effects of a single dose of prazosin on the cerebral blood flow in hypertensive patients. Postgrad Med J 56:818–822
Schmitz A, Grillon C (2012) Assessing fear and anxiety in humans using the threat of predictable and unpredictable aversive events (the NPU-threat test). Nat Protoc 7:527–532. https://doi.org/10.1038/nprot.2012.001
Schwandt ML, Cortes CR, Kwako LE, George DT, Momenan R, Sinha R, Grigoriadis DE, Pich EM, Leggio L, Heilig M (2016) The CRF1 antagonist verucerfont in anxious alcohol dependent women: translation of neuroendocrine, but not of anti-craving effects. Neuropsychopharmacology 41:2818–2829. https://doi.org/10.1038/npp.2016.61
Shackman AJ, Fox AS (2016) Contributions of the central extended amygdala to fear and anxiety. J Neurosci 36:8050–8063. https://doi.org/10.1523/JNEUROSCI.0982-16.2016
Shankman SA, Nelson BD, Sarapas C, Robison-Andrew EJ, Campbell ML, Altman SE, McGowan SK, Katz AC, Gorka SM (2013) A psychophysiological investigation of threat and reward sensitivity in individuals with panic disorder and/or major depressive disorder. J Abnorm Psychol 122:322–338. https://doi.org/10.1037/a0030747
Simmons JP, Nelson LD, Simonsohn U (2012) A 21 word solution. https://doi.org/10.2139/ssrn.2160588 . Accessed 21 Mar 2016, A 21 Word Solution
Simpson TL, Saxon A, Meredith C et al (2009) A pilot trial of the alpha-1 adrenergic antagonist, prazosin, for alcohol dependence. Alcohol Clin Exp Res 33:255–263. https://doi.org/10.1111/j.1530-0277.2008.00807.x
Simpson TL, Saxon AJ, Stappenbeck C et al (2018) Double-blind randomized clinical trial of prazosin for alcohol use disorder. Am J Psychiatry 175:1216-1224. https://doi.org/10.1176/appi.ajp.2018.17080913
Skelly MJ, Weiner JL (2014) Chronic treatment with prazosin or duloxetine lessens concurrent anxiety-like behavior and alcohol intake: evidence of disrupted noradrenergic signaling in anxiety-related alcohol use. Brain Behav 4:468–483. https://doi.org/10.1002/brb3.230
Smith R, Aston-Jones G (2008) Noradrenergic transmission in the extended amygdala: role in increased drug-seeking and relapse during protracted drug abstinence. Brain Struct Funct 213:43–61. https://doi.org/10.1007/s00429-008-0191-3
Stine S, Grillon C, Morgan CA III et al (2001) Methadone patients exhibit increased startle and cortisol response after intravenous yohimbine. Psychopharmacology 154:274–281. https://doi.org/10.1007/s002130000644
Varty GB, Bakshi VP, Geyer MA (1999) M100907, a serotonin 5-HT2A receptor antagonist and putative antipsychotic, blocks dizocilpine-induced prepulse inhibition deficits in Sprague-Dawley and Wistar rats. Neuropsychopharmacology 20:311–321. https://doi.org/10.1016/S0893-133X(98)00072-4
Verplaetse TL, Weinberger AH, Oberleitner LM, Smith KMZ, Pittman BP, Shi JM, Tetrault JM, Lavery ME, Picciotto MR, McKee SA (2017) Effect of doxazosin on stress reactivity and the ability to resist smoking. J Psychopharmacol 31:830–840. https://doi.org/10.1177/0269881117699603
Vincent J, Meredith PA, Reid JL, Elliott HL, Rubin PC (1985) Clinical pharmacokinetics of prazosin--1985. Clin Pharmacokinet 10:144–154
Walker D, Davis M (1997) Double dissociation between the involvement of the bed nucleus of the stria terminalis and the central nucleus of the amygdala in startle increases produced by conditioned versus unconditioned fear. J Neurosci 17:9375–9383
Walker D, Miles LA, Davis M (2009) Selective participation of the bed nucleus of the stria terminalis and CRF in sustained anxiety-like versus phasic fear-like responses. Prog Neuro-Psychopharmacol Biol Psychiatry 33:1291–1308. https://doi.org/10.1016/j.pnpbp.2009.06.022
Acknowledgements
We thank Heather M. Williams for assistance with data collection and the University of Wisconsin (UW) Clinical Research Unit and UW Pharmaceutical Research Center for study support. Portions of this research have previously been presented at the annual conferences of the Society for Psychophysiology Research. This manuscript has been published on the preprint server PsyArXiv.
Funding
Research reported in this publication was supported by the National Institute of Alcohol Abuse and Alcoholism (NIAAA) of the National Institutes of Health (NIH) under award numbers R01 AA024388 (J Curtin) and F31 AA022845 (J Kaye), NIH National Center for Advancing Translational Science under the Clinical and Translational Science Award number UL1TR000427 to the UW Institute for Clinical and Translational Research, and by intramural research awards from the UW Office of the Vice Chancellor for Research and Graduate Education (J Curtin).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, VA, or UW. The authors have no biomedical financial interests or potential conflicts of interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
ESM 1
(DOCX 78 kb)
Rights and permissions
About this article
Cite this article
Kaye, J.T., Fronk, G.E., Zgierska, A.E. et al. Acute prazosin administration does not reduce stressor reactivity in healthy adults. Psychopharmacology 236, 3371–3382 (2019). https://doi.org/10.1007/s00213-019-05297-x
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-019-05297-x