• Postdoctoral training – Harvard University
• Postdoctoral training – Wake Forest University Health Sciences

Research Interests: Neural basis of motivated behavior, hypocretin/orexin, dopamine, norepinephrine, behavioral pharmacology, sleep/arousal, substance abuse, fast scan cyclic voltammetry, fiber photometry, multi-unit electrophysiology, optogenetics, DREADDs

Research Staff:
Phil Clark, Graduate Student
Kyle Samson, Graduate Student
Volodar Migovich, Research Assistant

Collaborators and Colleagues:
Maria E. Andres, PhD, Pontificia Universidad Católica de Chile
Caroline E. Bass, PhD, University at Buffalo
Sara R. Jones, PhD, Wake Forest School of Medicine
Ole V. Mortensen, PhD, Drexel University College of Medicine
Ramesh Raghupathi, Drexel University College of Medicine
Sandhya Kortagere, PhD, Wake Forest School of Medicine
Jessica Barson, PhD, Drexel University College of Medicine

Dr. España's doctoral thesis at the University of Wisconsin focused on the behavioral and physiological functions of the hypocretins, particularly as they relate to arousal-related processes including sleep/wake behavior and stress. His postdoctoral research in the Department of Neurology at the Harvard Institutes of Medicine focused on elucidating the afferent innervation of the hypocretin neurons with an emphasis on aminergic inputs. In this work, Dr. España showed that the hypocretin neurons receive input from regions that govern motivation, homeostatic drive, behavioral state, and autonomic tone.

Dr. España later joined the Department of Physiology and Pharmacology at Wake Forest School of Medicine where he used behavioral and neurochemical approaches to demonstrate that the hypocretins regulate the reinforcing effects of cocaine via actions on the mesolimbic dopamine system. His current research focuses on hypocretin, dopamine, and norepinephrine regulation of arousal-related processes including sleep/wake function, stress and drug reinforcement.

His laboratory uses a multidisciplinary approach to investigate the involvement of hypocretins in reward and addiction processes. Techniques include:

• Electrophysiological recordings of sleep/wake behavior
• Fast scan cyclic voltammetry in anesthetized and freely moving preparations
• Circuit- and cell type-specific manipulations
• Fiber photometry
• DREADDs
• Optogenetics
• Self-administration of drugs of abuse
• Single and multi-unit recordings in behaving animals

Selected Grants Funded

• 2R01DA03190 - Hypocretin/Orexin Regulation of Dopamine and Cocaine Reinforcement. These studies examine whether hypocretin receptor 1 antagonism early in abstinence disrupts the development of intensified behavioral and dopaminergic responses to cocaine.
• Commonwealth of PA CURE - Involvement of Hypocretin/Orexin in Opioid Withdrawal and Relapse. This project examines if treatment with the FDA approved dual hypocretin receptor 1 and receptor 2 antagonist Suvorexant (Belsomra®) during oxycodone abstinence reduces relapse to opioid use.
• Commonwealth of PA CURE - Involvement of Hypocretin/Orexin in Opioid Withdrawal and Relapse. This project examines if treatment with the FDA approved dual hypocretin receptor 1 and receptor 2 antagonist Suvorexant (Belsomra®) during oxycodone abstinence reduces relapse to opioid use.

Completed

• R01DA03190 - Hypocretin/Orexin Regulation of Dopamine and Cocaine Reinforcement. These studies used a combination of voltammetry, drug reinforcement, and virus-mediated gene manipulation techniques to examine the extent to which hypocretin signaling participates in the regulation of motivated behavior.
• R21DA043787 - Pre-existing individual differences in dopamine uptake dynamics govern the motivation for cocaine. These studies examined the contribution of inherent, individual differences in dopamine neurotransmission to the subsequent risk and intensity of cocaine-associated behavior.
• K01DA025279 - Hypocretin/Orexin Modulation of Reward and Addiction Processes. These studies utilize self-administration and microdialysis techniques in behaving rats, and voltammetry in anesthetized rats to examine whether the hypocretin system influences cocaine-self administration and whether these actions involved changes in the dopamine system.
• NARSAD Award - Hypocretin regulation of dopamine neurotransmission. This study will use hypocretin knockout mice to examine the extent to which the hypocretin system is necessary for normal dopamine function under normal conditions and in response to stimulant drugs of abuse.

"What Happens to Your Body When You Overdose – and Other Questions on the Opioid Crisis"
Drexel News Blog (2018)

"A brain chemical tied to narcolepsy may play a role in opioid addiction"
Science News (June 27, 2018)

"Neuroscientists Talk Shop"
SHOP (UTSA) Neurobiology Podcast (2015)

Inside the Brain: The Wiring of Addiction
Exel, Drexel's Research Magazine (2014)

"Neuropeptide Promotes Behaviors Tied to Addiction and Overeating"
NIDA Notes (2011)

Selected Publications

"Neurochemistry of sleep"
Alonso IP, España RA
In: The encyclopedia of sleep. (C. A. Kushida, Ed.). San Diego, Elsevier, 485–489 (2021)

"Pharmacological Characterization of 4-Methylthioamphetamine Derivatives"
Guajardo FG, Velásquez VB, Raby D, Núñez-Vivanco G, IturriagaVásquez P, España RA, Reyes-Parada M, Sotomayor-Zárate R
Molecules. Nov 13;25(22) (2020)

"Chemogenetic Manipulation of Dopamine Neurons Dictates Cocaine Potency at Distal Dopamine Transporters"
Brodnik ZD, Xu W, Batra A, Lewandowski SI, Ruiz CM, Mortensen OV, Kortagere S, Mahler SV, España RA
J Neurosci. Nov 4;40(45):8767-8779 (2020)

"Chronic modafinil administration to preadolescent rats impairs social play behavior and dopaminergic system"
Cid-Jofré V, Gárate-Pérez M, Clark PJ, Valero-Jara V, España RA, Sotomayor-Zárate R, Cruz G, Renard GM
Neuropharmacology. Feb 1;183:108404 (2021)

"Dopamine transporter function fluctuates across sleep/wake state: potential impact for addiction"
Alonso IP, Pino JA, Kortagere S, Torres GE, España RA
Neuropsychopharmacology. Online ahead of print. (2021)

"Study of the release of endogenous amines in Drosophila brain in vivo in response to stimuli linked to aversive olfactory conditioning"
Hidalgo S, Fuenzalida-Uribe N, Molina-Mateo D, Escobar AP, Oliva C, España RA, Andrés ME, Campusano JM
J Neurochem. Feb;156(3):337-351 (2021)

"Individual differences in dopamine uptake in the dorsomedial striatum prior to cocaine exposure predict motivation for cocaine in male rats"
Shaw JK, Pamela Alonso I, Lewandowski SI, Scott MO, O’Connor BM, Aggarwal S, De Biasi M, Mortensen OV, España RA
Neuropsychopharmacology. May 5 (2021)

"Spinal Dopaminergic Mechanisms Regulating the Micturition Reflex in Male Rats with Complete Spinal Cord Injury"
Qiao Y, Brodnik ZD, Zhao S, Trueblood CT, Li Z, Tom VJ, España RA, Hou S
J Neurotrauma. Mar 15;38(6):803-817 (2021)

"Restoring lost nigrostriatal fibers in Parkinson’s disease based on clinically-inspired design criteria"
Gordián-Vélez WJ, Chouhan D, España RA, Chen HI, Burdick JA, Duda JE, Cullen DK
Brain Res Bull. Oct;175:168-185. doi: 10.1016/j.brainresbull.2021.07.016. Epub 2021 Jul 28. PMID: 34332016 (2021)

"Striatal low-threshold spiking interneurons locally gate dopamine"
Holly EN, Davatolhagh MF, España RA, Fuccillo MV
Curr Biol. Sep 27;31(18):4139-4147.e6 (2021)

"Diazepam Concurrently Increases the Frequency and Decreases the Amplitude of Transient Dopamine Release Events in the Nucleus Accumbens"
Schelp SA, Brodnik ZD, Rakowski DR, Pultorak KJ, Sambells AT, España RA, Oleson EB
J Pharmacol Exp Ther.;364(1):145-155. doi: 10.1124/jpet.117.241802. (Epub Oct 20, 2017), Jan 2018

"Hypocretin receptor 1 knockdown in the ventral tegmental area attenuates mesolimbic dopamine signaling and reduces motivation for cocaine"
Bernstein DL, Badve PS, Barson JR, Bass CE, España RA
Addict Biol., doi: 10.1111/adb.12553. [Epub ahead of print] Oct 2, 2017

"Susceptibility to traumatic stress sensitizes the dopaminergic response to cocaine and increases motivation for cocaine"
Brodnik ZD, Black EM, Clark MJ, Kornsey KN, Snyder NW, España RA
Neuropharmacology;125:295-307. doi: 10.1016/j.neuropharm.2017.07.032. (Epub Aug 1, 2017) Oct 2017

"Hypocretin receptor 1 blockade produces bimodal modulation of cocaine-associated mesolimbic dopamine signaling"
Levy KA, Brodnik ZD, Shaw JK, Perrey DA, Zhang Y, España RA.
Psychopharmacology (Berl). ;234(18):2761-2776. doi: 10.1007/s00213-017-4673-y (Epub Jun 30, 2017) Sep 2017

"L-Tyrosine availability affects basal and stimulated catecholamine indices in prefrontal cortex and striatum of the rat"
Brodnik ZD, Double M, España RA, Jaskiw GE
Neuropharmacology;123:159-174. doi: 10.1016/j.neuropharm.2017.05.030 (Epub May 29, 2017), Sep 1, 2017

"Mechanisms of Kappa Opioid Receptor Potentiation of Dopamine D2 Receptor Function in Quinpirole-Induced Locomotor Sensitization in Rats"
Escobar AP, González MP, Meza RC, Noches V, Henny P, Gysling K, España RA, Fuentealba JA, Andrés ME
Int J Neuropsychopharmacol.;20(8):660-669. doi: 10.1093/ijnp/pyx042, Aug 1, 2017

"Suvorexant, an orexin/hypocretin receptor antagonist, attenuates motivational and hedonic properties of cocaine"
Gentile TA, Simmons SJ, Barker DJ, Shaw JK, España RA, Muschamp JW
Addict Biol.;23(1):247-255. doi: 10.1111/adb.12507 (Epub Apr 17, 2017) Jan 2018

"Norepinephrine at the nexus of arousal, motivation and relapse"
España RA, Schmeichel BE, Berridge CW
Brain Res.;1641(Pt B):207-16. doi: 10.1016/j.brainres.2016.01.002 (Epub Jan 7, 2016) Review, Jun 15, 2016

"Reinforcing Doses of Intravenous Cocaine Produce Only Modest Dopamine Uptake Inhibition"
Brodnik ZD, Ferris MJ, Jones SR, España RA
ACS Chem Neurosci. (2016)

"Clozapine N-Oxide Administration Produces Behavioral Effects in Long-Evans Rats: Implications for Designing DREADD Experiments"
MacLaren DA, Browne RW, Shaw JK, Krishnan Radhakrishnan S, Khare P, España RA, Clark SD"
eNeuro (2016)

"Hypocretin/orexin knock-out mice display disrupted behavioral and dopamine responses to cocaine"
Shaw JK, Ferris MJ, Locke JL, Brodnik ZD, Jones SR, España RA
Addict Biol. (2016)

"Dopamine uptake dynamics are preserved under isoflurane anesthesia"
Brodnik ZD, España RA
Neurosci Lett, 606:129-134 (2015)

"Hypocretin receptor 1 blockade preferentially reduces high effort responding for cocaine without promoting sleep"
Brodnik ZD, Bernstein DL, Prince CD, España RA
Behav Brain Res, 291:377-384 (2015)

"Hypocretin/Orexin Regulation of Dopamine Signaling and Cocaine Self-Administration is Mediated Predominantly by Hypocretin Receptor 1"
Prince CD, Rau AR, Yorgason JT, España RA
ACS Chem Neurosci, 6,1:138-146 (2015)

"Dopamine transporters govern diurnal variation in extracellular dopamine tone"
Ferris MJ, España RA, Locke JL, Konstantopoulos JK, Rose JH, Chen R, Jones SR
Proc Natl Acad Sci, 111,26:E2751-E2759 (2014)

"Enduring increases in anxiety-like behavior and rapid nucleus accumbens dopamine signaling in socially isolated rats"
Yorgason JT, España RA, Konstantopoulos JK, Weiner JL, Jones SR
Eur J Neurosci, 37(6):1022-31 (2013)

"Hypocretin/orexin regulation of dopamine signaling: implications for reward and reinforcement mechanisms"
Calipari ES, España RA
Front Behav Neurosci, 6:54. (2012)

"Demon voltammetry and analysis software: Analysis of cocaine-induced alterations in dopamine signaling using multiple kinetic measures"
Yorgason, JT, España, RA, Jones SR
Journal of Neuroscience Methods, 2:158-164 (2011)

"Low and high affinity dopamine transporter inhibitors block dopamine uptake within 5 sec of intravenous injection"
Yorgason, JT, Jones SR, España, RA
Neuroscience, 182:125-32 (2011)

"Hypocretin 1/orexin A in the ventral tegmental area enhances dopamine responses to cocaine and promotes cocaine self-administration"
España RA, Melchior JR, Roberts DCS, Jones SR
Psychopharmacology (Berl), 214(2):415-426 (2011)

"Hypocretin/Orexin regulates cocaine self-administration via actions on the mesolimbic dopamine system"
España, RA, Oleson, E, Locke, JL Roberts, DCS, Jones, SR
European Journal of Neuroscience, 31:336-348 (2010)

"Hypocretin/orexin in arousal and stress"
Berridge CW, España RA, Vittoz NM
Brain Research, 1314:91-102 (2010)

"Short-acting cocaine and long-acting GBR-12909 both elicit rapid dopamine uptake inhibition following intravenous delivery"
España, RA, Roberts DCS, Jones, SR
Neuroscience, 155:250-257, 2008

"Organization of noradrenergic efferents to arousal-related basal forebrain structures"
España, RA, and Berridge, CW
Journal of Comparative Neurology, 496 (5):668-683 (2006)

"Circadian-dependent and circadian-independent behavioral actions of hypocretin/orexin"
España, RA, Plahn, S, and Berridge, CW 
Brain Research, 943 (2): 224–236 (2002)

"Wake-promoting and sleep-suppressing actions of hypocretin (orexin): basal forebrain sites of action"
España, RA, Baldo, BA, Kelley, AE, and Berridge, CW
Neuroscience, 106 (4): 699-715 (2001)