Contact
Triad Technology Center333 Cassell Drive
Room 4500
Baltimore, MD 21224
Phone: 443-740-2161
Email: wrea@intra.nida.nih.gov
Education
M.A. - Experimental Psychology, Towson University, Towson, Maryland
B.S. - Psychology, Towson State University, Towson Maryland
Research Interests
William Rea received his B.S. degree in Psychology at Towson State University in 1990. He received his M.A. in Experimental Psychology at Towson University in 1998. He started his research career at NIDA/IRP in the Etiology Branch and has worked in both the Integrative Neuroscience department, as well as the Neuroimaging Research Branch. He accepted his current position in the Integrative Neurobiology Section in 2013. He currently uses micro-dialysis and behavioral testing techniques to investigate the functional and pharmacological significance of neurotransmitter and receptor interactions. The goal of his research is to find new pharmacological targets, that can be used to develop more effective drugs treatments for neuropsychiatric disorders including drug addiction.
Publications
Selected Publications
2021
Navarro, Gemma; Rea, William; Quiroz, César; Moreno, Estefanía; Gomez, Devan; Wenthur, Cody J; Casadó, Vicent; Leggio, Lorenzo; Hearing, Matthew C; Ferré, Sergi
In: J Neurosci, 2021, ISSN: 1529-2401.
@article{pmid34876469,
title = {Complexes of ghrelin GHS-R1a, GHS-R1b and dopamine D receptors localized in the ventral tegmental area as main mediators of the dopaminergic effects of ghrelin},
author = {Gemma Navarro and William Rea and César Quiroz and Estefanía Moreno and Devan Gomez and Cody J Wenthur and Vicent Casadó and Lorenzo Leggio and Matthew C Hearing and Sergi Ferré},
url = {https://pubmed.ncbi.nlm.nih.gov/34876469/},
doi = {10.1523/JNEUROSCI.1151-21.2021},
issn = {1529-2401},
year = {2021},
date = {2021-12-01},
urldate = {2021-12-01},
journal = {J Neurosci},
abstract = {Ghrelin receptor, also known as growth hormone secretagogue receptor or GHS-R1a, is co-expressed with its truncated isoform GHS-R1b, which does not bind ghrelin or signal, but oligomerizes with GHS-R1a, exerting a complex modulatory role that depends on its relative expression. D and D dopamine receptors (D1R and D5R) constitute the two D-like receptor subtypes. Previous studies showed GHS-R1b also facilitates oligomerization of GHS-R1a with D1R, conferring GHS-R1a distinctive pharmacological properties. Those include a switch in the preferred coupling of GHS-R1a from Gq to Gs and the ability of D1R/D5R agonists and antagonists to counteract GHS-R1a signaling. Activation of ghrelin receptors localized in the ventral tegmental area (VTA) seems to play a significant role in ghrelin's contribution to motivated behavior. In view of the evidence indicating that dopaminergic cells of the VTA express ghrelin receptors and D5R but not D1R, we investigated the possible existence of functional GHS-R1a:GHS-R1b:D5R oligomeric complexes in the VTA. GHS-R1a:GHS-R1b:D5R oligomers were first demonstrated in mammalian transfected cells and their pharmacological properties were found to be different from those of GHS-R1a:GHS-R1b:D1R oligomers, including weak Gs coupling and the ability of D1R/D5R antagonists, but not agonists, to counteract the effects of ghrelin. However, analyzing the effect of ghrelin in the rodent VTA on MAPK activation with experiments, on somato-dendritic dopamine release with microdialysis and on activation of dopaminergic cells with patch-clamp electrophysiology, provided evidence for a predominant role of GHS-R1a:GHS-R1b:D1R oligomers in the rodent VTA as main mediators of the dopaminergic effects of ghrelin.The activation of ghrelin receptors localized in the ventral tegmental area (VTA) plays a significant role in ghrelin's contribution to motivated behavior. We present evidence that indicates these receptors form part of oligomeric complexes that include the functional ghrelin receptor GHS-R1a, its truncated non-signaling isoform GHS-R1b and the dopamine D receptor (D1R). Binding of ghrelin to these complexes promotes activation of the dopaminergic neurons of the VTA by activation of AC-PKA signaling, which can be counteracted by both GHS-R1a and D1R antagonists. Our study provides evidence for a predominant role of GHS-R1a:GHS-R1b:D1R oligomers in rodent VTA as main mediators of the dopaminergic effects of ghrelin.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Ghrelin receptor, also known as growth hormone secretagogue receptor or GHS-R1a, is co-expressed with its truncated isoform GHS-R1b, which does not bind ghrelin or signal, but oligomerizes with GHS-R1a, exerting a complex modulatory role that depends on its relative expression. D and D dopamine receptors (D1R and D5R) constitute the two D-like receptor subtypes. Previous studies showed GHS-R1b also facilitates oligomerization of GHS-R1a with D1R, conferring GHS-R1a distinctive pharmacological properties. Those include a switch in the preferred coupling of GHS-R1a from Gq to Gs and the ability of D1R/D5R agonists and antagonists to counteract GHS-R1a signaling. Activation of ghrelin receptors localized in the ventral tegmental area (VTA) seems to play a significant role in ghrelin's contribution to motivated behavior. In view of the evidence indicating that dopaminergic cells of the VTA express ghrelin receptors and D5R but not D1R, we investigated the possible existence of functional GHS-R1a:GHS-R1b:D5R oligomeric complexes in the VTA. GHS-R1a:GHS-R1b:D5R oligomers were first demonstrated in mammalian transfected cells and their pharmacological properties were found to be different from those of GHS-R1a:GHS-R1b:D1R oligomers, including weak Gs coupling and the ability of D1R/D5R antagonists, but not agonists, to counteract the effects of ghrelin. However, analyzing the effect of ghrelin in the rodent VTA on MAPK activation with experiments, on somato-dendritic dopamine release with microdialysis and on activation of dopaminergic cells with patch-clamp electrophysiology, provided evidence for a predominant role of GHS-R1a:GHS-R1b:D1R oligomers in the rodent VTA as main mediators of the dopaminergic effects of ghrelin.The activation of ghrelin receptors localized in the ventral tegmental area (VTA) plays a significant role in ghrelin's contribution to motivated behavior. We present evidence that indicates these receptors form part of oligomeric complexes that include the functional ghrelin receptor GHS-R1a, its truncated non-signaling isoform GHS-R1b and the dopamine D receptor (D1R). Binding of ghrelin to these complexes promotes activation of the dopaminergic neurons of the VTA by activation of AC-PKA signaling, which can be counteracted by both GHS-R1a and D1R antagonists. Our study provides evidence for a predominant role of GHS-R1a:GHS-R1b:D1R oligomers in rodent VTA as main mediators of the dopaminergic effects of ghrelin.
Ferré, Sergi; Guitart, Xavier; Quiroz, César; Rea, William; García-Malo, Celia; Garcia-Borreguero, Diego; Allen, Richard P; Earley, Christopher J
Akathisia and Restless Legs Syndrome: Solving the Dopaminergic Paradox Journal Article
In: Sleep Med Clin, vol. 16, no. 2, pp. 249–267, 2021, ISSN: 1556-4088.
@article{pmid33985651,
title = {Akathisia and Restless Legs Syndrome: Solving the Dopaminergic Paradox},
author = {Sergi Ferré and Xavier Guitart and César Quiroz and William Rea and Celia García-Malo and Diego Garcia-Borreguero and Richard P Allen and Christopher J Earley},
url = {https://pubmed.ncbi.nlm.nih.gov/33985651/},
doi = {10.1016/j.jsmc.2021.02.012},
issn = {1556-4088},
year = {2021},
date = {2021-06-01},
urldate = {2021-06-01},
journal = {Sleep Med Clin},
volume = {16},
number = {2},
pages = {249--267},
abstract = {Akathisia is an urgent need to move that is associated with treatment with dopamine receptor blocking agents (DRBAs) and with restless legs syndrome (RLS). The pathogenetic mechanism of akathisia has not been resolved. This article proposes that it involves an increased presynaptic dopaminergic transmission in the ventral striatum and concomitant strong activation of postsynaptic dopamine D receptors, which form complexes (heteromers) with dopamine D and adenosine A receptors. It also proposes that in DRBA-induced akathisia, increased dopamine release depends on inactivation of autoreceptors, whereas in RLS it depends on a brain iron deficiency-induced down-regulation of striatal presynaptic A receptors.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Akathisia is an urgent need to move that is associated with treatment with dopamine receptor blocking agents (DRBAs) and with restless legs syndrome (RLS). The pathogenetic mechanism of akathisia has not been resolved. This article proposes that it involves an increased presynaptic dopaminergic transmission in the ventral striatum and concomitant strong activation of postsynaptic dopamine D receptors, which form complexes (heteromers) with dopamine D and adenosine A receptors. It also proposes that in DRBA-induced akathisia, increased dopamine release depends on inactivation of autoreceptors, whereas in RLS it depends on a brain iron deficiency-induced down-regulation of striatal presynaptic A receptors.
2018
Blum, David; Chern, Yijuang; Domenici, Maria Rosaria; Buée, Luc; Lin, Chien-Yu; Rea, William; Ferré, Sergi; Popoli, Patrizia
The Role of Adenosine Tone and Adenosine Receptors in Huntington's Disease Journal Article
In: Journal of Caffeine and Adenosine Research, vol. 8, no. 2, pp. 43-58, 2018.
@article{doi:10.1089/caff.2018.0006,
title = {The Role of Adenosine Tone and Adenosine Receptors in Huntington's Disease},
author = {David Blum and Yijuang Chern and Maria Rosaria Domenici and Luc Buée and Chien-Yu Lin and William Rea and Sergi Ferré and Patrizia Popoli},
url = {https://doi.org/10.1089/caff.2018.0006},
doi = {10.1089/caff.2018.0006},
year = {2018},
date = {2018-01-01},
journal = {Journal of Caffeine and Adenosine Research},
volume = {8},
number = {2},
pages = {43-58},
abstract = {Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by a mutation in the IT15 gene that encodes for the huntingtin protein. Mutated hungtingtin, although widely expressed in the brain, predominantly affects striato-pallidal neurons, particularly enriched with adenosine A2A receptors (A2AR), suggesting a possible involvement of adenosine and A2AR is the pathogenesis of HD. In fact, polymorphic variation in the ADORA2A gene influences the age at onset in HD, and A2AR dynamics is altered by mutated huntingtin. Basal levels of adenosine and adenosine receptors are involved in many processes critical for neuronal function and homeostasis, including modulation of synaptic activity and excitotoxicity, the control of neurotrophin levels and functions, and the regulation of protein degradation mechanisms. In the present review, we critically analyze the current literature involving the effect of altered adenosine tone and adenosine receptors in HD and discuss why therapeutics that modulate the adenosine system may represent a novel approach for the treatment of HD.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by a mutation in the IT15 gene that encodes for the huntingtin protein. Mutated hungtingtin, although widely expressed in the brain, predominantly affects striato-pallidal neurons, particularly enriched with adenosine A2A receptors (A2AR), suggesting a possible involvement of adenosine and A2AR is the pathogenesis of HD. In fact, polymorphic variation in the ADORA2A gene influences the age at onset in HD, and A2AR dynamics is altered by mutated huntingtin. Basal levels of adenosine and adenosine receptors are involved in many processes critical for neuronal function and homeostasis, including modulation of synaptic activity and excitotoxicity, the control of neurotrophin levels and functions, and the regulation of protein degradation mechanisms. In the present review, we critically analyze the current literature involving the effect of altered adenosine tone and adenosine receptors in HD and discuss why therapeutics that modulate the adenosine system may represent a novel approach for the treatment of HD.
2015
Bonaventura, Jordi; Navarro, Gemma; Casado-Anguera, Veronica; Azdad, Karima; Rea, William; Moreno, Estefania; Brugarolas, Marc; Mallol, Josefa; Canela, Enric I; Lluis, Carme; Cortes, Antoni; Volkow, Nora D; Schiffmann, Serge N; Ferre, Sergi; Casado, Vicent
Allosteric interactions between agonists and antagonists within the adenosine A2A receptor-dopamine D2 receptor heterotetramer. Journal Article
In: Proc Natl Acad Sci U S A, vol. 112, no. 27, pp. E3609-18, 2015.
@article{Bonaventura:2015aa,
title = {Allosteric interactions between agonists and antagonists within the adenosine A2A receptor-dopamine D2 receptor heterotetramer.},
author = {Jordi Bonaventura and Gemma Navarro and Veronica Casado-Anguera and Karima Azdad and William Rea and Estefania Moreno and Marc Brugarolas and Josefa Mallol and Enric I Canela and Carme Lluis and Antoni Cortes and Nora D Volkow and Serge N Schiffmann and Sergi Ferre and Vicent Casado},
url = {https://www.ncbi.nlm.nih.gov/pubmed/26100888},
doi = {10.1073/pnas.1507704112},
year = {2015},
date = {2015-07-07},
journal = {Proc Natl Acad Sci U S A},
volume = {112},
number = {27},
pages = {E3609-18},
abstract = {Adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) heteromers are key modulators of striatal neuronal function. It has been suggested that the psychostimulant effects of caffeine depend on its ability to block an allosteric modulation within the A2AR-D2R heteromer, by which adenosine decreases the affinity and intrinsic efficacy of dopamine at the D2R. We describe novel unsuspected allosteric mechanisms within the heteromer by which not only A2AR agonists, but also A2AR antagonists, decrease the affinity and intrinsic efficacy of D2R agonists and the affinity of D2R antagonists. Strikingly, these allosteric modulations disappear on agonist and antagonist coadministration. This can be explained by a model that considers A2AR-D2R heteromers as heterotetramers, constituted by A2AR and D2R homodimers, as demonstrated by experiments with bioluminescence resonance energy transfer and bimolecular fluorescence and bioluminescence complementation. As predicted by the model, high concentrations of A2AR antagonists behaved as A2AR agonists and decreased D2R function in the brain.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Adenosine A2A receptor (A2AR)-dopamine D2 receptor (D2R) heteromers are key modulators of striatal neuronal function. It has been suggested that the psychostimulant effects of caffeine depend on its ability to block an allosteric modulation within the A2AR-D2R heteromer, by which adenosine decreases the affinity and intrinsic efficacy of dopamine at the D2R. We describe novel unsuspected allosteric mechanisms within the heteromer by which not only A2AR agonists, but also A2AR antagonists, decrease the affinity and intrinsic efficacy of D2R agonists and the affinity of D2R antagonists. Strikingly, these allosteric modulations disappear on agonist and antagonist coadministration. This can be explained by a model that considers A2AR-D2R heteromers as heterotetramers, constituted by A2AR and D2R homodimers, as demonstrated by experiments with bioluminescence resonance energy transfer and bimolecular fluorescence and bioluminescence complementation. As predicted by the model, high concentrations of A2AR antagonists behaved as A2AR agonists and decreased D2R function in the brain.
2013
Liu, Hua-Shan; Chefer, Svetlana; Lu, Hanbing; Guillem, Karine; Rea, William; Kurup, Pradeep; Yang, Yihong; Peoples, Laura; Stein, Elliot A
Dorsolateral caudate nucleus differentiates cocaine from natural reward-associated contextual cues. Journal Article
In: Proc Natl Acad Sci U S A, vol. 110, no. 10, pp. 4093–4098, 2013, ISSN: 1091-6490 (Electronic); 0027-8424 (Linking).
@article{Liu:2013aa,
title = {Dorsolateral caudate nucleus differentiates cocaine from natural reward-associated contextual cues.},
author = {Hua-Shan Liu and Svetlana Chefer and Hanbing Lu and Karine Guillem and William Rea and Pradeep Kurup and Yihong Yang and Laura Peoples and Elliot A Stein},
url = {https://www.ncbi.nlm.nih.gov/pubmed/23431137},
doi = {10.1073/pnas.1207531110},
issn = {1091-6490 (Electronic); 0027-8424 (Linking)},
year = {2013},
date = {2013-03-05},
journal = {Proc Natl Acad Sci U S A},
volume = {110},
number = {10},
pages = {4093--4098},
address = {Neuroimaging Research Branch, National Institute on Drug Abuse, Intramural Research Program, National Institutes of Health, Baltimore, MD 21224, USA.},
abstract = {Chronic drug administration induces neuroplastic changes within brain circuits regulating cognitive control and/or emotions. Following repeated pairings between drug intake and environmental cues, increased sensitivity to or salience of these contextual cues provoke conscious or unconscious craving and enhance susceptibility to relapse. To explore brain circuits participating in such experience-induced plasticity, we combined functional MRI with a preclinical drug vs. food self-administration (SA) withdrawal model. Specifically, two groups of rats were trained to associate odor cues with the availability of i.v. cocaine or oral sucrose, respectively. After 20 d of cocaine or sucrose SA followed by prolonged (30 d) forced abstinence, animals were presented with odor cues previously associated with or without (S+/S-) reinforcer (cocaine/sucrose) availability while undergoing functional MRI scans. ANOVA results demonstrate that a learning effect distinguishing S+ from S- was seen in the insula and nucleus accumbens, with the insula response reflecting the individual history of cocaine SA intake. A main effect of group, distinguishing cocaine from sucrose, was seen in the medial prefrontal cortex (infralimbic, prelimbic, and cingulate cortex) and dorsolateral striatum. Critically, only the dorsomedial striatum demonstrated a double dissociation between the two SA groups and learning (S+ vs. S-). These findings demonstrate altered cortico-limbic-striatal reward-related processing to learned, environment reward-associated contextual odor cues, which may serve as potential biomarkers for therapeutic interventions.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Chronic drug administration induces neuroplastic changes within brain circuits regulating cognitive control and/or emotions. Following repeated pairings between drug intake and environmental cues, increased sensitivity to or salience of these contextual cues provoke conscious or unconscious craving and enhance susceptibility to relapse. To explore brain circuits participating in such experience-induced plasticity, we combined functional MRI with a preclinical drug vs. food self-administration (SA) withdrawal model. Specifically, two groups of rats were trained to associate odor cues with the availability of i.v. cocaine or oral sucrose, respectively. After 20 d of cocaine or sucrose SA followed by prolonged (30 d) forced abstinence, animals were presented with odor cues previously associated with or without (S+/S-) reinforcer (cocaine/sucrose) availability while undergoing functional MRI scans. ANOVA results demonstrate that a learning effect distinguishing S+ from S- was seen in the insula and nucleus accumbens, with the insula response reflecting the individual history of cocaine SA intake. A main effect of group, distinguishing cocaine from sucrose, was seen in the medial prefrontal cortex (infralimbic, prelimbic, and cingulate cortex) and dorsolateral striatum. Critically, only the dorsomedial striatum demonstrated a double dissociation between the two SA groups and learning (S+ vs. S-). These findings demonstrate altered cortico-limbic-striatal reward-related processing to learned, environment reward-associated contextual odor cues, which may serve as potential biomarkers for therapeutic interventions.
2000
Shippenberg, T S; Rea, W; Slusher, B S
Modulation of behavioral sensitization to cocaine by NAALADase inhibition. Journal Article
In: Synapse, vol. 38, no. 2, pp. 161–166, 2000, ISSN: 0887-4476 (Print); 0887-4476 (Linking).
@article{Shippenberg:2000aa,
title = {Modulation of behavioral sensitization to cocaine by NAALADase inhibition.},
author = {T S Shippenberg and W Rea and B S Slusher},
url = {https://www.ncbi.nlm.nih.gov/pubmed/11018790},
doi = {10.1002/1098-2396(200011)38:2<161::AID-SYN7>3.0.CO;2-G},
issn = {0887-4476 (Print); 0887-4476 (Linking)},
year = {2000},
date = {2000-11-01},
journal = {Synapse},
volume = {38},
number = {2},
pages = {161--166},
address = {Integrative Neuroscience Unit, Behavioral Neuroscience Laboratory, NIH/NIDA Intramural Research Program, Baltimore, Maryland 21224, USA. tshippen@intra.nida.nih.gov},
abstract = {Sensitization to cocaine has been attributed to alterations in excitatory amino acid and dopamine neurotransmission in the mesolimbic system. The present study sought to determine whether inhibition of NAALADase, an enzyme that cleaves glutamate from the endogenous neuropeptide, N-acetyl-aspartyl-glutamate (NAAG), attenuates sensitization to the psychomotor stimulant effects of cocaine. Rats received daily injections of cocaine (20.0 mg/kg/day; i.p.) or saline for 5 days. Fifteen minutes prior to these injections they received an i.p. injection of the NAALADase inhibitor, 2-PMPA (50.0-100 mg/kg), or vehicle. Locomotor activity and stereotypy produced by a challenge dose of cocaine (15.0 mg/kg) were assessed 3 days later. Acute cocaine administration increased locomotor activity in control animals. In animals with a prior history of cocaine administration, the behavioral response to cocaine was significantly enhanced. In animals that had received 2-PMPA in combination with cocaine, the enhancement of cocaine-induced locomotor activity was attenuated. No alteration in cocaine-evoked activity was observed in animals that had received once daily injections of 2-PMPA, alone. Acute administration of 2-PMPA also did not modify saline-induced locomotor activity or activity produced by an acute cocaine challenge. These data demonstrate that NAALADase inhibition attenuates the development of sensitization to the locomotor-activating effects of cocaine. Furthermore, this action cannot be attributed to an antagonism of the acute effects of cocaine.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Sensitization to cocaine has been attributed to alterations in excitatory amino acid and dopamine neurotransmission in the mesolimbic system. The present study sought to determine whether inhibition of NAALADase, an enzyme that cleaves glutamate from the endogenous neuropeptide, N-acetyl-aspartyl-glutamate (NAAG), attenuates sensitization to the psychomotor stimulant effects of cocaine. Rats received daily injections of cocaine (20.0 mg/kg/day; i.p.) or saline for 5 days. Fifteen minutes prior to these injections they received an i.p. injection of the NAALADase inhibitor, 2-PMPA (50.0-100 mg/kg), or vehicle. Locomotor activity and stereotypy produced by a challenge dose of cocaine (15.0 mg/kg) were assessed 3 days later. Acute cocaine administration increased locomotor activity in control animals. In animals with a prior history of cocaine administration, the behavioral response to cocaine was significantly enhanced. In animals that had received 2-PMPA in combination with cocaine, the enhancement of cocaine-induced locomotor activity was attenuated. No alteration in cocaine-evoked activity was observed in animals that had received once daily injections of 2-PMPA, alone. Acute administration of 2-PMPA also did not modify saline-induced locomotor activity or activity produced by an acute cocaine challenge. These data demonstrate that NAALADase inhibition attenuates the development of sensitization to the locomotor-activating effects of cocaine. Furthermore, this action cannot be attributed to an antagonism of the acute effects of cocaine.
