Anthony R. West, PhD
In this section
Dr. Anthony R. West, Associate Professor in the Department of Neuroscience at the Chicago Medical School, received his Ph.D. in Cellular and Clinical Neurobiology in 1997 from Wayne State University, School of Medicine. From 1997-2002, he trained as a Postdoctoral Research Fellow with Professor Anthony A. Grace in the Department of Neuroscience at the University of Pittsburgh. Dr. West joined the Department of Neuroscience at the Chicago Medical School in 2002. Dr. West's research focuses on the interaction between striatal nitric oxide producing interneurons and dopamine afferents and their role in regulating the neural activity of striatal medium spiny projection neurons.
The overarching goal of Dr. West's research is to improve our understanding of how these systems function to regulate striatal output in normal animals and rodent models of the pathophysiology of Parkinson's disease and schizophrenia. Dr. West's research has been supported by the National Alliance for Research on Schizophrenia and Depression, the Tourette Syndrome Association, Pfizer Inc., the Parkinson’s Disease Foundation, and the National Institute of Neurological Disorders and Stroke. Honors include predoctoral and postdoctoral National Research Service Awards from NIH, NARSAD Young Investigator Awards (2000-2002; 2004-2006), CINP Rafaelsen Fellowship, and the Rosalind Franklin University of Medicine and Science Board of Trustees Award. Dr. West is a member of the Society for Neuroscience, the International Basal Ganglia Society, and the American Physiological Society.
Dr. West’s research is focused on determining the role of dopamine and nitric oxide (NO) in modulating the electrophysiological activity of striatal medium spiny projection neurons. NO is a gaseous neurotransmitter produced by a subclass of striatal aspiny interneurons. The function of these interneurons is intimately tied to that of the striatal dopamine system and is compromised in neurological disorders such as Parkinson’s disease (PD). Thus, recent studies indicate that dopaminergic afferents innervate NO-releasing interneurons in the nucleus accumbens and dorsal striatum and modulate their activity via D1 receptor activation. Our studies have shown that striatal NO signaling potently modulates the activity of striatal projection neurons and indirectly regulates dopamine neuron activity via its influence on corticostriatal and striatonigral circuits. In order to further examine the influence of tonic dopamine and NO on the membrane properties of identified striatal projection neurons, we have developed a novel method for combining microdialysis and intracellular recording in vivo. Our studies have revealed that this is a powerful technique for studying the influence of NO and dopamine on the function of identified neural networks in the intact brain. We anticipate that further characterization of the function of these neuromodulatory systems will advance our understanding of normal and pathological basal ganglia function and identify potential molecular targets for pharmacotherapy for brain disorders, such as PD and schizophrenia.
I. NO and Parkinson's disease
A considerable body of data indicates that corticostriatal glutamatergic and nigrostriatal dopaminergic systems are critically involved in the integration of motor information by medium spiny projection neurons (MSNs). Dysfunctional neurotransmission within these striatal networks is believed to underlie the pathophysiology of several neurological disorders including Parkinson's disease (PD) and schizophrenia. Recently, evidence has accumulated suggesting that striatal nitric oxide (NO) producing interneurons may play an important role in mediating a component of corticostriatal neurotransmission. In addition to their corticostriatal inputs, these interneurons receive synaptic contacts from midbrain dopamine (DA) neurons. Indirect measures of NO synthase (NOS) activity also suggest that NO interneurons may be differentially regulated by DA D1 and D2 receptor activation. Additionally glutamatergic and/or dopaminergic activation of striatal NOS-containing interneurons may play an important role in integrating motor information and synchronizing the activity of functionally related striatal output pathways. This is supported by studies demonstrating that corticostriatal activation of NO signaling mediates the induction of electrotonic coupling and long-term depression of synaptic activity in MSNs. Similarly to D1 agonists, NO has been shown to activate DA and cAMP-regulated phosphoprotein (DARPP-32) via cyclic nucleotide-dependent pathways. These studies suggest that the activation of NO-dependent signaling pathways may represent an additional means by which higher cortical centers coordinate the neural activity of striatal MSNs. Thus, NO may play a key role in the integration of corticostriatal information and the generation of normal motor activity. In support of this, multiple behavioral studies have demonstrated that pharmacological blockade of NO signaling decreases basal locomotor activity and activity induced by substance P and DA agonists. Moreover, NOS activity is depressed in 6-hydroxydopamine (6-OHDA) lesioned animals and NOS interneuron numbers and mRNA are reduced significantly in post-mortem Parkinsonian brains. The above findings indicate that the characterization of the functional effects of striatal afferents on NOS activity and the role of NO effector pathways in modulating the activity of MSNs will be relevant for understanding information integration in the normal striatum and in pathophysiological conditions such as PD and schizophrenia.
Specific ongoing projects include the following:
1) ) Examine how glutamatergic and dopaminergic afferent systems regulate striatal NOS activity in vivo. Pharmacological studies have shown that striatal NOS activity is stimulated by NMDA and DA D1 receptor activation. However, the role of different afferent systems in regulating NOS activity has not been examined directly. Additionally, the role of DA receptor activation in modulating glutamatergic activation of striatal NOS has not been investigated. Thus our ongoing studies utilize electrical and chemical stimulation procedures to activate specific striatal afferents involved in regulating the activity of NOS. Striatal NO synthesis is routinely assessed in the intact animal and in brain slice preparations using electrochemical microsensor measures of extracellular NO levels. Our systems-oriented approach has already provided novel information as to the role of specific striatal afferent systems and their interactions in regulating NO neurotransmission in the intact animal.
2) Examine how the activation of striatal NO signaling pathways affects activity states and responsiveness of MSNs to DA. It is known that the nigrostriatal dopaminergic projection innervate both striatal MSNs and NOS interneurons. The influence of NO interneurons on the membrane activity of MSNs and the signaling mechanisms involved in mediating NO neurotransmission remain to be characterized thoroughly. Thus, our ongoing studies are aimed examining the impact of NO signaling on MSN activity in the intact and 6-OHDA lesioned (parkinsonian) animal using combined in vivo intracellular recordings and microdialysis (for local drug manipulations to selectively activate or inhibit nitrergic and dopaminergic effector pathways). Intracellular recordings also will be performed in brain slice preparations in order to elucidate the signaling mechanisms involved in NO neurotransmission. These different yet complementary approaches should provide valuable information regarding the interaction between striatal dopaminergic and nitrergic signaling, and their influence on the membrane activity of electrophysiologically and morphologically identified MSNs.
II. NO, glutamate and dopamine interactions in schizophrenia
Dysfunction of prefrontal cortical and temporal lobe inputs to the limbic striatum may play an important role in the pathophysiology of schizophrenia. Although the precise nature of this dysfunction remains to be characterized, recent studies indicate that inappropriate gating of synaptic signals transmitted through prefrontal-limbic circuits at the level of the nucleus accumbens may be involved. The nucleus accumbens is densely innervated by glutamatergic (GLUergic) projections from the prefrontal cortex (PFC), hippocampus, and amygdala. These GLUergic afferents primarily target the dendritic spines of medium-sized projection neurons (MSNs), but also make synaptic contacts on the dendrites of nitric oxide synthase (NOS)-containing interneurons. A role for nitric oxide (NO) in modulating nucleus accumbens function is supported by recent studies demonstrating that electrical stimulation of the fimbria/fornix increased local GLU and GABA efflux via stimulation of NOS activity. Additionally, NO generated via the activation of NOS stimulates DA and GLU efflux and MSN firing activity. This NO-dependent facilitation of DA and GLU release has been shown to be critically involved in the induction of synaptic plasticity in corticostriatal pathways.
Given the important role of NO signaling in synaptogenesis and synaptic plasticity, it is likely that a dysfunction within prefrontal or temporal corticostriatal circuits may cause alterations in NO signaling and disrupt the integration of information within ventral striatal neuronal networks. The possibility that abnormal NO signaling may play a role in the neurodevelopmental pathogenesis of schizophrenia is supported by studies showing alterations in the density of NOS-containing interneurons in multiple brain regions of patients with schizophrenia. Additionally, recent genetic studies examining a large population of schizophrenic patients have revealed that a polymorphism in the NOS-1 gene may confer increased susceptibility to schizophrenia. Abnormal NOS activity has also been observed in the striatum in a rodent model of the developmental prefrontal-temporolimbic pathology of schizophrenia. Moreover, animals treated with NOS inhibitors on postnatal days 3-5 exhibit enhanced sensitivity to amphetamine and PCP, as well as deficits in prepulse inhibition and social interaction in adulthood. Taken together, the above findings indicate that the characterization of NO signaling in the nucleus accumbens will be relevant for the development of novel pharmacotherapies for the treatment of schizophrenia.
Thus, the goal of this project is to utilize the combined techniques of in vivo intracellular recordings and microdialysis to study the role of nitrergic systems in modulating the interactions between afferent inputs involved in regulating the excitability of MSNs in the nucleus accumbens of normal animals and animals exposed to the neuronal NOS inhibitor 7-nitroindazole (7-NI) on postnatal days 3-5. It is anticipated that these studies characterizing the impact of these systems on neuronal activity in the nucleus accumbens of control and 7-NI treated rats will further our understanding of information integration within nucleus accumbens networks involved in normal and pathophysiological states such as schizophrenia.
Nivea Falcao Volkner, Ph.D.
Postdoctoral Research Associate
Phone: (847) 578-3000 x8755
Phone: (847) 578-3000 x3592
Peer Reviewed Publications
Hoque KE, Blume SR, Sammut S, West AR. (2017). Electrical stimulation of the hippocampal fimbria facilitates neuronal nitric oxide synthase activity in the medial shell of the rat nucleus accumbens: Modulation by dopamine D1 and D2 receptor activation. Neuropharmacology. 126: 151-157.
Chakroborty S, Thomas GR, Dale E, Pehrson AL, Sanchez C, West, A.R. (2017). Impact of Vortioxetine on Synaptic Integration in Prefrontal-Subcortical Circuits: Comparisons with Escitalopram. Frontiers in Pharmacology. 8:764.
Padovan-Neto FE, West AR. (2017) Regulation of Striatal Neuron Activity by Cyclic Nucleotide Signaling and Phosphodiesterase Inhibition: Implications for the Treatment of Parkinson's Disease. Adv Neurobiol. 17:257-283.
Jayasinghe VR, Flores-Barrera E, West AR,# Tseng K-Y.# (2017). Frequency-dependent corticostriatal disinhibition resulting from chronic dopamine depletion: role of local striatal cGMP and GABAAR signaling. Cerebral Cortex. 27 (1): 625-634.
Beaumont V, Zhong S, Lin H, Xu W, Bradaia A, Steidl E, Gleyzes M, Wadel K, Buisson B, Padovan-Neto FE, Chakroborty S, Ward KM, Harms JF, Beltran J, Kwan M, Ghavami A, Häggkvist J, Tóth M, Halldin C, Varrone A, Schaab C, Dybowski JN, Elschenbroich S, Lehtimäki K, Heikkinen T, Park L, Rosinski J, Mrzljak L, Lavery D, West AR, Schmidt CJ, Zaleska MM, Munoz-Sanjuan I. (2016) Phosphodiesterase 10A Inhibition Improves Cortico-Basal Ganglia Function in Huntington's Disease Models. Neuron. 92(6):1220-1237. Published online.
Chakroborty S, Kim J, Schneider C, West AR, Stutzmann GE. (2015). Nitric oxide signaling is recruited as a compensatory mechanism for sustaining synaptic plasticity in Alzheimer's disease mice. Journal of Neuroscience. 35(17): 6893-6902.
Padovan-Neto FE, Sammut S, Chakroborty S, Dec AM, Threlfell S, Campbell PW, Mudrakola V, Harms JF, Schmidt CJ, West AR. (2015). Facilitation of corticostriatal transmission following pharmacological inhibition of striatal phosphodiesterase 10A: Role of nitric oxide-soluble guanylyl cyclase-cGMP signaling pathways. Journal of Neuroscience. 35(14): 5781-5791.
Bari A, Dec A, Lee AW, Lee J, Song D, Dale E, Peterson J, Zorn S, Huang X, Campbell B, Robbins TW, West AR. (2015). Enhanced inhibitory control by neuropeptide Y Y5 receptor blockade in rats. Psychopharmacology, 232:959-973. Published online.
Dec AM, Kohlhaas KL, Nelson CL, Hoque KE, Leilabadi SN, Folk J, Wolf ME, West AR. (2014). Impact of neonatal NOS-1 inhibitor exposure on neurobehavioral measures and prefrontal-temporolimbic integration in the rat nucleus accumbens. International Journal of Neuropsychopharmacology. 17 (2): 275-287.
Selvakumar B, Campbell PW, Milovanovic M, Park DJ, West AR, Snyder SH, Wolf ME. (2014). AMPA receptor upregulation in the nucleus accumbens shell of cocaine-sensitized rats is mediated by S-nitrosylation of stargazing. Neuropharmacology. 77: 28-38. Published online.
Threlfell S, West AR. (2013) Review: Modulation of striatal neuron activity by cyclic nucleotide signaling and phosphodiesterase inhibition. Basal Ganglia. 3(3):137-146.
Hoque KE, West AR. (2012). Dopaminergic modulation of nitric oxide synthase activity in subregions of the rat nucleus accumbens. Synapse. 66: 220-231.
West AR, Tseng KY. (2011) Nitric Oxide-Soluble Guanylyl Cyclase-Cyclic GMP Signaling in the Striatum: New Targets for the Treatment of Parkinson's Disease? Front Syst Neurosci. 5:55.
Tseng KY, Caballero A, Dec A, Cass DK, Simak N, Sunu E, Park MJ, Blume SR, Sammut S, Park DJ, West AR. (2011). Inhibition of striatal soluble guanylyl cyclase-cGMP signaling reverses basal ganglia dysfunction and akinesia in experimental parkinsonism. PLoS ONE , 6(11): e27187.
Sammut S, Threlfell S, West AR. (2010). Nitric oxide-soluble guanylyl cyclase-cGMP signaling regulates corticostriatal transmission and short-term synaptic plasticity of striatal projection neurons recorded in vivo. Neuropharmacology, 58: 624-631.
Ondracek JM, Willuhn I, Steiner H, West AR. (2010). Interactions between procedural learning and cocaine exposure alter spontaneous and cortically-evoked spike activity in the dorsal striatum. Frontiers in Neuroscience, 4:206.
Hoque KE, Indorkar RP, Sammut S, West AR. (2010). Impact of dopamine-glutamate interactions on striatal neuronal nitric oxide synthase activity. Psychopharmacology, 207: 571-581.
Park DJ, West AR. (2009). Regulation of striatal NO synthesis by local dopamine and glutamate interactions. Journal of Neurochemistry, 111: 1457-1465.
Threlfell S, Sammut S, Menniti FS, Schmidt CJ, West AR. (2009). Inhibition of phosphodiesterase 10A increases the responsiveness of striatal projection neurons to cortical stimulation. Journal of Pharmacology and Experimental Therapeutics, 328(3): 785-795.
Sammut S, West AR. (2008). Acute cocaine administration increases NO efflux in the rat prefrontal cortex via a neuronal NOS-dependent mechanism. Synapse, 62(9):710-713.
Ondracek JM, Dec A, Hoque KE, Lim SA, Rasouli G, Indorkar RP, Linardakis J, Klika B, Mukherji SJ, Burnazi M, Threlfell S, Sammut S, West AR. (2008). Feed-forward excitation of striatal neuron activity by frontal cortical activation of nitric oxide signaling in vivo. European Journal of Neuroscience, 27: 1739-1754.
Sammut S, Park DJ, West AR. (2007). Frontal cortical afferents facilitate striatal nitric oxide transmission in vivo via a NMDA receptor and neuronal nitric oxide synthase-dependent mechanism. Journal of Neurochemistry, 103: 1145-1156.
Sammut S, Bray KE, West AR. (2007). Dopamine D2 receptor-dependent modulation of striatal NO synthase activity. Psychopharmacology, 191: 793-803.
Sammut S, Dec A, Mitchell D, Linardakis J, Ortiguela M, West AR. (2006). Phasic dopaminergic transmission increases NO efflux in the rat dorsal striatum via a neuronal NOS and a dopamine D1/5 receptor-dependent mechanism. Neuropsychopharmacology, 31: 493-505. Note: A cover image was included from our manuscript.
#Contributed equally to this work.
Review Articles and Commentaries in Peer Reviewed Journals
Threlfell, S., and West, A.R. (2013). Modulation of striatal neuron activity by cyclic nucleotide signaling and phosphodiesterase inhibition. Basal Ganglia. 3 (3): 137-146. dx.doi.org/10.1016/j.baga.2013.08.001.
West, A.R. and Tseng, KY. (2011). Nitric oxide-soluble guanylyl cyclase signaling in the striatum: New targets for the treatment of Parkinson's disease? Frontiers in Neuroscience, 5:1-9. doi: 10.3389/fnins.2011.00055.
Floresco, S.B., West, A.R., and Grace, A.A. (2004). Reply to: Extrasynaptic dopamine and phasic neuronal activity. Nature Neuroscience, 7 (3): 199.
West, A.R., Floresco, S.B., Charara, A., Rosenkranz, J.A., and Grace, A.A. (2003). Electrophysiological interactions between striatal glutamatergic and dopaminergic systems. Annals of the New York Academy of Sciences. 1003: 53-74.
West A.R., Galloway, M.P., and Grace, A.A. (2002). Regulation of striatal dopamine neurotransmission by nitric oxide: Effector pathways and signaling mechanisms. Synapse. 44: 227-245.
Onn, S.P., West, A.R. and Grace, A.A. (2000). Dopaminergic regulation of striatal neuronal and network interactions. Trends in Neuroscience, 23 (Suppl.) S48-s56.
Moore, H.M., West, A.R., and Grace, A.A. (1999). The regulation of forebrain dopamine transmission: Relevance to the pathophysiology and psychopharmacology of schizophrenia. Biological Psychiatry. 46 (1): 40-55.
Padovan-Neto, P.E., and West, A.R. (2017). Regulation of striatal neuron activity by cyclic nucleotide signaling and phosphodiesterase inhibition: Implications for the treatment of Parkinson's disease. In: Phosphodiesterases: CNS Functions and Diseases. (Ed. H. Zhang, Y. Zhu, and J. O'Donnell) Springer Inc. (in press)
Sammut, S., Chakroborty, S., Padovan-Neto, P.E., Rosenkranz, J.A., and West, A.R. (2017). Neurophysiological approaches for in vivo neuropharmacology. In: In Vivo Neuropharmacology and Neurophysiology. (Ed: A. Philippou). Springer. Epub July 2016.
West, A.R. (2017). Nitric Oxide Signaling in the Striatum. In: Handbook of Basal Ganglia Structure and Function, a Decade of Progress. 2nd Edition (Ed. H. Steiner and K.Y. Tseng) Elsevier Inc. Academic Press, London, UK. In press.
Threlfell, S., and West, A.R. (2014). Role of cyclic nucleotide phosphodiesterases in the modulation of electrophysiological activity of central neurons. In: Cyclic-nucleotide Phosphodiesterases in the Central Nervous System: from biology to disease. (Ed. N. Brandon and A.R. West) John Wiley & Sons, Inc. Published online: D OI: 10.1002/9781118836507.ch11.
West, A.R. (2010). Nitric Oxide Signaling in the Striatum. In: Handbook of Basal Ganglia Structure and Function, a Decade of Progress. (Ed. H. Steiner and K.Y. Tseng) Elsevier Inc. Academic Press, London, UK. pp 187-196.
Grace, A.A., Rosenkranz, J.A. and West, A.R. (2009). Electrophysiology. In: American Psychiatric Press Textbook of Psychopharmacology, Fourth Edition. (Ed. C.B. Nemeroff and A.F. Schatzberg). American Psychiatric Press, Washington, D.C. pp 135-151.
West, A.R., Sammut, S., and Ariano, M.A. (2009). Striatal Nitric Oxide-Guanylyl Cyclase Signaling in an Animal Model of Parkinson’s Disease. In: Cortico-subcortical Dynamics in Parkinson’s Disease. (Ed. K.Y. Tseng) Humana Press. Pp 171-184.
Liu, D-T., Sammut, S., and West, A.R. (2005). Nitric oxide signaling modulates the responsiveness of striatal medium spiny neurons to electrical stimulation of the substantia nigra: Striatal nitrergic signaling. In: The Basal Ganglia VIII (Editors: Bolam, J.P., Ingham, C.A. and Magill, P.J.) Springer Science and Business Media, New York. pp 503-512.
Cyclic-nucleotide Phosphodiesterases in the Central Nervous System: from biology to disease. (Ed. N. Brandon and A.R. West). 2014. John Wiley & Sons, Inc. Published online: DOI: 10.1002/9781118836507.
Member: Student Evaluation and Promotions Committee (SEPAC)
Member: Internal Animal Use and Care Committee (IACUC)