Veronica A. Alvarez, PhD, Section Chief

Research

We are interested in understanding the morphological and functional changes that take place at synapses during acute exposure to drugs of abuse and as a consequence of chronic treatment with them. It is currently believed that a person or research animal “learns how to beome addicted” with repetitive exposures to drug and that addictive behaviors share common features with models of learning. Then, a reasonable hypothesis has been that at a cellular level, addiction makes use of similar mechanisms as learning. Indeed, addictive substances such as cocaine and alcohol, induce long-term changes in synaptic strength in areas of the brain involved in reward-related learning (e.g. the nucleus accumbens). Now, exactly what are all these changes in synaptic function, what signaling pathways are involved and what are the consequence to the excitability and output of the neurons affected are questions

In addition, evidences exists that prolong exposure to cocaine and amphetamines produces long-lasting changes in neuronal morphology and increases the density of dendritic spine in neurons of the nucleus accumbens and prefrontal cortex. Because the location and density of dendritic spines can predict those of the glutamatergic synapses in many regions of the brain, we propose that these morphological changes reflect changes in neuronal connectivity. The increases in spine density are long-lived (as they are seen more than 1 month after last administration) and they suggest that drug-induced structural plasticity might play a role in the long lasting behavioral abnormalities that characterize addiction. Many important questions remain unanswered with respect to the structural plasticity and its significance.

The laboratory uses a combination of techniques including electrophysiology to record synaptic responses and 2-photon laser scanning microscopy to measure calcium signals in spines and image synaptic morphology simultaneously. Two-photon uncaging of caged neurotransmitters and peptides as well as biochemistry are other techniques applied in order to understand the role of neurotransmitters, signaling molecules, and of the actin cytoskeleton in the regulation of spine structure and synaptic function. Our main goal is to better understand the changes that occur when animals are exposed and become addicted to alcohol and other drugs of abuse. 

At one side of the river, the apical dendritic tree of hippocampal pyramidal neurons with reduced expression of NR1 subunit and severe loss of synaptic NMDA receptor currents resembling leaf-less tree in a winter landscape. On the other side of the river, the apical dendritic tree of hippocampal pyramidal neurons in control condition display dendritic spines stained in red. (Cover image from J. Neurosci. 2007 (28):7365-76)

Lab Members

Gail Seabold, PhD

Postdoctoral Fellow, seaboldg@mail.nih.gov

(start day: August 2008)

Alice Dobi (Yue Wu), PhD

Postdoctoral Fellow, wuyue2@intra.nida.nih.gov

(start day: June 2008)

Roland Bock, MSc

Lab Technician, bockr2@mail.nih.gov

Elizabeth Kirby

Lab Secretary, kirbye@mail.nih.gov

Selected Publications

V. A. Alvarez, D.A. Ridenour and B.L. Sabatini. (2007). Distinct Structural and Ionotropic Roles of NMDA Receptors in Controlling Spine and Synapse Stability. J. Neurosci. 28:7365-76.

V.A. Alvarez and B.L. Sabatini. (2007) Anatomical and physiological plasticity of dendritic spines. Annu. Rev. Neurosci. 30:79-97.

V.A. Alvarez, D.A. Ridenour and B.L. Sabatini. (2006). Retraction of synapses and dendritic spines induced by off-target effects of RNA interference. J. Neurosci. 26: 7820-5

S.F. Tavazoie*, V.A. Alvarez*, D.A. Ridenour, D.J. Kwiatkowski, B.L. Sabatini (2005). Regulation of neuronal morphology and function by the tumor suppressors Tsc1 and Tsc2. Nat Neurosci. 8, 1727-34

V.A. Alvarez, C. Chow, E.J. Van Bockstaele and J.T. Williams. (2002). Frequency-dependent synchronization of locus coeruleus neurons: role of electrotonic coupling. Proc Natl Acad Sci U S A. 99: 4032-6

V.A. Alvarez*, S. Arttamangkul*, J. Whistler, M. van Zastrow, D. Grandy and J.T. Williams. (2002). J Neurosci. 22: 5769-76.

V.A. Alvarez, S. Arttamangkul, and J. T. Williams. (2001). A RAVE about Opioid Withdrawal. Neuron 32: 761-763. New and Views.

V.A. Alvarez, Maubecin, F. Garcia-Hernandez, J.T. Williams and E. Van Bockstaele. (2000). Functional coupling between neurons and glia. J. Neurosci. 20: 4091-4098.