Brief Research Focus: Cellular Neurobiology
Our research aims to achieve a broader understanding of the functional and synaptic underpinnings that alter neurocircuits associated with the transition from occasional drug intake to drug addiction, with the long-term goal of elucidating treatment targets to alleviate drug dependence and prevent relapse.
Long Research Focus: Neuronal Function and Synaptic Communication: Neuropeptides and Drugs of Abuse
Alcoholism is a chronic relapsing illness that accounts for major disability worldwide and available treatments are insufficient. Current and future studies in my laboratory aim to understand the specific neuronal mechanisms that underlie synaptic and/or molecular changes to influence the development of dependence to alcohol and other drugs of abuse (nicotine, cocaine etc.). Tolerance occurs through adaptations at the cellular level, as the brain attempts to overcome the acute effects of drugs of abuse. With prolonged drug use, these adaptations often lead to significant changes in the structure and function of neurons. The synapse is the primary point for information transfer between neurons, and a central hypothesis is that synapses are the most sensitive sites of action for drugs of abuse. We primarily study the synapses of the central nucleus of the amygdala (CeA), a brain region that plays a central role in the behavioral effects of acute and chronic drug consumption, and in the physiological responses to fearful stimuli and stressful stimuli.
The aim of my group is to understand the effects of drugs of abuse on neuronal function and synaptic transmission using electrophysiological, pharmacological, and molecular methods. We have characterized several neuroadaptative changes that provide seminal insights into synaptic transmission will be useful towards developing new therapeutic agents to alleviate drug dependence, and particularly alcohol dependence. In parallel, our studies identified key functional roles for neuropeptide in the neurocircuits that mediate motivated behavior.
Our early studies significantly advanced the field of alcohol research by elucidating critical synaptic and molecular mechanisms regarding the unique sensitivity of the γ-aminobutyric acid (GABA) and glutamatergic systems in CeA to acute and chronic ethanol. We found that an anti-epileptic drug gabapentin (a structural analogue of GABA) reverses several behavioral aspects of ethanol dependence. These behavioral and cellular findings with gabapentin suggest the potential for use as a possible medication for the treatment of alcoholism. A fundamental dichotomy exists between systems that mediate positively reinforced alcohol consumption (“reward drinking”) versus negatively reinforced intake (“relief drinking”). Over time, chronic excessive alcohol consumption results in neuroadaptations that involve the recruitment and pathological activity of extrahypothalamic stress systems, providing an incentive for negatively reinforced alcohol intake. The neuropeptide corticotropin-releasing factor (CRF) in the CeA has been hypothesized to have an important role in brain emotional function. We have characterized the synaptic action of CRF in the CeA and the involvement of this system and other stress-related neurotransmitters/neuroregulators (e.g.; nociceptin and neuropeptide Y) in alcohol dependence.
New Research Directions
We are also examining the actions of other neuromessenger systems, such as those for PACAP, endocannabinoids and opioids, on CeA synaptic transmission, and how these systems are affected by alcohol dependence and stress. The characterization of the amygdala neurocircuitry and connections with other brain regions (e.g. ventral tegmental area, prefrontal cortex, the bed nucleus of stria terminalis), as well as neuroinflammation, are new areas of interest of my lab. Our findings provide a framework for further molecular and cellular research that will facilitate medication development and may help tailor personalized therapies for alcoholism and other addictive disorders.
Bajo M., Herman M.A., Varodayan F.P., Oleata C.S., Madamba S.G., Harris R.A., Blednov Y. A., and
Roberto M. Role of the IL-1 receptor antagonist in ethanol-induced regulation of GABAergic transmission in the central amygdala. Brain Behav Immun. 2014 Dec 3. pii: S0889-1591(14)00555-8. doi: 10.1016/j.bbi.2014.11.011. [Epub ahead of print]
Cippitelli A., Ayanwuyi LO., Barbier E., Domi E., Lerma-Cabrera JM., Carvajal F., Scuppa G., Li H., Ubaldi M., Heilig M.,
Roberto M., Ciccocioppo R. (2014) Polymorphism in the corticotropin-releasing factor receptor 1 (CRF1-R) gene plays a role in shaping the high anxious phenotype of Marchigian Sardinian alcohol-preferring (msP) rats. Psychopharmacology (Berl). 2014 Sep 27. [Epub ahead of print]
Grieder T.E., Vargas-Perez H., Herman M., Contet C., Tan L.A., Freiling J., Clark L., Crawford E., Koebel P., Repunte-Canonigo V, Sanna P., Tapper A.R.,
Roberto M., Kieffer B.L., Sawchenko P.E., Koob G.F., van der Kooy D., George O. “Identification of CRF neurons in the ventral tegmental area that control the aversive effects of nicotine withdrawal. Nat Neurosci. 2014 Dec;17(12):1751-8. doi: 10.1038/nn.3872. Epub 2014 Nov 17.
Herman M.A and
Roberto M. (2014) Cell-type-specific tonic GABA signaling in the rat central amygdala is selectively altered by acute and chronic ethanol. Addiction Biology, Aug 29. doi: 10.1111/adb.12181. [Epub ahead of print]
Repunte-Canonigo V., Herman M.A, Kawamuraa T., Kranzler H.R., Sherva R., Gelernter J., Farrer L.A.,
Roberto M. and Sanna P.P. (2014) The neurofibromatosis type 1 (Nf1) gene regulates alcohol intake, GABA release in the central amygdala, and is associated with alcohol dependence in humans. In Press in Biological Psychiatry.
Ciccocioppo R., de Guglielmo G., Hansson A.C., Ubaldi M., Kallupi M., Cruz M.T., Oleata C.S., Heilig M. and
Roberto M. (2014) Restraint Stress alters Nociceptin/Orphanin FQ and CRF systems in the rat central amygdala: Significance for anxiety-like behaviors. The Journal of Neuroscience, Jan8; 34(2):363-72. doi: 10.1523/JNEUROSCI.2400-13.2014.
Nimitvilai S., Herman H., You C., Arora D.S., McElvain M.A.,
Roberto M. and Brodie M.S. (2014) Dopamine D2 receptor desensitization by dopamine or corticotropin releasing factor in ventral tegmental area neurons is associated with increased glutamate release. Neuropharmacology. Mar 19;82C:28-40. doi: 10.1016/j.neuropharm.2014.03.006. [Epub ahead of print]
Herman M.A., Contet C., Justice N.J., Vale W. and
Roberto M. (2013) Subunit-specific tonic GABA currents and differential effects of ethanol within the central amygdala circuitry of CRF1 reporter mice. The Journal of Neuroscience, 20;33(8):3284-98.
Kallupi M., Wee S., Edwards S., Whitfield T.W., Oleata C.S., Luu G., Schmeichel B.E., Koob G.F. and
Roberto M. (2013) Kappa Opioid Receptor-Mediated Dysregulation of GABAergic Transmission in the Central Amygdala in Cocaine Addiction. Biological Psychiatry, 2013 Oct 1;74(7):520-8. doi: 10.1016/j.biopsych.2013.04.028. Epub 2013 Jun 14.
Kallupi M., Varodayan F., Oleata C.S., Correia D., Luu G. and
Roberto M. (2013) Nociceptin/ orphanin FQ decreases glutamate transmission and blocks ethanol-induced effects in the central amygdala of naïve and ethanol-depended rats. Neuropsychopharmacology, Oct 30. doi: 10.1038/ npp.2013.308. [Epub ahead of print]
Cruz M.T., Herman M., Kallupi M. and
Roberto M. (2012) Nociceptin/orphanin FQ blockade of the CRF-induced GABA Release in the Central Amygdala is enhanced after chronic ethanol treatment. Biological Psychiatry 15;71(8):666-76. Epub ahead of print on Dec 5.
Gilpin N.W., Misra K., Herman M., Cruz M.T., Koob G.F. and
Roberto M. (2011) Neuropeptide Y opposes alcohol effects on GABA release in amygdala and blocks the transition to alcohol dependence. Biological Psychiatry Jun 1;69(11):1091-9. Epub ahead of print on Apr 3 2011.
Roberto M., Cruz M.T., Gilpin N.W., Sabino V., Schweitzer P., Bajo M., Cottone P., Madamba S.M, Stouffer D.G., Zorrilla E.P., Koob G.F., Siggins G.R, Parsons L.H. (2010) Corticotropin releasing factor-induced amygdala gamma-aminobutyric Acid release plays a key role in alcohol dependence Biological Psychiatry 67(9):831-9. Epub 2010 Jan 8.
Roberto M., Cruz M.T, Bajo M., Siggins G.R., Parsons L.H. and Schweitzer P. (2010) The CB1 system tonically regulates inhibitory transmission and depresses the effect of ethanol in central amygdala. Neuropsycopharmacology 35(9):1962-72.
Cottone P., Sabino V.,
Roberto M., Bajo M, Pockros L., Steardo L.; Rice K.C., Grigoriadis D.E, Conti B., Koob G.F., Zorrilla E.P. (2009) CRF system recruitment mediates dark side of compulsive eating. Proceedings of National Academy of Sciences USA 24;106(47):20016-20.
Bajo M., Cruz M.T., Siggins G.R., Messing R. and
Roberto M. (2008) Protein kinase C epsilon mediation of CRF- and ethanol-induced GABA release in central amygdala. Proceedings of National Academy of Sciences USA 105(24):8410-5.
Roberto M., Gilpin N., O’Dell L.E., Cruz M.T., Morse A.C., Siggins G.R. and Koob G.F. (2008) Cellular and behavioral rationale for GABApentin treatment of alcohol dependence. Journal of Neuroscience 28 (22): 5762-5771.
Roberto M. and Siggins G.R. (2006) Nociceptin/Orphanin FQ inhibits the ethanol-induced enhancement of GABAergic transmission in the central amygdala. Proceedings of National Academy of Sciences USA 103: 9715-9721.
Roberto M., Schweitzer P., Madamba S., Stouffer D.G., Parsons L.H. and Siggins G.R. (2004) Acute and chronic ethanol alter glutamatergic synaptic transmission in rat central amygdala: an in vitro and in vivo analysis. Journal of Neuroscience 24 (7): 1594-603.
Roberto M., Madamba S.G., Stouffer D.G., Parsons L.H. and Siggins G.R. (2004) Increased GABA release in the central amygdala of ethanol-dependent rats. Journal of Neuroscience 24(45):10159-66.
Roberto M., Madamba S., Moore S.D., Tallent M.K. and Siggins G.R. (2003) Ethanol increases GABAergic transmission at both pre- and postsynaptic sites in rat central amygdala neurons. Proceedings of National Academy of Sciences USA 100:4, 2053-2058.
Committee on the Neurobiology of Addictive Disorders