Skip to Main Content
Psychiatry
Make a Gift
YSM Home

INFORMATION FOR

Current CTNA Projects:

Behavioral and Neural Mechanisms Underlying the Therapeutic Effects of Mavoglurant in AUD

Overview

caption default

Our studies focus on how precise mechanisms of cortico-striatal circuit activity are altered during alcohol seeking and chronic alcohol-induced decision-making impairments and how the novel mGlu5 negative allosteric modulator mavoglurant modulates these dynamics. We have refined tests of habit-related decision-making, using the novel rodent version of the multi-stage decision-making task and other paradigms to assess cue-associated alcohol-seeking behaviors. Our methods can importantly dissociate habitual from goal-directed decision-making processes based on online trial-by-trial choices.

Activities

The proposed studies will investigate how pre-existing individual variation in reward sensitivity promotes habitual ethanol-seeking and cue-induced relapse in animal models. We will identify neural mechanisms of dopaminergic and glutamatergic dysfunction in corticostriatal circuits that underlie the vulnerability to habitual ethanol-seeking behavior and relapse. The goal of these animal studies is to provide a neurobiological basis for the determination and assessment of new targets for treatment of heavy drinking or alcoholism.

Relevant Publications

  1. Torregrossa MM, Corlett PR, Taylor JR. (2011). Aberrant learning and memory in addiction. Neurobiol Learn Mem. [Epub ahead of print] PubMed PMID: 21376820.
  2. Gourley SL, Lee AS, Howell JL, Pittenger C, Taylor JR. (2010) Dissociable regulation of instrumental action within mouse prefrontal cortex. Eur J Neurosci. 32(10):1726-34. PMID: 21044173.
  3. Löf E, Olausson P, Stomberg R, Taylor JR, Söderpalm B. (2010). Nicotinic acetylcholine receptors are required for the conditioned reinforcing properties of sucrose-associated cues. Psychopharmacology (Berl). 212(3):321-8. PMID: 20676610.
  4. Barker JM, Torregrossa MM, Arnold AP, Taylor JR. (2010). Dissociation of genetic and hormonal influences on sex differences in alcoholism-related behaviors. J Neurosci. 30(27):9140-4. PMID: 20610747.
  5. Gourley SL, Howell JL, Rios M, DiLeone RJ, Taylor JR. (2009). Prelimbic cortex bdnf knock-down reduces instrumental responding in extinction. Learn Mem. 16(12):756-60. PMID: 19926781.
  6. Potenza MN, Taylor JR. (2009). Found in translation: understanding impulsivity and related constructs through integrative preclinical and clinical research. Biol Psychiatry. 66(8):714-6. PMID: 19800484.
  7. Kimchi EY, Torregrossa MM, Taylor JR, Laubach M. (2009). Neuronal correlates of instrumental learning in the dorsal striatum. J Neurophysiol. 102(1):475-89. PMID: 19439679.
  8. Taylor JR, Olausson P, Quinn JJ, Torregrossa MM. (2009). Targeting extinction and reconsolidation mechanisms to combat the impact of drug cues on addiction. Neuropharmacology. 56 Suppl 1:186-95. PMID: 18708077.
  9. Torregrossa MM, Quinn JJ, Taylor JR. (2008). Impulsivity, compulsivity, and habit: the role of orbitofrontal cortex revisited. Biol Psychiatry. 63(3):253-5. PMID: 18194683.
  10. Becker JB, Monteggia LM, Perrot-Sinal TS, Romeo RD, Taylor JR, Yehuda R, Bale TL. (2007). Stress and disease: is being female a predisposing factor? J Neurosci. 27(44):11851-5. PMID: 17978023.
  11. Quinn JJ, Hitchcott PK, Umeda EA, Arnold AP, Taylor JR. (2007). Sex chromosome complement regulates habit formation. Nat Neurosci. 10(11):1398-400. PMID: 17952068.
  12. Löf E, Olausson P, deBejczy A, Stomberg R, McIntosh JM, Taylor JR, Söderpalm B. (2007). Nicotinic acetylcholine receptors in the ventral tegmental area mediate the dopamine activating and reinforcing properties of ethanol cues. Psychopharmacology (Berl). 195(3):333-43. PMID: 17703283.
  13. Hitchcott PK, Quinn JJ, Taylor JR. (2007). Bidirectional modulation of goal-directed actions by prefrontal cortical dopamine. Cereb Cortex. 17(12):2820-7. PMID: 17322558.
  14. Olausson P, Jentsch JD, Tronson N, Neve RL, Nestler EJ, Taylor JR. (2006). DeltaFosB in the nucleus accumbens regulates food-reinforced instrumental behavior and motivation. J Neurosci. 26(36):9196-204. PMID: 16957076.
  15. Lambe EK, Olausson P, Horst NK, Taylor JR, Aghajanian GK. (2005). Hypocretin and nicotine excite the same thalamocortical synapses in prefrontal cortex: correlation with improved attention in rat. J Neurosci. 25(21):5225-9. PMID: 15917462.

Project 2

Functional Neuroimaging of Alcoholism Vulnerability: Probing Glutamate and Reward, Using the mGluR5 Inhibitor, Mavoglurant

Overview

caption default

Principal Investigator: Dr. Godfrey Pearlson. CTNA will use the mGluR5 negative allosteric modulator drug mavoglurant as a probe in conjunction with 4 functional MRI paradigms to understand how the drug targets the brain systems implicated in familial alcoholism risk. These fMRI paradigms are 1. Response to rewards and punishments (monetary incentive delay task, MID), 2. Inhibiting response to prepotent cues (go/no-go task, GNG), 3. Responsiveness to alcohol-related as opposed to soft-drink or neutral cues (alcohol cue reactivity task, ACR) and 4. the ability to benefit from “model-based,” goal-directed learning strategies versus “model-free” learning, that is a less advantageous strategy involving dominance of immediate rewards or habit over behavior (multi-stage decision-making, MSDM task). This project will compare equal numbers of individuals who have strong positive family history of alcoholism and are thus at increased risk for the disorder (family history positive or FHP) to those who have no affected relatives (family history negative or FHN).

Activities

This study builds on our current findings and extends the study of dopaminergic transmission to a high-risk population. It will characterize the biology of vulnerability versus habit. This could lead to developing a biomarker for identifying at risk subjects and possibly designing specific therapeutic strategies for prevention.

Participation Opportunities

Healthy control subjects with a biological father who drinks heavily

Contact: 203-932-5711 x 5688. All calls are confidential

We are looking for healthy individuals, ages 21-30, to take part in a research study designed to look at the function of dopamine receptors using PET imaging. This study will require an initial screening session which will take about 2 hours. If you are found to be eligible then you will be scheduled for an MRI which will take about 30 minutes and 2 PET Scans (on different days) which will take about 6 hours each. Both scans will be done after oral administration of a drink. On one of the scan days, the drink will contain alcohol. We may ask you to come for an additional day to complete neuropsychological assessments. You will be able to complete this study in 4-5 test days. Compensation is up to $765 for participation in all test days. HIC 1008007217, HSS IP0035

Read about other participation opportunities

Relevant Publications

  1. Urban NB, Kegeles LS, Slifstein M, Xu X, Martinez D, Sakr E, Castillo F, Moadel T, O'Malley SS, Krystal JH, Abi-Dargham A. (2010). Sex differences in striatal dopamine release in young adults after oral alcohol challenge: a positron emission tomography imaging study with [¹¹C]raclopride. Biol Psychiatry. 68(8):689-96. PMID: 20678752.
  2. Martinez D, Slifstein M, Gil R, Hwang DR, Huang Y, Perez A, Frankle WG, Laruelle M, Krystal J, Abi-Dargham A. (2009). Positron emission tomography imaging of the serotonin transporter and 5-HT(1A) receptor in alcohol dependence. Biol Psychiatry. 65(2):175-80. PMID: 18962444.
  3. Martinez D, Gil R, Slifstein M, Hwang DR, Huang Y, Perez A, Kegeles L, Talbot P, Evans S, Krystal J, Laruelle M, Abi-Dargham A. (2005). Alcohol dependence is associated with blunted dopamine transmission in the ventral striatum. Biol Psychiatry. 58(10):779-86. PMID: 16018986.
  4. Urban NB, Slifstein M, Meda, S, Xu X, Ayoub R, Medina O, Pearlson GD, Krystal JH, Abi-Dargham A. (In Review). Imaging reward function with PET and fMRI. Psychopharmacology.

Project 3

Influence of Mavoglurant on Alcohol Craving and Drinking in Heavy Drinkers

Overview

caption default

Principal Investigator: Dr. Godfrey Pearlson. This project will clarify the neurobiology of various forms of impulsivity and disordered reward mechanisms seen in individuals at risk for alcoholism. In particular it will use pharmacologic probes of the NMDA system to explore NMDA/DA interactions in the ventral striatum in a series of fMRI tasks related to reward to assess the relevant circuitry related to the above questions.

Activities

The project explores the effects of memantine in a double-blind, randomized, counterbalanced manner on alcoholism risk- relevant tasks. More specifically, Project 3 examines 4 functional MRI tasks related to different aspects of reward and/or impulsivity-related behavior in different contexts, compares the underlying neural circuitry across tasks, and uses a pharmacologic probe of the glutamatergic system to examine NMDA/DA interactions. The combined measures provide the opportunity to advance our understanding of specific aspects of brain function related to familial alcoholism vulnerability in an already well-characterized population as some members evolve into alcohol abuse. In addition, as well as conventional within-task analyses, functional network connectivity and allied approaches will be used to examine brain networks across the above tasks.

Participation Opportunities

For questions about participation in this study please contact:

Rachel Kelly
200 Retreat Ave
Olin Neuropsychiatry Research Center
IOL/ Hartford Hospital
Hartford, CT 06106
Phone: 860-545-7179
Fax: 860-545-7797

Relevant Publications

  1. Andrews MM, Meda SA, Thomas AD, Potenza MN, Krystal JH, Worhunsky P, Stevens MC, O'Malley S, Book GA, Reynolds B, Pearlson GD. (2011). Individuals family history positive for alcoholism show functional magnetic resonance imaging differences in reward sensitivity that are related to impulsivity factors. Biol Psychiatry. 69(7):675-83. PMID: 21126735
  2. Meda SA, Stevens MC, Potenza MN, Pittman B, Gueorguieva R, Andrews MM, Thomas AD, Muska C, Hylton JL, Pearlson GD. (2009). Investigating the behavioral and self-report constructs of impulsivity domains using principal component analysis. Behav Pharmacol. 20(5-6):390-9. PMID: 19724194

Project 4

Fyn Kinase Inhibitors and Alcohol Drinking Behaviors in Heavy Drinkers (Project Completed)

Principal Investigator:  Dr. Suchitra Krishnan-Sarin. This protocol examined the influence a Src/Fyn protein tyrosine kinase inhibitor (that modulates NMDA-R signaling via Fyn inhibition), when compared with a matched placebo on alcohol drinking behaviors among heavy drinkers with alcohol use disorder. Alcohol drinking behaviors were assessed using an experimental alcohol drinking paradigm (ADP) which involves exposure to a priming drinking of alcohol and subsequent ad-lib drinking of up to 12 drinks over the three-hour period. Participants completed a baseline ADP and were then randomized to receive active study medication or placebo for a 7-8 day period; participants were seen or contacted daily to observe medication administration and check for adverse events. At the end of this period they completed the second ADP. The primary outcome included the number of drinks consumed, and alcohol craving during the second ADP. Participants also completed a one week follow and one-month follow up appointments.

Clinical Core

The Clinical Core has established common methodologies to facilitate cognitive and clinical research domains and allow us to compare and pool data across projects for secondary analyses to help us define issues of vulnerability.

Read More

Translational Technologies Core

The goal of the Genetics Core is to support the genetic components of each of the projects participating in this Center to help understand the nature of genetic influences on the phenotypes measured, and to allow for the ascertainment of genetic covariates that might affect those outcomes.

Read More

Administrative Core

The CTNA places a high priority on maintaining an efficient flow of information in order to promote the safe and successful completion of proposed studies, to support the initiation of novel pilot studies, to facilitate the career development of trainees and junior faculty affiliated with the Center, and to promote the dissemination of research advances.

Read More

Pilot Core

The Pilot Projects Core provides a mechanism to initiate small-scale investigations that implement new technologies or to test important hypotheses associated with the CTNA mission. These projects serve the CTNA by 1) testing hypotheses or addressing methodologic issues central to the CTNA, 2) bringing new investigators into the CTNA and the field of alcoholism research, 3) generating new alcoholism RO1’s, 4) enabling CTNA to rapidly adapt to advances in the field, and 5) guiding the next iteration of the CTNA. Pilot Project Proposals are solicited through an open and public solicitation process. Proposal are developed in collaboration with the CTNA Cores (Data Management and Biostatistics, Clinical, Genetics) and refined with feedback from the Executive Committee.


Read More