Marisa Roberto, PhD

Neuronal Functions and Synaptic Communication: Neuropeptides and Drugs of Abuse

Alcohol Use Disorder (AUD) 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 and that 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 neurotransmitters 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 G-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 elevated alcohol consumption results in neuroadaptations that involve the recruitment and pathological activity of extrahypothalamic stress systems, providing an incentive for negatively reinforced alcohol intake. We have characterized synaptic action of the neuropeptide corticotropin-releasing factor (CRF) in CeA and the involvement of this system and other stress-related neurotransmitters/neuroregulators (e.g.; nociceptin, oxytocin, and neuropeptide Y) in alcohol dependence and withdrawal. We are also examining the actions of other neuromessenger systems, such as those for endocannabinoids, opioids, immune-related factors 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 AUD, post-traumatic stress disorder (PTSD) and other addictive disorders.