Cocaine-induced adaptations in metabotropic inhibitory signaling in the mesocorticolimbic system (original) (raw)

Abstract

The addictive properties of psychostimulants such as cocaine are rooted in their ability to activate the mesocorticolimbic dopamine (DA) system. This system consists primarily of dopaminergic projections arising from the ventral tegmental area (VTA) and projecting to the limbic and cortical brain regions, such as the nucleus accumbens (NAc) and prefrontal cortex (PFC). While the basic anatomy and functional relevance of the mesocorticolimbic DA system is relatively well-established, a key challenge remaining in addiction research is to understand where and how molecular adaptations and corresponding changes in function of this system facilitate a pathological desire to seek and take drugs. Several lines of evidence indicate that inhibitory signaling, particularly signaling mediated by the Gi/o class of heterotrimeric GTP-binding proteins (G proteins), plays a key role in the acute and persistent effects of drugs of abuse. Moreover, recent evidence argues that these signaling pathways are targets of drug-induced adaptations. In this review we discuss inhibitory signaling pathways involving DA and the inhibitory neurotransmitter GABA in two brain regions – the VTA and PFC – that are central to the effects of acute and repeated cocaine exposure and represent sites of adaptations linked to addiction-related behaviors including sensitization, craving, and relapse.

Corresponding author: Kevin Wickman, Department of Pharmacology, University of Minnesota, Minneapolis, MN 55455, USA

About the authors

Matthew C. Hearing

Matthew Hearing received his BS in Biomedical Science from Marquette University in 2003, and a PhD in Neuroscience from the Medical University of South Carolina in 2010. His pre-doctoral research focused on mapping the selective regional patterns and identifying the function of activity-regulated genes in a variety of brain areas, including the prefrontal cortex, striatum, hippocampus and amygdala, in context-dependent relapse and extinction of drug-seeking in rats. Currently, he is a postdoctoral fellow at the University of Minnesota in the Department of Pharmacology, where he is exploring the role of inhibitory metabotropic signaling within the mesocorticolimbic system in associative learning, mood disorders, and reward-related behavior. His research utilizes a number of neurobehavioral animal models in conjunction with slice electrophysiology and pharmacological manipulation of receptor signaling and gene expression.

Anastasia N. Zink

Anastasia Zink received her BS in Neuroscience from Macalester College in 2008. Prior to pursuing a PhD in Neuroscience from the University of Minnesota (expected 2015), she gained critical knowledge and skills performing research in the fields of reward learning, pain, and neurodegeneration. Ms. Zink’s thesis work is assessing the role of inhibitory metabotropic signaling in associative learning and hippocampal function through the use of targeted genetic and pharmacological manipulations

Kevin Wickman

Dr. Wickman earned a B.A. in Chemistry from St. Olaf College in Northfield, Minnesota (1991), and a PhD in Molecular Neuroscience from the Mayo Foundation for Biomedical Research in Rochester Minnesota (1995; mentor: Dr. David Clapham). After completing postdoctoral fellowships at the Mayo Clinic in Scottsdale, Arizona, and Children’s Hospital in Boston, Massachusetts, Dr. Wickman joined the faculty as an Assistant Professor in the Department of Pharmacology at the University of Minnesota in Minneapolis (1999). Currently, Dr. Wickman is a Professor of Pharmacology at the University of Minnesota, where he pursues research aimed at understanding the role of G protein signaling and ion channels on complex behaviors related to addiction, learning and memory, nociception.

Received: 2012-5-15

Accepted: 2012-6-11

Published Online: 2012-08-01

Published in Print: 2012-08-01