Elsevier

Brain Research

Volume 1628, Part A, 2 December 2015, Pages 130-146
Brain Research

Research Report
Differential roles of medial prefrontal subregions in the regulation of drug seeking

https://doi.org/10.1016/j.brainres.2014.12.024Get rights and content

Highlights

  • The prefrontal cortex is important in regulating cognition and behavior.

  • It plays an important role in seeking and taking, extinction, and reinstatement of drugs and natural rewards.

  • Current theories of the relationship between rodent medial prefrontal cortex (mPFC) and behavior associate specific functions with specific subregions, e.g., dorsal mPFC plays a role in driving drug and reward seeking and ventral mPFC plays a role in inhibiting reward and drug seeking.

  • Recent results challenge this framework and suggest alternate conceptualizations of how mPFC relates to drug/reward seeking.

  • These results and alternate hypotheses connecting mPFC to drug and reward seeking are discussed as are important future directions necessary to develop a comprehensive understanding of the relationship between mPFC, reward seeking, and addiction.

Abstract

The prefrontal cortex plays an important role in shaping cognition and behavior. Many studies have shown that medial prefrontal cortex (mPFC) plays a key role in seeking, extinction, and reinstatement of cocaine seeking in rodent models of relapse. Subregions of mPFC appear to play distinct roles in these behaviors, such that the prelimbic cortex (PL) is proposed to drive cocaine seeking and the infralimbic cortex (IL) is proposed to suppress cocaine seeking after extinction. This dichotomy of mPFC function may be a general attribute, as similar dorsal–ventral distinctions exist for expression vs. extinction of fear conditioning. However, other results indicate that the role of mPFC neurons in reward processing is more complex than a simple PL-seek vs. IL-extinguish dichotomy. Both PL and IL have been shown to drive and inhibit drug seeking (and other types of behaviors) depending on a range of factors including the behavioral context, the drug-history of the animal, and the type of drug investigated. This heterogeneity of findings may reflect multiple subcircuits within each of these PFC areas supporting unique functions. It may also reflect the fact that the mPFC plays a multifaceted role in shaping cognition and behavior, including those overlapping with cocaine seeking and extinction. Here we discuss research leading to the hypothesis that dorsal and ventral mPFC differentially control drug seeking and extinction. We also present recent results calling the absolute nature of a PL vs. IL dichotomy into question. Finally, we consider alternate functions for mPFC that correspond less to response execution and inhibition and instead incorporate the complex cognitive behavior for which the mPFC is broadly appreciated.

This article is part of a Special Issue entitled Addiction circuits.

Introduction

The prefrontal cortex (PFC) includes a collection of brain regions intimately associated with the regulation of cognitive, emotional, and motivational processes. Included among these functions are those related to control of behavior: attention, response inhibition, planning, and decision-making (Balleine and Dickinson, 1998, Dalley et al., 2004, Euston et al., 2012, Miller and Cohen, 2001). Dysregulaton of these functions is at the core of addiction, and, ultimately related to the balance between execution and inhibition of behavior (Goldstein and Volkow, 2011). Although considerable research has focused on the role of motivational processes in addiction, it is ultimately a disorder of the balance between motivation and self-regulation, where self-regulation is underpinned by behavioral control functions described above. Given the primacy that deficits in self-control play in driving compulsive drug use and addiction, it is no surprise that there is substantial interest in understanding how PFC both moderates reward or drug seeking behaviors as well as in how its dysfunction can result in diseases such as addiction.

There have been a number of reviews relating PFC function to reward seeking-related behaviors and its dysfunction to addiction (Goldstein and Volkow, 2011, Kalivas, 2008, Peters et al., 2013). The goals of the current review are to (1) summarize the preclinical findings associating the PFC with drug seeking, particularly seeking of cocaine and related psychostimulants, (2) discuss models relating PFC subdivision function to drug seeking and addiction, and (3) provide a discussion of future directions necessary to provide a comprehensive understanding of how best to study the PFC in relation to drug seeking and addiction. Given the widespread use and powerfully predictive outcomes of rodent models (Bentzley et al., 2013, Crombag et al., 2008, Epstein et al., 2006, Mahler et al., 2012), we will focus on these for the majority of the review. However, we do so knowing that there are significant differences between rodent and primate (including human) PFC (Kesner and Churchwell, 2011, Uylings et al., 2003, Wise, 2008) and that there have been substantial advances in understanding how the human PFC functions in relation to drug abuse and addiction as described in a number of comprehensive reviews (Goldstein and Volkow, 2011, Moeller and Goldstein, 2014). We first briefly discuss the role of the human PFC in drug abuse and addiction before turning to a more comprehensive discussion of rodent models.

Section snippets

PFC in drug abuse and addiction in humans

There are a number of reasons why a consideration of human PFC function in drug abuse and addiction is worth briefly discussing in this review that focuses on rodent models of drug seeking. First, addiction is exclusively a human disease. Second, the prefrontal cortex plays an important role in the regulation of behaviors disrupted in addiction such as impulse control, response inhibition and executive function, and this area is massively expanded in human and non-human primates relative to

Anatomy of the rodent medial prefrontal cortex

The mPFC is a key element of the mesocorticolimbic system that is thought to regulate drug-taking behavior (Kalivas, 2008, Kalivas, 2009). Rat mPFC receives dopaminergic input from fibers originating from the A10 group within the ventral tegmental area (Swanson, 1982), as well as from various limbic and sensory regions, including amygdala and hippocampus (Hoover and Vertes, 2007). Together, these inputs allow mPFC to evaluate the salience and motivational significance of drug associated

Animal models of drug use and abuse: A micro-primer

Rodent models of drug use and addiction are a critical component of our understanding the neuroscience of addiction, down to the molecular level, as addressed in the introduction. There are a number of behavioral paradigms associated with modeling drug use and abuse in animals. The benefits and drawbacks of different behavioral models are described elsewhere (Ahmed, 2012, Bentzley et al., 2013, Crombag et al., 2008, Epstein et al., 2006, Mahler et al., 2012, Marchant et al., 2013, Martin-Fardon

Dichotomous functions for dorsal (PL) and ventral (IL) mPFC in drug seeking: Going vs. stopping?

Most research investigating the functional differences in mPFC subregion has focused on distinguishing differences between the dorsal (PL) and ventral (IL) cortices. Research in this vein has revealed a substantial number of interesting differences that bear relevance on the regulation of drug seeking. In particular, the dorsal regions of the mPFC (typically PL, and sometimes including ACC, although see note in “Anatomy of the rodent medial prefrontal cortex,” above) have been demonstrated to

Evidence for an imperfect mapping between PL/IL and go/stop

The results presented thus far have supported the idea of a push-pull relationship between PL and IL in both fear and reward/drug seeking contexts (Gass and Chandler, 2013, Ma et al., 2014, Peters et al., 2009, Van den Oever et al., 2010). Although this model has been important in developing experiments to probe the function of the PFC in drug abuse and addiction, this go/stop dichotomy likely represents an overly simplistic framework. The prefrontal cortex is a massively complex collection of

Alternate models of PL/IL dichotomous function

The mPFC has been demonstrated to play a role in a wide range of cognitive and behavioral functions including attention, learning and memory, response planning and inhibition, sequence representation, flexible behavior, and decision-making (Bissonette et al., 2013, Cassaday et al., 2014, Dalley et al., 2004, De Bruin et al., 2000, Kesner and Churchwell, 2011, Miller and Cohen, 2001, St Onge and Floresco, 2010). Given the complexity and diversity of mPFC function, it is unsurprising that a

Future directions

One perspective that seems to emerge from a consideration of studies investigating dorsal and ventral mPFC is that there is no simple functional demarcation that respects this anatomical boundary. In certain behavioral frameworks, notably fear conditioning and extinction, a basic dichotomy of response execution vs. inhibition appears consistent (Maren and Quirk, 2004, Quirk and Mueller, 2008). However, these boundaries quickly break down upon consideration of the function of these brain areas

Acknowledgments

Supported by grants from the National Institutes of Health to DEM (R21 DA032005), EMM (F31 DA035561), GAJ (R01 DA006214) and the National Health and Medical Research Council CJ Martin Fellowship to MHJ (1072706).

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