Research ReportDifferential roles of medial prefrontal subregions in the regulation of drug seeking
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).
References (219)
The science of making drug-addicted animals
Neuroscience
(2012)- et al.
Goal-directed instrumental action: contingency and incentive learning and their cortical substrates
Neuropharmacology
(1998) - et al.
Neural structures underlying set-shifting: roles of medial prefrontal cortex and anterior cingulate cortex
Behav. Brain Res.
(2013) Orbitofrontal cortex dysfunction in abstinent cocaine abusers performing a decision-making task
Neuroimage
(2003)Neural systems and cue-induced cocaine craving
Neuropsychopharmacology
(2002)Acute effects of cocaine on human brain activity and emotion
Neuron
(1997)Neural substrates of resisting craving during cigarette cue exposure
Biol. Psychiatry
(2007)- et al.
Visual attention task performance in Wistar and Lister hooded rats: response inhibition deficits after medial prefrontal cortex lesions
Neuroscience
(1999) Neuronal responses in prefrontal cortex and nucleus accumbens during heroin self-administration in freely moving rats
Brain Res.
(1997)- et al.
Neuronal and behavioral correlations in the medial prefrontal cortex and nucleus accumbens during cocaine self-administration by rats
Neuroscience
(2000)
Dissociable aspects of performance on the 5-choice serial reaction time task following lesions of the dorsal anterior cingulate, infralimbic and orbitofrontal cortex in the rat: differential effects on selectivity, impulsivity and compulsivity
Behav Brain Res.
The role of prelimbic cortex in instrumental conditioning
Behav. Brain Res.
Inactivation of the infralimbic prefrontal cortex reinstates goal-directed responding in overtrained rats
Behav. Brain Res.
The frontal assessment battery (FAB) reveals neurocognitive dysfunction in substance-dependent individuals in distinct executive domains: abstract reasoning, motor programming, and cognitive flexibility
Addict. Behav.
Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates
Neurosci. Biobehav. Rev.
Distinct patterns of neural activation associated with ethanol seeking: effects of naltrexone
Biol. Psychiatry
Role of the prefrontal cortex of the rat in learning and decision making: effects of transient inactivation
Prog. Brain Res.
Role of the prelimbic cortex in the acquisition, re-acquisition or persistence of responding for a drug-paired conditioned reinforcer
Neuroscience
Haloperidol attenuates conditioned place preferences produced by electrical stimulation of the medial prefrontal cortex
Pharmacol. Biochem. Behav.
The role of medial prefrontal cortex in memory and decision making
Neuron
Involvement of the nucleus accumbens and medial prefrontal cortex in the expression of conditioned hyperactivity to a cocaine-associated environment in rats
Neuropsychopharmacology
Prefrontal cortical regulation of fear learning
Trends Neurosci.
Relapse induced by cues predicting cocaine depends on rapid, transient synaptic potentiation
Neuron
Neuropharmacological assessment of cocaine self-administration into the medial prefrontal cortex
Pharmacol. Biochem. Behav.
Reinforcing properties of cocaine in the medical prefrontal cortex: primary action on presynaptic dopaminergic terminals
Pharmacol. Biochem. Behav.
Renewal of extinguished cocaine-seeking
Neuroscience
The medial prefrontal cortex in the rat: evidence for a dorso-ventral distinction based upon functional and anatomical characteristics
Neurosci. Biobehav. Rev.
Contributions of the amygdala and medial prefrontal cortex to incentive cue responding
Neuroscience
An analysis of rat prefrontal cortex in mediating executive function
Neurobiol. Learn. Mem.
Regulation of craving by cognitive strategies in cigarette smokers
Drug Alcohol Depend.
Functions of the frontal cortex of the rat: a comparative review
Brain Res.
Role of ventral medial prefrontal cortex in incubation of cocaine craving
Neuropharmacology
Expectation modulates human brain responses to acute cocaine: a functional magnetic resonance imaging study
Biol. Psychiatry
Neural responses to acute cocaine administration in the human brain detected by fMRI
Neuroimage
Attenuation of cue-induced heroin-seeking behavior by cannabinoid CB1 antagonist infusions into the nucleus accumbens core and prefrontal cortex, but not basolateral amygdala
Neuropsychopharmacology
Excitotoxic lesions of the infralimbic, but not prelimbic cortex facilitate reversal of appetitive discriminative context conditioning: the role of the infralimbic cortex in context generalization
Front. Behav. Neurosci.
Orbitofrontal and anterior cingulate cortex neurons selectively process cocaine-associated environmental cues in the rhesus monkey
J. Neurosci.
Neuroadaptations in cystine-glutamate exchange underlie cocaine relapse
Nat. Neurosci.
Differential involvement of prelimbic and infralimbic medial prefrontal cortex in discrete cue-induced reinstatement of 3,4-methylenedioxymethamphetamine (MDMA; ecstasy) seeking in rats
Psychopharmacology (Berl)
Prefrontal and monoaminergic contributions to stop-signal task performance in rats
J. Neurosci.
An autoradiographic examination of corticocortical and subcortical projections of the mediodorsal-projection (prefrontal) cortex in the rat
J. Comp. Neurol.
The behavioral economics of drug self-administration: a review and new analytical approach for within-session procedures
Psychopharmacology (Berl)
Topographical organization and relationship with ventral striatal compartments of prefrontal corticostriatal projections in the rat
J. Comp. Neurol.
A BDNF infusion into the medial prefrontal cortex suppresses cocaine seeking in rats
Eur. J. Neurosci.
A single intra-PFC infusion of BDNF prevents cocaine-induced alterations in extracellular glutamate within the nucleus accumbens
J. Neurosci.
Ventral medial prefrontal cortex neuronal ensembles mediate context-induced relapse to heroin
Nat. Neurosci.
Role of projections from ventral medial prefrontal cortex to nucleus accumbens shell in context-induced reinstatement of heroin seeking
J. Neurosci.
Phasic alterations in dopamine and serotonin release in striatum and prefrontal cortex in response to cocaine predictive cues in behaving rhesus macaques
Neuropsychopharmacology
Persistent alterations in cognitive function and prefrontal dopamine D2 receptors following extended, but not limited, access to self-administered cocaine
Neuropsychopharmacology
Brain metabolic changes during cigarette craving
Arch. Gen. Psychiatry
Cited by (164)
Sex differences in the rodent medial prefrontal cortex – What Do and Don't we know?
2024, Neuropharmacology