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Human Biology
Uwe Erb

DUPE AINA 997536527 I The Role Of The Prefrontal Cortex In The Reinstatement of Drug Use And Its Relevance To Incubation Of Drug Craving This review paper explores recent finding on the role of the prefrontal cortex (PFC) in the incubation of drug craving and reinstatement. It looks into the individual role played by the anterior cingulate cortex (ACC), orbitofrontal Cortex (OFC), ventral medial prefrontal cortex (ventral mPFC) and dorsal medial prefrontal cortex (dorsal mPFC); regions highly implicated in drug addiction. The first sections looks into recent findings on the role of the OFC and ACC in cue induced reinstatement and incubation of craving. In subsequent sections the ventral mPFC is implicated in reinstatement and incubation with studies that suggest a higher activity in this region than other regions of the PFC. Finally this review is brought to a close with concluding remarks that suggest the neural circuitries involved in reinstatement and incubation are more extensive and might include other regions beyond the PFC. Background A rapid transition from recreational to regular patterns of drug use is considered an important prognosticator of whether an individual will later develop problems with substance abuse and dependence. (Smith, 2011). Consequently, one of the goals of substance abuse prevention programs is to discourage the development of regular patterns of drug use and relapse in at-risk populations. (Smith, 2011). Reinstatement is the acquisition of regular patterns of drug intake after initial drug exposure. (Smith, 2011). The reinstatement model is currently used in many laboratories to investigate mechanisms underlying relapse to drug seeking. (Shaham et al., 2003). Reinstatement can DUPE AINA 997536527 II be modeled in the laboratory using either of two behavioral procedures; self- administration, and conditioned place preference (CPP). Both models are characterized by a training phase where a behavior is reinforced by contingent pairing with access to drug. This is followed by the extinction phase where extinction of the drug-reinforced behavior occurs. The animal is then tested for reinstatement of drug seeking after extinction. (Shaham et al., 2003). Factors that influence the reinstatement of drug seeking in laboratory animals are often identical to the factors that influence the likelihood an individual will develop problems with substance use and dependence. For instance, social isolation or change in context (context-induced reinstatement), stress (stress-induced reinstatement), previous drug exposure (primed or drug induced reinstatement) and drug- associated stimuli (cue-induced reinstatement) increase the rate of reinstatement of drug use in laboratory animals and are considered risk factors for relapse in humans with substance dependence. (Smith, 2011). Prefrontal cortex (PFC) Anatomy In this review general definitions described for both rodents and primates by Price (2007) will be used. The extent to which region specific neurobehavioral processes are similar across species is controversial, primarily because prefrontal cortex (PFC) shows species-specific variation in size relative to other cortical areas (encephalization), anatomical cytoarchitecture, neurochemistry and connectivity. (Perry et al., 2011). Rather than emphasizing cross-species differences, this review instead will use common nomenclature where possible to allow for generalizing behavioral results across rodents and primates. (Perry et al., 2011). Price (2007) differentiates between two major PFC DUPE AINA 997536527 III networks: the medial, and the orbital networks. The medial prefrontal cortex (mPFC) often refers to various structures located along the medial wall of PFC. (Price, 2007). The precentral cortex (PrC) and anterior cingulate cortex (ACC) together are often referred to as dorsal mPFC, whereas the prelimbic (PrL), infralimbic (IL), medial orbital (MO), and ventral orbital (VO) cortices together are referred to as ventral medial prefrontal cortex (ventral mPFC). We are now going to explore these brain regions individually in relation to their effects on reinstatement and incubation of drug craving. Anterior Cingulate Cortex (ACC) and Orbitofrontal Cortex (OFC) Addiction is increasingly considered to involve maladaptation in the ACC and OFC. These regions are known to influence cognitive function related to goal-directed behavior, and are particularly reactive to drug cues in humans and animals. (Goldstein et al., 2009). In a study conducted by Gremel et al. (2011) CPP procedure was used to test for reinstatement. It consisted of 3 phases: conditioning, extinction and testing as outlined above. An opioid receptor antagonist methylnaloxonium was infused into the ACC immediately before the testing phase where the expression of cue-induced ethanol CPP was assessed. It was observed that the blockage of opioid receptors in the ACC reduced cue-induced ethanol-seeking behavior in mice. In another study by Li et al. (2012) neuroimaging techniques were used to explore regional brain activations associated with craving during the presentation of smoking-related cues. ACC activity was observed in response to cigarette cues and real-time functional magnetic resonance imaging (rtfMRI) neurofeedback was applied to improve their ability to reduce their neural and subjective craving response to smoking cues. Using rtfMRI, nicotine-dependent cigarette smokers DUPE AINA 997536527 IV were able to decrease the BOLD signal in their ACC and temporarily reduce subjective cue craving ratings. This was the first therapeutic application of neurofeedback rtfMRI to an addictive disorder and also this further implicates the ACC in cue induced drug seeking. Similar findings have being observed for the OFC. (Brebner et al., 2002). Hutcheson and Everitt (2003) observed that the OFC was required for the reinforcing effects of cocaine-associated cues, as measured in a second-order schedule of reinforcement procedure, a procedure in which completion of a minor chain requirement leads to presentation of a conditioned stimulus (cue that is associated with cocaine). They reported that bilateral neurotoxic OFC lesions impaired the ability of the cocaine- associated cues to maintain instrumental responding. This suggests that this cortical area plays an important role in cue-controlled drug seeking which generalizes even to the acquisition of second-order schedules of reinforcement where association power between the cue and drug is weaker. Similarly in a functional magnetic resonance imaging (fMRI) study recently conducted by Hartwell et al. (2011), smoking-related cues were associated with increased activation of the OFC and ACC. This raises the question of how the contribution of each of these two distinct brain regions to reinforcement and cue induced drug seeking differ; because it is unlikely that the roles of two very extensive regions of cortex are identical in every respect. Therefore the specific role of these brain regions in reinstatement remains unknown. Following up from these findings is recent work that set out to find out whether the OFC plays a role in the incubation of cue-induced heroin craving versus the more general role we have seen it play in cue-induced drug seeking. In a study conducted by Fanous et al. (2012) Daun02 inactivation procedure was used to test this hypothesis. With DUPE AINA 997536527 V this method, selective inactivation of neurons activated in response to a behavior is carried out by injecting the pro-drug Daun02 into specific brain areas of c-fos–lacZ transgenic rats that express βgal (the lacZ gene protein product) in neurons strongly activated during behavior. It was observed that cue-induced heroin seeking after 14 days of withdrawal was attenuated by previous Daun02 inactivation of only the OFC neurons that were selectively activated by heroin cues. These findings implicate the OFC in the incubation of drug craving and also suggest that a small subset of OFC neurons forms neuronal ensembles that encode learned associations between heroin reward and heroin- associated contexts. (Fanous et al., 2012). Dorsal mPFC versus Ventral mPFC A study by Koya et al. (2009) explored the role of the dorsal mPFC and ventral mPFC in the incubation of drug craving. They assessed whether Extracellular signal- regulated kinases (ERK) activity in mPFC plays a role in incubation of cocaine craving; the progressive increase in cue-induced cocaine seeking after withdrawal. This hypothesis was based on previous studies that showed exposure to cocaine cues in extinction tests increases phosphorylated ERK (p-ERK, a measure of ERK activity) in central amygdala after 30 days but not 1 day after withdrawal from cocaine. (Lu et al., 2005). The results implicated ventral mPFC activity in the incubation of cocaine craving. Exposure to cocaine cues in extinction tests increased ventral mPFC p-ERK immunoreactivity (a neuronal activity marker) after 30 days but not 1 day of withdrawal; consistent with the incubation phenomenon. Inhibition of ventral mPFC neuronal activity by GABA agonist baclofen/muscimol (B/M) also decreased cue-induced cocaine seeking DUPE AINA 997536527 VI after 30 days but not 1 day of withdrawal. In contrast, a role for dorsal mPFC in incubation of cocaine craving was not evident in the study as it was observed that exposure to cocaine cues only modestly increased dorsal mPFC p-ERK after 30 days of withdrawal. Therefore
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