Prelimbic and infralimbic cortical regions differentially encode cocaine‐associated stimuli and cocaine‐seeking before and following abstinence

Abstract

Cocaine stimuli often trigger relapse of drug-taking, even following periods of prolonged abstinence. Here, electrophysiological recordings were made in rats (n = 29) to determine how neurons in the prelimbic (PrL) or infralimbic (IL) regions of the medial prefrontal cortex (mPFC) encode cocaine-associated stimuli and cocaine-seeking, and whether this processing is differentially altered after 1 month of cocaine abstinence. After self-administration training, neurons (n=308) in the mPFC were recorded during a single test session conducted either the next day or 1 month later. Test sessions consisted of three phases during which (i) the tone–houselight stimulus previously paired with cocaine infusion during self-administration was randomly presented by the experimenter, (ii) rats responded on the lever previously associated with cocaine during extinction and (iii) the tone–houselight was presented randomly between cocaine-reinforced responding during resumption of cocaine self-administration. PrL neurons showed enhanced encoding of the cocaine stimulus and drug-seeking behavior (under extinction and self-administration) following 30 days of abstinence. In contrast, although IL neurons encoded cocaine cues and cocaine-seeking, there were no pronounced changes in IL responsiveness following 30 days’ abstinence. Importantly, cue-related changes do not represent a generalized stimulus-evoked discharge as PrL and IL neurons in control animals (n=4) exhibited negligible recruitment by the tone–houselight stimulus. The results support the view that, following abstinence, neural encoding in the PrL but not IL may play a key role in enhanced cocaine-seeking, particularly following re-exposure to cocaine-associated cues.

Extinction and reinstatement to cocaine-associated cues in male and female juvenile rats and the role of D1 dopamine receptor

“…Consistent with the first hypothesis, juveniles require more cocaine than adults to form an initial place preference to cocaine (Brenhouse et al, 2008) or simultaneous elevated D1 activity in the plPFC and dopamine activity- presumably in the accumbens – for such associations to form. Neuronal activity within the plPFC, but not the ilPFC, is observed during self-administration and extinction of cocaine and its cues (West et al, 2014). These two regions influence extinction in opposing ways as described by the oversimplified Go/Stop model (Moorman et al, 2014; Peters et al, 2009).…”

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

“…Arc and c-fos mRNA and their respective proteins (markers of neuronal activation) show increased expression in mPFC regions during acquisition of drug self-administration and cocaine reinstatement paradigms (Ciccocioppo et al, 2001; Fumagalli et al, 2009; Neisewander et al, 2000). Recordings of single mPFC neuron activity during cocaine and heroin self-administration reveal a strong behavioral association: a substantial number of mPFC neurons are modulated (excited or inhibited) at different phases during drug seeking behaviors (Chang et al, 1997a; Chang et al, 1997b; Chang et al, 1998; Chang et al, 2000; Moorman and Aston-Jones, Submitted-b; Rebec and Sun, 2005; Sun and Rebec, 2006; West et al, 2014). …”

“…Silent synapses in projections from PL to NAc core emerge after cocaine self-administration, and electrophysiological induction of long-term depression at these synapses both reverses the expression of these synapses and decreases cocaine seeking elicited by 45 days withdrawal (Ma et al, 2014). Recordings of PL neurons demonstrated these cells fire during cocaine self-administration and reinstatement, and the proportion of modulated neurons is enhanced after 1 month abstinence or in cocaine-induced reinstatement (Chang et al, 1997a; Moorman and Aston-Jones, Submitted-b; Rebec and Sun, 2005; Sun and Rebec, 2006; West et al, 2014). …”

Neural mechanisms regulating different forms of risk-related decision-making: Insights from animal models

“…Similarly, although IL has been characterized as suppressing behavior, particularly after extinction (Ishikawa et al, 2008b;Peters et al, 2008Peters et al, , 2009LaLumiere et al, 2010;Rhodes and Killcross, 2007;Peters and De Vries, 2013;Van den Oever et al, 2013;Chudasama et al, 2003;Murphy et al, 2005Murphy et al, , 2012, the region is also important for driving the seeking of drugs or natural rewards (Bossert et al, 2011;Ishikawa et al, 2008b;Koya et al, Q4 2009;Rogers et al, 2008;Sangha et al, 2014) in other contexts. In fact, neurons in both areas appear to be activated during both execution and inhibition of reward and drug-seeking (Burgos-Robles et al, 2013;Narayanan and Laubach, 2009;West et al, 2014). This lack of consistent association between region and function has profound relevance for the role of these areas in decision-making tasks, particularly those motivated by reward acquisition.…”