Altered Prelimbic Cortex Output during Cue-Elicited Drug Seeking

Abstract

Cocaine treatment paired with environmental cues establishes a conditioned place preference (CPP) for that environment. After expression of this preference, rats show elevated levels of immediate early genes (IEGs; e.g. c-fos) in the prelimbic cortex (PrL), basolateral amygdala complex (BLC), and nucleus accumbens core (NAcc) compared with drug-unpaired controls. These findings, together with the known connections between these regions, suggest that they function as a circuit contributing to cue-elicited craving. To investigate the function of this circuit during drug-seeking, we characterized Fos immunoreactivity of particular neuron classes in each region. To distinguish between IEG activation of GABAergic and non-GABAergic (principally, excitatory projection) neurons, we combined Fos immunohistochemistry with immunohistochemistry for glutamic acid decarboxylase 67 (GAD 67 ) or calcium/calmodulin-dependent protein kinase II (CAMKII) proteins. Within the BLC and NAcc of drug-paired and drug-unpaired animals tested for CPP, we observed no significant differences in the percentage of Fos-immunoreactive (IR) cells that were also GAD 67 -IR. We also observed no group difference in the degree of Fos/CAMKII overlap in the BLC. However, in PrL, the degree of Fos/GAD 67 overlap in the drug-paired group was significantly higher than in the drug-unpaired group. Also, the Fos/CAMKII overlap in the entire PrL as well as just its layer V was significantly lower in the drug-paired animals compared with controls. These findings suggest that, during CPP expression in cocainepaired animals, the PrL GABAergic interneurons are preferentially activated while PrL output is attenuated, perhaps through greater inhibition of layer V pyramidal neurons. These results suggest a shifting prefrontal cortex cell population response during cocaineseeking.

Extracellular Matrix Plasticity and GABAergic Inhibition of Prefrontal Cortex Pyramidal Cells Facilitates Relapse to Heroin Seeking

“…Increased GABAergic transmission on exposure to heroin-conditioned cues is in line with our previous observation that infusion of GABA receptor agonists muscimol and baclofen in the prelimbic area enhances cue-induced reinstatement of heroin seeking (Schmidt et al, 2005). Similarly, cocaine-seeking assessed with the conditioned place preference model is accompanied by robust activation of GABAergic interneurons, as opposed to pyramidal neurons, in the prelimbic area (Miller and Marshall, 2004). In addition, mPFC GABAergic transmission appears to be critically involved in cocaine sensitization (Steketee, 2005) and reinstatement of cocaine seeking (McFarland et al, 2003;Peters et al, 2008b).…”

Transient D1Dopamine Receptor Expression on Prefrontal Cortex Projection Neurons: Relationship to Enhanced Motivational Salience of Drug Cues in Adolescence

“…These findings, and those of others (Miller and Marshall, 2004), illustrate the importance of distinguishing the population of cells that are activated. For example, adult rats exposed to cocaine-paired cues have greater immediate early gene activity in the GABAergic inhibitory neurons of the PFC, and not in CAMK-II-expressing output neurons (Miller and Marshall, 2004). Similarly elegant studies have not been done in juveniles.…”

Differential laminar effects of amphetamine on prefrontal parvalbumin interneurons

“…Within the regions evaluated in the present study, previous work has shown that prenatal exposure to cocaine leads to the loss of the synaptic cartridges of the PV+ chandelier cells in the PrL region (Morrow et al, 2003), and animals subjected to cocaine-induced conditioned place preference (CPP) show a significant induction of Fos in the PrL but not the IL (Miller and Marshall, 2004). Thus, the pyramidal outflow from the PrL, which affects targets important for reward such as the nucleus accumbens and BLA (Vertes, 2004), is critical for the expression of CPP (Miller and Marshall, 2005) and possibly for sensitization to repeated AMPH administration (present results).…”