Infralimbic Prefrontal Cortex Is Responsible for Inhibiting Cocaine Seeking in Extinguished Rats

Abstract

The rat prelimbic prefrontal cortex and nucleus accumbens core are critical for initiating cocaine seeking. In contrast, the neural circuitry responsible for inhibiting cocaine seeking during extinction is unknown. The present findings using inhibition of selected brain nuclei with GABA agonists show that the suppression of cocaine seeking produced by previous extinction training required activity in the rat infralimbic cortex. Conversely, the reinstatement of drug seeking by a cocaine injection in extinguished animals was suppressed by increasing neuronal activity in infralimbic cortex with the glutamate agonist AMPA. The cocaine seeking induced by inactivating infralimbic cortex resembled other forms of reinstated drug seeking by depending on activity in prelimbic cortex and the basolateral amygdala. A primary efferent projection from the infralimbic cortex is to the nucleus accumbens shell. Akin to infralimbic cortex, inhibition of the accumbens shell induced cocaine seeking in extinguished rats. However, bilateral inhibition of the shell also elicited increased locomotor activity. Nonetheless, unilateral inhibition of the accumbens shell did not increase motor activity, and simultaneous unilateral inactivation of the infralimbic cortex and shell induced cocaine seeking, suggesting that an interaction between these two structures is necessary for extinction training to inhibit cocaine seeking. The infralimbic cortex and accumbens shell appear to be recruited by extinction learning because inactivation of these structures before extinction training did not alter cocaine seeking. Together, these findings suggest that a neuronal network involving the infralimbic cortex and accumbens shell is recruited by extinction training to suppress cocaine seeking.

Endogenous Opioid Signaling in the Medial Prefrontal Cortex is Required for the Expression of Hunger-Induced Impulsive Action

“…Our recent work, for example, suggests that intra-vmPFC μOR stimulation engenders heightened glutamate signaling in multiple terminal fields, including the Acb and hypothalamus (Mena et al, 2013). Considering evidence of PFC-Acb functional connections in modulating drug reinstatement, attentional performance, and other processes that tax inhibitory control (Bossert et al, 2012;Christakou et al, 2004;Peters et al, 2008), this pathway may be particularly relevant for PFC-opioid-induced impulsive action seen here.…”

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

“…Moreover, a similar change in protein levels was observed in synapses of the mPFC and NAc, but not in dorsal striatum, after extinction of heroin self-administration. This suggests that long-term cessation of heroin self-administration is associated with adaptation of the ECM in the mPFC-NAc pathway, a neural circuit that has a pivotal role in relapse to drug seeking (McFarland and Kalivas, 2001;Peters et al, 2008a;Van den Oever et al, 2009). Bcan interacts with its C-type lectin domain with the ECM glycoprotein Tnr (Aspberg et al, 1997).…”

“…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). When infused in the infralimbic area, GABA agonists augment cocaine seeking under extinction conditions by reducing glutamatergic output to the NAc shell (Peters et al, 2008a). Although changes in ECM proteins were not analyzed at the subregional level within the mPFC, potentially, molecular changes in ECM constituents may account for the enhanced responsivity of ventral mPFC (comprising the ventral prelimbic and infralimbic area) GABAergic interneurons to heroin-conditioned cues, thereby increasing inhibition of ventral mPFC pyramidal neurons during cue-induced reinstatement.…”

“…This, together with our previous observation that synaptic strength in ventral mPFC pyramidal neurons is reduced after exposure to heroinconditioned cues (Van den Oever et al, 2008), suggests that excitatory output from the ventral mPFC is diminished. Consequently, response inhibition to drug-associated cues may be impaired (Peters et al, 2008a;Van den Oever et al, 2009). Moreover, the observation that inhibition of MMP activity also impairs acquisition and reconsolidation of cocaine conditioned place preference (Brown et al, 2007), suggests that long-term adaptation of the ECM may have a more general role in the persistence of drug-seeking behavior.…”

Amphetamine in Adolescence Disrupts the Development of Medial Prefrontal Cortex Dopamine Connectivity in a dcc-Dependent Manner

“…Thus, our results suggest that aberrant dopamine innervation leads to modifications in infralimbic cortex function. The infralimbic cortex controls cueinduced reinstatement of drug-seeking behavior following extinction (Peters et al, 2008;LaLumiere et al, 2012). In fact, this region has been proposed as a key component of the 'stop circuit' substrate mediating the transition from regulated to compulsive drug use (Kalivas, 2008;Peters et al, 2009).…”