Extinction Of Cocaine-induced Place Preference Research Articles

Extinction of Cocaine Memory Depends on a Feed-Forward Inhibition Circuit Within the Medial Prefrontal Cortex

BackgroundCocaine-associated environments (i.e., contexts) evoke persistent memories of cocaine reward and thereby contribute to the maintenance of addictive behavior in cocaine users. From a therapeutic perspective, enhancing inhibitory control over cocaine-conditioned responses is of pivotal importance but requires a more detailed understanding of the neural circuitry that can suppress context-evoked cocaine memories, e.g., through extinction learning. The ventral medial prefrontal cortex (vmPFC) and dorsal medial prefrontal cortex (dmPFC) are thought to bidirectionally regulate responding to cocaine cues through their projections to other brain regions. However, whether these mPFC subregions interact to enable adaptive responding to cocaine-associated contextual stimuli has remained elusive. MethodsWe used antero- and retrograde tracing combined with chemogenetic intervention to examine the role of vmPFC-to-dmPFC projections in extinction of cocaine-induced place preference in mice. In addition, electrophysiological recordings and optogenetics were used to determine whether parvalbumin-expressing inhibitory interneurons and pyramidal neurons in the dmPFC are innervated by vmPFC projections. ResultsWe found that vmPFC-to-dmPFC projecting neurons are activated during unreinforced re-exposure to a cocaine-associated context, and selective suppression of these cells impairs extinction learning. Parvalbumin-expressing inhibitory interneurons in the dmPFC receive stronger monosynaptic excitatory input from vmPFC projections than local dmPFC pyramidal neurons, consequently resulting in disynaptic inhibition of pyramidal neurons. In line with this, we show that chemogenetic suppression of dmPFC parvalbumin-expressing inhibitory interneurons impairs extinction learning. ConclusionsOur data reveal that vmPFC projections mediate extinction of a cocaine-associated contextual memory through recruitment of feed-forward inhibition in the dmPFC, thereby providing a novel neuronal substrate that promotes extinction-induced inhibitory control.

Regulation of extinction of cocaine-induced place preference by midkine is related to a differential phosphorylation of peroxiredoxin 6 in dorsal striatum

The neurotrophic factors Midkine (MK) and Pleiotrophin (PTN) have been suggested to modulate drugs of abuse-induced effects. To test this hypothesis, cocaine (10 and 15mg/kg)-induced conditioned place preference (CPP) was rendered in PTN knockout (PTN−/−), MK knockout (MK−/−) and wild type (WT+/+) mice, and then extinguished after repeated saline injections (distributed in 4 extinction sessions). Cocaine induced a similar CPP in all the three genotypes. We found a significantly increased percentage of MK−/− mice that did not extinguish cocaine CPP at the end of the extinction sessions. Particularly, 40% of MK−/− mice did not extinguish cocaine (15mg/kg)-induced CPP compared to WT+/+ and PTN−/− mice (∼0–6%). Interestingly, we found that a greater magnitude of extinction of CPP after the first extinction session (5 days after last administration of cocaine) correlates with increased tyrosine phosphorylation of the enzyme peroxiredoxin 6 in the dorsal striatum of MK−/− mice. On the other hand, a greater magnitude of CPP extinction correlates with increased tyrosine phosphorylation of aconitase 2 in the prefrontal cortex of WT+/+ mice. In contrast, a lower magnitude of CPP extinction correlates with increased phosphorylation of aconitase 2 in the prefrontal cortex of PTN−/− mice, suggesting that the correlation between the tyrosine phosphorylation levels of aconitase 2 and magnitude of CPP extinction depends on the genotype considered. The data demonstrate that MK is a novel genetic factor that plays a role in the extinction of cocaine-induced CPP by mechanisms that may involve specific phosphorylation of striatal peroxiredoxin 6.

Acute systemic blockade of D2 receptors does not accelerate the extinction of cocaine-associated place preference

Facilitation of extinction can be used as a therapeutic tool in treatment of both post-traumatic stress disorder and drug addiction. The present study examined whether the blockade of D2 receptors before each extinction trial would accelerate the extinction of cocaine-induced place preference. Male Wistar rats were initially conditioned and tested for a cocaine-associated place-preference (20 mg/kg). On the following day after the initial test, the animals were submitted to extinction training. This training consisted of daily sessions in which the subjects were alternatively confined during 30 min in the saline and cocaine-associated environment. However, 30 min before each extinction trial the animals received a systemic injection of D2 antagonist sulpiride. While one group was treated with a dose of 50 mg/kg (ip), the other group was treated with a dose of 100 mg/kg. An additional control group received injections of saline during extinction trials. Twenty-four hours after the last extinction trial, the animals were tested again for their preferences to cocaine and saline associated environments. Since one round of extinction trial was not sufficient to produce extinction of cocaine associated place preference, the animals were submitted to a second cycle of extinction trials and test. The systemic administration of the two doses of sulpiride (50 and 100 mg/kg) 30 min before each conditioning did not enhance the extinction of cocaine-associated place preference. This finding suggests that the D2 receptors are not involved in a acute protocol of extinction of cocaine-induced place preference.