Cocaine-induced synaptic changes in the nucleus accumbens: role in drug-motivated behaviour and relapse risk
von Myrto Panopoulou
Datum der mündl. Prüfung:2020-05-18
Erschienen:2021-05-17
Betreuer:Dr. Dr. Oliver Schlüter
Gutachter:Dr. Dr. Oliver Schlüter
Gutachter:Prof. Dr. André Fischer
Dateien
Name:Dissertation_Myrto Panopoulou_no cv.pdf
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Zusammenfassung
Englisch
Chronic drug use creates robust and durable memories which, even after years of abstinence, can be reawakened by drug-associated cues and trigger craving and relapse. Addictive drugs elevate extracellular dopamine levels in a key area of the brain’s reward system, the nucleus accumbens (NAc). Drugs of abuse, such as cocaine, hijack plasticity mechanisms to rejuvenate and reorganise the reward circuit, thus inducing drug-seeking behaviours. One such mechanism is the generation of silent synapses in the adult NAc, synapses that lack functional AMPARs and hence do not transmit at resting potentials. Silent synapses mature over prolonged drug withdrawal. If the cocaine experience is paired with a context, this maturation will occur via recruitment of calcium-permeable, higher conductance AMPARs (CP-AMPARs). The understanding of the role of CP-AMPARs in drug-motivated behaviour remains elusive. It has been reported that CP-AMPARs are induced with drug-context associations, but are not required for long-term retention of cocaine-associated memories. However, other studies emphasise their specific role in incubation of cocaine craving, and they were found to be required for morphine-induced reinstatement. Here, I used a mouse model of relapse by reinstating cocaine-conditioned place preference (cocaine-CPP) after extinction. To study the role of silent synapses and their CP-AMPAR mediated maturation, I used a combination of pharmacological and genetic interrogations with PSD-95 and SAP102 KO mice that impair this process. In these KO mice, silent synapses are induced by cocaine, but they do not mature by CP-AMPAR incorporation. Using ex vivo slice electrophysiology, I found that CP-AMPARs are increased in the WT NAc after reinstatement. My results reveal that CP-AMPARs are crucial for a low intensity cue to induce reinstatement, whereas a strong stimulus does not require their concurrent activity. I also show that impairing maturation of silent synapses, via lack of PSD-95, causes a cocaine challenge injection to abolish, rather than reinstate, the remaining preference after extinction. Additionally, since the KO has a global effect, I used an RNAi-approach to specifically target silent synapses and CP-AMPAR expression in the NAc. My preliminary results indicate no impairment in terms of high and intermediate dose-induced reinstatement. The diverging behaviours I describe in the PSD-95 and SAP102 KO mice further support the notion that these two members of the same protein family fulfil different roles in the fate of excitatory synapses, rather than a similar, redundant function. More importantly, I show that CP-AMPARs amplify the gain of a weak cue to tip it over the threshold and trigger reinstatement. Taken together with existing knowledge, the results of this thesis suggest that CP-AMPARs gate the intensity with which addiction-driven behaviours are expressed and, thereby, may constitute major targets in the fight against addiction.
Keywords: cocaine; addiction; relapse; nucleus accumbens; conditioned place preference