Cocaine- and stress-primed reinstatement of drug-associated memories elicit differential behavioral and frontostriatal circuit activity patterns via recruitment of L-type Ca2+ channels.
| Publication Type | Academic Article |
| Authors | Bavley C, Fetcho R, Burgdorf C, Walsh A, Fischer D, Hall B, Sayles N, Contoreggi N, Hackett J, Antigua S, Babij R, De Marco García N, Kash T, Milner T, Liston C, Rajadhyaksha A |
| Journal | Mol Psychiatry |
| Volume | 25 |
| Issue | 10 |
| Pagination | 2373-2391 |
| Date Published | 09/09/2019 |
| ISSN | 1476-5578 |
| Keywords | Calcium Channels, L-Type, Cocaine, Corpus Striatum, Frontal Lobe, Memory, Neural Pathways, Stress, Psychological |
| Abstract | Cocaine-associated memories are critical drivers of relapse in cocaine-dependent individuals that can be evoked by exposure to cocaine or stress. Whether these environmental stimuli recruit similar molecular and circuit-level mechanisms to promote relapse remains largely unknown. Here, using cocaine- and stress-primed reinstatement of cocaine conditioned place preference to model drug-associated memories, we find that cocaine drives reinstatement by increasing the duration that mice spend in the previously cocaine-paired context whereas stress increases the number of entries into this context. Importantly, both forms of reinstatement require Cav1.2 L-type Ca2+ channels (LTCCs) in cells of the prelimbic cortex that project to the nucleus accumbens core (PrL→NAcC). Utilizing fiber photometry to measure circuit activity in vivo in conjunction with the LTCC blocker, isradipine, we find that LTCCs drive differential recruitment of the PrL→ NAcC pathway during cocaine- and stress-primed reinstatement. While cocaine selectively activates PrL→NAcC cells prior to entry into the cocaine-paired chamber, a measure that is predictive of duration in that chamber, stress increases persistent activity of this projection, which correlates with entries into the cocaine-paired chamber. Using projection-specific chemogenetic manipulations, we show that PrL→NAcC activity is required for both cocaine- and stress-primed reinstatement, and that activation of this projection in Cav1.2-deficient mice restores reinstatement. These data indicate that LTCCs are a common mediator of cocaine- and stress-primed reinstatement. However, they engage different patterns of behavior and PrL→NAcC projection activity depending on the environmental stimuli. These findings establish a framework to further study how different environmental experiences can drive relapse, and supports further exploration of isradipine, an FDA-approved LTCC blocker, as a potential therapeutic for the prevention of relapse in cocaine-dependent individuals. |
| DOI | 10.1038/s41380-019-0513-2 |
| PubMed ID | 31501511 |
| PubMed Central ID | PMC7927165 |