Details

Autor(en) / Beteiligte

• Bavley, Charlotte C
• Fetcho, Robert N
• Burgdorf, Caitlin E
• Walsh, Alexander P
• Fischer, Delaney K
• Hall, Baila S
• Sayles, Nicole M
• Contoreggi, Natalina H
• Hackett, Jonathan E
• Antigua, Susan A
• Babij, Rachel
• De Marco García, Natalia V
• Kash, Thomas L
• Milner, Teresa A
• Liston, Conor
• Rajadhyaksha, Anjali M

Titel

Cocaine- and stress-primed reinstatement of drug-associated memories elicit differential behavioral and frontostriatal circuit activity patterns via recruitment of L-type Ca 2+ channels

Ist Teil von

• Molecular psychiatry, 2020-10, Vol.25 (10), p.2373

Ort / Verlag

England

Erscheinungsjahr

2020

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 Ca 1.2 L-type Ca 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 Ca 1.2-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.