Contribution of D1R-expressing neurons of the dorsal dentate gyrus and Ca v 1.2 channels in extinction of cocaine conditioned place preference

• Published in: Neuropsychopharmacology (New York, N.Y.) Vol. 45; no. 9; p. 1506
• Main Authors: Burgdorf, Caitlin E, Bavley, Charlotte C, Fischer, Delaney K, Walsh, Alexander P, Martinez-Rivera, Arlene, Hackett, Jonathan E, Zallar, Lia J, Ireton, Kyle E, Hofmann, Franz, Hell, Johannes W, Huganir, Richard L, Rajadhyaksha, Anjali M
• Format: Journal Article
• Language: English
• Published: England 01-08-2020
• Subjects: Animals; Calcium Channels, L-Type - physiology; Cocaine - pharmacology; Cocaine-Related Disorders; Conditioning, Classical; Dentate Gyrus; Dopamine Uptake Inhibitors - pharmacology; Extinction, Psychological; Male; Mice; Receptors, Dopamine; Receptors, Dopamine D1 - physiology
• ISSN: 1740-634X

Cocaine-associated contextual cues can trigger relapse behavior by recruiting the hippocampus. Extinction of cocaine-associated contextual memories can reduce cocaine-seeking behavior, however the molecular mechanisms within the hippocampus that underlie contextual extinction behavior and subsequent reinstatement remain poorly understood. Here, we extend our previous findings for a role of Ca
1.2 L-type Ca
channels in dopamine 1 receptor (D1R)-expressing cells in extinction of cocaine conditioned place preference (CPP) in adult male mice. We report that attenuated cocaine CPP extinction in mice lacking Ca
1.2 channels in D1R-expressing cells (D1
, Ca
1.2
) can be rescued through chemogenetic activation of D1R-expressing cells within the dorsal dentate gyrus (dDG), but not the dorsal CA1 (dCA1). This is supported by the finding that Ca
1.2 channels are required in excitatory cells of the dDG, but not in the dCA1, for cocaine CPP extinction. Examination of the role of S1928 phosphorylation of Ca
1.2, a protein kinase A (PKA) site using S1928A Ca
1.2 phosphomutant mice revealed no extinction deficit, likely due to homeostatic scaling up of extinction-dependent S845 GluA1 phosphorylation in the dDG. However, phosphomutant mice failed to show cocaine-primed reinstatement which can be reversed by chemogenetic manipulation of excitatory cells in the dDG during extinction training. These findings outline an essential role for the interaction between D1R, Ca
1.2, and GluA1 signaling in the dDG for extinction of cocaine-associated contextual memories.