Chemogenetic Activation of an Extinction Neural Circuit Reduces Cue-Induced Reinstatement of Cocaine Seeking

Abstract

The ventromedial prefrontal cortex (vmPFC) has been shown to negatively regulate cocaine-seeking behavior, but the precise conditions by which vmPFC activity can be exploited to reduce cocaine relapse are currently unknown. We used viral-mediated gene transfer of designer receptors (DREADDs) to activate vmPFC neurons and examine the consequences on cocaine seeking in a rat self-administration model of relapse. Activation of vmPFC neurons with the Gq-DREADD reduced reinstatement of cocaine seeking elicited by cocaine-associated cues, but not by cocaine itself. We used a retro-DREADD approach to confine the Gq-DREADD to vmPFC neurons that project to the medial nucleus accumbens shell, confirming that these neurons are responsible for the decreased cue-induced reinstatement of cocaine seeking. The effects of vmPFC activation on cue-induced reinstatement depended on prior extinction training, consistent with the reported role of this structure in extinction memory. These data help define the conditions under which chemogenetic activation of extinction neural circuits can be exploited to reduce relapse triggered by reminder cues.

Significance statement: The ventromedial prefrontal cortex (vmPFC) projection to the nucleus accumbens shell is important for extinction of cocaine seeking, but its anatomical proximity to the relapse-promoting projection from the dorsomedial prefrontal cortex to the nucleus accumbens core makes it difficult to selectively enhance neuronal activity in one pathway or the other using traditional pharmacotherapy (e.g., systemically administered drugs). Viral-mediated gene delivery of an activating Gq-DREADD to vmPFC and/or vmPFC projections to the nucleus accumbens shell allows the chemogenetic exploitation of this extinction neural circuit to reduce cocaine seeking and was particularly effective against relapse triggered by cocaine reminder cues.

Keywords: DREADD; extinction; infralimbic; memory; nucleus accumbens shell.

Figure 1.

Activation of vmPFC with a Gq-DREADD reduces cue-induced cocaine seeking after extinction. A, Active (shaded bars) and inactive (white bars) lever presses are shown for the cue-induced and cocaine-primed reinstatement tests. *p < 0.05, comparing vehicle with CNO for active lever. B, Histological verification of the extent of DREADD expression indicated robust and restricted expression in vmPFC. C, A representative photomicrograph demonstrating expression of the Gq-DREADD (HA tag) located primarily within infralimbic cortex.

Figure 2.

Activation of vmPFC with a Gq-DREADD does not alter cocaine seeking in the presence of cocaine cues after abstinence. A, Neither active (shaded bars) nor inactive (white bars) lever presses differed for CNO versus vehicle-treated animals during the cocaine-seeking test (p > 0.8). B, Histological verification of the extent of DREADD expression indicated robust and restricted expression in vmPFC.

Figure 3.

Activation of the vmPFC projection to the NAshell using a retro-DREADD approach reduces cue-induced reinstatement of cocaine seeking. A, The retro-DREADD approach used to target the vmPFC projection to the NAshell is depicted. CAV2-Cre was infused into the NAshell (blue pipet), and the AAV-DIO-hM3Dq(Gq) DREADD (yellow pipet) was infused into vmPFC. Cre-lox recombination thus restricts expression of the hM3Dq to vmPFC neurons projecting to the NAshell (green). Representative photomicrographs demonstrating expression of the Gq-DREADD (mCherry tag) in vmPFC cell bodies and dendrites (left) and NAshell fibers and terminals (right), relative to the anterior commissure (a.c.). B, Histological verification of the extent of DREADD expression indicated robust and restricted expression in vmPFC. C, Active (shaded bars) and inactive (white bars) lever presses are shown for the cue-induced and cocaine-primed reinstatement tests. *p < 0.05, comparing vehicle with CNO for active lever. D, The number of Fos⁺ nuclei in vmPFC (per mm² tissue) induced by a final CNO injection is shown, along with a representative image. *p < 0.05, comparing vehicle with CNO.

Figure 4.

Activation of the vmPFC projection to the NAshell using a retro-DREADD approach does not alter cocaine seeking in the presence of cocaine cues after abstinence. A, Neither active (shaded bars) nor inactive (white bars) lever presses differed for CNO versus vehicle-treated animals during the cocaine-seeking test (p > 0.3). B, Histological verification of the extent of DREADD expression indicated robust and restricted expression in vmPFC.