Orexin-1 receptor signaling increases motivation for cocaine-associated cues

Abstract

The orexin/hypocretin system is involved in multiple cocaine addiction processes that involve drug-associated environmental cues, including cue-induced reinstatement of extinguished cocaine seeking and expression of conditioned place preference. However, the orexin system does not play a role in several behaviors that are less cue-dependent, such as cocaine-primed reinstatement of extinguished cocaine seeking and low-effort cocaine self-administration. We hypothesized that cocaine-associated cues, but not cocaine alone, engage signaling at orexin-1 receptors (OX1Rs), and this cue-engaged OX1R signaling increases motivation for cocaine. Motivation for cocaine was measured in Sprague-Dawley rats with behavioral-economic demand curve analysis after pretreatment with the OX1R antagonist SB-334867 (SB) or vehicle with and without light + tone cues. Demand for cocaine was higher when cocaine-associated cues were present, and SB only reduced cocaine demand in the presence of these cues. We then investigated whether cocaine demand was linked to the cued reinstatement of cocaine seeking, as both procedures are partially driven by cocaine-associated cues in an orexin-dependent manner. SB blocked cue-induced reinstatement behavior, and baseline demand predicted SB efficacy with the largest effect in high-demand animals, i.e. animals with the greatest cue-dependent behavior. We conclude that OX1R signaling increases the reinforcing efficacy of cocaine-associated cues but not that of cocaine alone. This supports our view that orexin plays a prominent role in the ability of conditioned cues to activate motivational responses.

Keywords: behavioral economics; demand curve; elasticity; rat; relapse; self-administration.

Fig. 1

Experimental design overview. Group 1 animals (n = 21) were trained to self-administer cocaine with light+tone cues and then trained on the within-session threshold procedure with light+tone cues. These animals were then pretreated with either SB or vehicle (veh) prior to testing on the within-session threshold procedure with cues. Group 1 animals were then split into 2 subgroups and re-stabilized on the threshold procedure either with (n = 8) or without light+tone cues (n = 13). Animals were again pretreated with either SB or vehicle prior to testing on the within-session threshold procedure. All Group 1 animals were then run on extinction sessions and tested for cue-induced reinstatement with SB or vehicle pretreatment in a counterbalanced fashion. Group 2 animals were trained to self-administer cocaine without light+tone cues and then trained and tested on the within-session threshold procedure without light+tone cues.

Fig. 2

Behavior during cocaine self-administration under an FR-1 schedule of reinforcement with light+tone cues for the 3 days before training and testing on the within-session threshold procedure (n = 21, Group 1).

Fig. 3

SB pretreatment increased cocaine demand elasticity without altering free cocaine consumption. (A) Normalized demand elasticity (α) was significantly higher in animals when they were pretreated with SB compared to when they were pretreated with vehicle (veh) (*P < 0.05). (B) Free cocaine consumption (Q₀) was not altered by SB pretreatment compared to vehicle pretreatment. (C) Demand curves constructed from mean α and Q₀ values to demonstrate the increased sensitivity of demand to price with SB treatment. (D) Baseline demand elasticity (abscissa) was not associated with change in demand elasticity from baseline with SB pretreatment (ordinate).

Fig. 4

Removal of response-contingent, cocaine-associated light+tone cues led to an increase in demand elasticity. Each line represents data from an individual subject. All animals received cues during their training and during their first baseline demand test. (A) Animals that were retested for baseline demand with cues showed no overall change in baseline demand from the initial test, i.e., median α remained unchanged, although 2 animals showed a notable increase in demand elasticity. (B) Animals that were retested for baseline demand without cues showed a significant increase in median demand elasticity (α) (*P < 0.05). (C & D) Both groups showed a similar magnitude increase in median free cocaine consumption (Q₀) during retesting (~0.5 mg/kg increase). This increase did not reach significance in the group retested with cues (C) but was significant in the group retested without cues (D; **P < 0.01).

Fig. 5

SB pretreatment significantly increased cocaine demand elasticity only when response-contingent, cocaine-associated light+tone cues were present. (A) In the group re-stabilized and retested with light+tone cues, SB pretreatment significantly increased demand elasticity (α) (*P = 0.05). (B) In contrast, SB pretreatment did not increase demand elasticity in the group re-stabilized and retested without light+tone cues. (C and D) Free cocaine consumption (Q₀) did not change as a function of SB treatment when cues were present (C) nor when cues were absent (D).

Fig. 6

(A) SB pretreatment did not increase cocaine demand elasticity (α) when animals were trained and tested without response-contingent, cocaine-associated light+tone cues. (B) SB pretreatment did not alter free cocaine consumption (Q₀) in this control group of animals trained and tested without cocaine-associated cues.

Fig. 7

Baseline demand predicted reinstatement propensity and efficacy of SB treatment. (A) Baseline demand elasticity (α), but not free cocaine consumption (Q₀), significantly predicted the magnitude of cue-induced reinstatement with vehicle pretreatment. (B) Baseline demand elasticity (α), but not free cocaine consumption (Q₀), significantly predicted the magnitude of the reduction of cue-induced reinstatement with SB pretreatment.