"Effects of the novel relatively short-acting kappa opioid receptor antagonist LY2444296 in behaviors observed after chronic extended-access cocaine self-administration in rats"

Abstract

Rationale: The recruitment of the stress circuitry contributes to a shift from positive to negative reinforcement mechanisms sustaining long-term cocaine addiction. The kappa opioid receptor (KOPr) signaling is upregulated by stress and chronic cocaine exposure. While KOPr agonists induce anhedonia and dysphoria, KOPr antagonists display antidepressant and anxiolytic properties. Most of the knowledge on KOPr antagonism is based on drugs with unusual pharmacokinetic and pharmacodynamic properties, complicating interpretation of results. Here we characterized in vivo behavioral and neuroendocrine effects of the novel relatively short-acting KOPr antagonist LY2444296. To date, no study has investigated whether systemic KOPr blockade reduced anxiety-like and depressive-like behaviors in animals previously exposed to chronic extended access cocaine self-administration.

Objectives: We tested the effect of LY2444296 in blocking KOPr-mediated aversive and neuroendocrine effects. Then, we tested acute systemic LY2444296 in reducing anxiety- and depression-like behaviors, as well as releasing the stress hormone corticosterone (CORT), observed after chronic extended access (18 h/day for 14 days) cocaine self-administration.

Results: LY2444296 blocked U69,593-induced place aversion and -reduced motor activity as well as U69,593-induced release of serum CORT, confirming its major site of action, without exerting an effect per se. Acute systemic administration of LY2444296 reduced anxiety-like and depressive-like behaviors, as well as CORT release, in rats tested after chronic extended access cocaine self-administration, but not in cocaine-naïve rats.

Conclusions: Results suggest that acute blockade of KOPr by a relatively short-acting antagonist produces therapeutic-like effects selectively in rats with a history of chronic extended access cocaine self-administration.

Keywords: Anxiety; Cocaine addiction; Cocaine self-administration; Cocaine withdrawal; Corticosterone; Depression; Extended access self-administration; Kappa opioid receptor OR KOR OR KOP OR KOP-r.

Figure 1

Effect of acute systemic administration of LY2444296 (0, 3 mg/kg i.p.) on U69,593 (0, 0.32 mg/kg s.c.)-mediated A) conditioned place aversion (n= 6/group), B) mean locomotor activity over 4 conditioning days (n= 6/group). Panel C shows the effect of acute systemic administration of LY2444296 (0, 1, 3 mg/kg i.p.) on U69,593 (0, 0.32 mg/kg s.c.)-increased serum corticosterone (n= 8–10/group). All panels show the Mean ±SEM. *** p<0.001, ** p<0.01, * p<0.05 versus vehicle/vehicle group; ### p<0.001, ## p<0.01, # p<0.05 versus LY2444296 vehicle/U69,593 0.32 mg/kg (SNK test).

Figure 2

Effect of acute systemic administration of LY2444296 (0, 1, 3 mg/kg) on A) time spent in the open arms, B) latency to the first entrance into an open arm, C) total number of entries in the closed arms, in cocaine naïve group-housed (n= 9–10/group; left graphs) and single-housed rats (n= 8/group; right graphs) tested in a 5-min EPM test. All panels show the Mean ±SEM. *** p<0.001, ** p<0.01 versus group-housed rats (ANOVA).

Figure 3

Effect of acute systemic administration of LY2444296 (0, 1, 3 mg/kg) on A) immobility behavior, B) latency to show immobility, in cocaine naïve group-housed (n= 9–10/group; left graphs) and single-housed rats (n= 8–12/group; right graphs) tested in a 5-min FST. All panels show the Mean ±SEM. *** p<0.01 versus group-housed rats (ANOVA), ## p<0.01 versus vehicle group-housed rats (SNK test).

Figure 4

Panel A and B show the cocaine intake of adult male Sprague Dawley rats (n= 22) during (A) the training and (B) the chronic (14 sessions) extended access (18 h/day) intravenous self-administration exposure. *** p<0.001, ** p<0.01, * p<0.05 versus the first session (Dunnett’s test). Panel C and Panel D show respectively the serum CORT concentration and the Pdyn gene expression of a separate cohort of rats exposed to chronic extended access cocaine self-administration (18 h/day for 14 days), and of their respective yoked-saline rats (n=6–8/group) sacrificed 30 h after their last operant session. * p<0.05 (Student’s t test). Panel E shows the Pearson’s correlation result between the Pdyn gene expression and the total cocaine intake that rats self-administered over 14 days. All panels show the Mean ±SEM.

Figure 5

Panels A to E show the effect of acute systemic administration of LY2444296 (0, 3 mg/kg) on A) the time spent in the open arms, B) the latency to the first entrance in an open arm and C) the total number of entries in the closed arms in an 5-min EPM test, as well as D) the immobility, E) the latency to show immobility in a 5-min FST, performed in rats tested 30 h after their last extended access cocaine self-administration session (n= 9–11/group). All panels show the Mean ±SEM. *** p< 0.001, ** p< 0.01, * p< 0.05 versus vehicle-injected cocaine rats (Student’s t test). Panel F shows the Mean ±SEM of serum corticosterone concentration measured in rats pre-treated with acute systemic administration of LY2444296 (0, 3 mg/kg; n= 4/group) 30 h after their last extended access cocaine self-administration session, with no exposure to FST or EPM. # p<0.05 versus vehicle-injected cocaine exposed rats (LSD test).