Esketamine Inhibits Cocaine-Seeking Behaviour Subsequent to Various Abstinence Conditions in Rats

Abstract

Background: Cocaine use disorder (CUD) is a relapsing brain disease caused by a chronic drug intake that involves neural mechanisms and psychological processes, including depression. Preclinical and clinical studies have demonstrated the promise of pharmacological drugs in controlling the reinstatement of cocaine by targeting the N-methyl-D-aspartate (NMDA) receptor. Recent evidence has revealed that esketamine, a (S) enantiomer of ketamine, shows a high affinity to NMDA receptors and has been used in clinical trials to treat moderate-to-severe depression.

Methods: In the present paper, we investigated the effects of esketamine in regulating cocaine-seeking behaviour induced through the use of cocaine (10 mg/kg) or the cocaine-associated conditioned cue after a short (10 days)-lasting period of drug abstinence with extinction training, home cage or enrichment environment conditions in male rats. Furthermore, we investigated the acute effects of esketamine on locomotor activity in drug-naïve animals.

Results: Esketamine (2.5-10 mg/kg) administered peripherally attenuated the reinstatement induced with cocaine priming or the drug-associated conditioned cue after different conditions of abstinence.

Conclusions: These results seem to support esketamine as a candidate for the pharmacological management of cocaine-seeking and relapse prevention; however, further preclinical and clinical research is needed to better clarify esketamine's actions in CUD.

Keywords: cocaine abstinence; cocaine-seeking behaviour; esketamine; rats.

Figure 1

Cocaine self-administration and extinction training in rats. Numbers of “active” (black dots) and “inactive” (white dots) lever presses during 2 h sessions. n = 11 rats. Data were expressed as mean ± SEM. Data were comparable between levers (*** p < 0.001; Friedman’s test, followed by Dunn’s multiple comparison test).

Figure 2

Effects of esketamine (ESK, 5–10 mg/kg) on (A) cocaine prime- (COC, 10 mg/kg) or (B) CUE (light and tone previously associated with cocaine self-administration)-induced reinstatement in rats that underwent cocaine abstinence with extinction training (EXT) from cocaine self-administration. n = 6 rats/COC group and 5 rats/CUE group. Data were expressed as mean ± SEM. Data were comparable to vehicle (VEH) + COC 10 or VEH + CUE group (* p < 0.05; ** p < 0.01; *** p < 0.001; two-way repeated measure ANOVA or Friedman’s tests, followed by Dunnett’s or Dunn’s multiple comparison tests, respectively).

Figure 3

Effects of esketamine (ESK, 5–10 mg/kg) on (A) cocaine prime- (COC, 10 mg/kg) or (B) CUE (light and tone previously associated with cocaine self-administration)-induced reinforcement in rats that underwent cocaine abstinence with social isolation from cocaine self-administration (COC SA). n = 7 rats/group. Data were expressed as mean ± SEM. Data were comparable to vehicle (VEH) + COC 10 or VEH + CUE group (* p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001; two-way repeated measure ANOVA or Friedman’s tests, followed by Dunnett’s or Dunn’s multiple comparison tests, respectively).

Figure 4

Effects of esketamine (ESK, 2.5–10 mg/kg) on (A) cocaine prime- (COC, 10 mg/kg) or (B) CUE (light and tone previously associated with cocaine self-administration)-induced reinstatement in rats that underwent cocaine abstinence in enrichment environment from cocaine self-administration (COC SA). n = 7 rats/group. Data were expressed as mean ± SEM. Data were comparable to vehicle (VEH) + COC 10 or VEH + CUE group (** p < 0.01; *** p < 0.001; two-way repeated measure ANOVA or Friedman’s tests, followed by Dunnett’s or Dunn’s multiple comparison tests, respectively).

Figure 5

Effects of esketamine (ESK, 5–15 mg/kg) on locomotor activity, expressed as distance travelled (cm) measured during 2 h recordings. n = 8 rats/group. Data were expressed as mean ± SEM. Data were comparable to vehicle (VEH) group (Kruskal–Wallis test).