Early-life ketamine exposure attenuates the preference for ethanol in adolescent Sprague-Dawley rats

Abstract

Ketamine, a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist, produces quick and effective antidepressant results in depressed juvenile and adult individuals. The long-term consequences of using ketamine in juvenile populations are not well known, particularly as it affects vulnerability to drugs of abuse later in life, given that ketamine is also a drug of abuse. Thus, the current study examined whether early-life ketamine administration produces long-term changes in the sensitivity to the rewarding effects of ethanol, as measured using the conditioned place preference (CPP) paradigm. On postnatal day (PD) 21, juvenile male and female rats were pretreated with ketamine (0.0 or 20 mg/kg) for 10 consecutive days (i.e., PD 21-30) and then evaluated for ethanol-induced CPP (0.0, 0.125, 0.5, or 2.0 g/kg) from PD 32-39. Results revealed that early-life ketamine administration attenuated the rewarding properties of ethanol in male rats, as ketamine pretreated rats failed to exhibit ethanol-induced CPP at any dose compared to saline pretreated rats, which showed an increased preference towards the ethanol-paired compartment in a dose-dependent manner. In females, ethanol-induced CPP was generally less robust compared to males, but ketamine pretreatment resulted in a rightward shift in the dose-response curve, given that ketamine pretreated rats needed a higher dose of ethanol compared to saline pretreated rats to exhibit ethanol-induced CPP. When considered together, the findings suggest that early use of ketamine does not appear to enhance the vulnerability to ethanol later in life, but in contrast, it may attenuate the rewarding effects of ethanol.

Keywords: Addiction; Adolescence; Alcohol; Anhedonia; CPP; Reward.

Figure 1.

Timeline and experimental design. During ketamine pretreatment, male and female rats were administered saline or ketamine (20 mg/kg) for 10 consecutive days, starting on postnatal day (PD) 21. During the last four days of ketamine pretreatment, rats were handled 2-3 min daily to reduce stress/anxiety due to experimental handling and/or behavioral procedures. The 10 day conditioned place preference (CPP) procedure began 24 h after the end of ketamine pretreatment. Subject compartment preference was initially obtained during a 20 min preconditioning test session on PD 31, and was followed by an eight-day conditioning phase (PD 32-39), which involved alternating daily 15 min sessions during which rats were injected with ethanol (0, 0.125, 0.5, or 2.0 g/kg) and confined to the rats’ nonpreferred compartment and saline injections paired with the rats’ preferred compartment in a counterbalanced design. Subject preference for the ethanol-paired compartment was then assessed during the 20 min postconditioning test (PD 40).

Figure 2.

(A) Mean weight of male (n = 46-47) and female (n = 45-49) rats pretreated with saline or ketamine (20 mg/kg) during postnatal day (PD) 21-30, and (B) activity levels of male and female rats during the preconditioning test (PD 31). Error bars depict standard error of the mean (SEM) for each respective group. There were no significant weight changes or differences in activity during the preconditioning test between the saline and ketamine groups for either male or female rats.

Figure 3.

(A) Individual and mean preference scores and (B) activity levels during the postconditioning test (postnatal day [PD] 40) for males (n = 11-12) pretreated (Pretx) with saline or ketamine (20 mg/kg) during PD 21-30 and conditioned with ethanol (0.0, 0.125, 0.5, or 2.0 g/kg) during PD 32-39. Error bars depict standard error of the mean (SEM) for each respective group. (*)Represents a significant increase between the groups (Tukey HSD, p<0.05); (#)Represents a significant decrease between the groups (Tukey HSD, p<0.05); (ρ)Represents a significant increase in time spent in the ethanol-paired chamber between the preconditioning and postconditioning tests within the group (planned comparison, p<0.05).

Figure 4.

(A) Individual and mean preference scores and (B) activity levels during the postconditioning test (postnatal [PD] 40) for females (n = 10-13) pretreated (Pretx) with saline or ketamine (20 mg/kg) during PD 21-30 and conditioned with ethanol (0.0, 0.125, 0.5, or 2.0 g/kg) during PD 32-39. Error bars depict standard error of the mean (SEM) for each respective group. (ρ)Represents a significant increase in time spent in the ethanol-paired chamber between the preconditioning and postconditioning tests within the group (planned comparison, p<0.05). (ε)Represents a significant decrease in the rats conditioned with 0.5 and 2.0 g/kg of ethanol (main effect of ethanol, p<0.05).