Locomotor sensitization to intermittent ketamine administration is associated with nucleus accumbens plasticity in male and female rats

Abstract

Clinical evidence suggests superior antidepressant response over time with a repeated, intermittent ketamine treatment regimen as compared to a single infusion. However, the club drug ketamine is commonly abused. Therefore, the abuse potential of repeated ketamine injections at low doses needs to be investigated. In this study, we investigated the abuse potential of repeated exposure to either 0, 2.5, or 5 mg/kg ketamine administered once weekly for seven weeks. Locomotor activity and conditioned place preference (CPP) were assayed to evaluate behavioral sensitization to the locomotor activating effects of ketamine and its rewarding properties, respectively. Our results show that while neither males nor females developed CPP, males treated with 5 mg/kg and females treated with either 2.5 or 5 mg/kg ketamine behaviorally sensitized. Furthermore, dendritic spine density was increased in the NAc of both males and females administered 5 mg/kg ketamine, an effect specific to the NAc shell (NAcSh) in males but to both the NAc core (NAcC) and NAcSh in females. Additionally, males administered 5 mg/kg ketamine displayed increased protein expression of ΔfosB, calcium calmodulin kinase II alpha (CaMKIIα), and brain-derived neurotrophic factor (BDNF), an effect not observed in females administered either dose of ketamine. However, males and females administered 5 mg/kg ketamine displayed increased protein expression of AMPA receptors (GluA1). Taken together, low-dose ketamine, when administered intermittently, induces behavioral sensitization at a lower dose in females than males, accompanied by an increase in spine density in the NAc and protein expression changes in pathways commonly implicated in addiction.

Sex Differences in the Antidepressant Effects of Ketamine in Animal Models of Depression

“…Locomotor sensitization after repeated exposure to drugs of abuse is indicative of plasticity in the reward circuitry that may underlie the transition to addiction. Interestingly in these studies, the same rats that displayed sensitization did not form a CPP to ketamine at any dose tested [62,63]; in fact, females displayed a conditioned place aversion to 5.0 mg/kg. Together, these findings suggest that divergent mechanisms may underlie the locomotor activating effects and the associative rewarding effects of ketamine.…”

“…Therefore, understanding dendritic spines is fundamental in uncovering the mechanisms underlying depression and also anti-depressant activities. Dendritic spine density was increased in the nucleus accumbens (NAc) of both males and females administered with ketamine, and this effect was specific to the NAc shell (NAcSh) in both sexes but also to the NAc core (NAcC) in females [62].…”

“…Female rats show increased locomotor sensitization to intermittent (weekly and every other day, respectively) repeated ketamine at depression-relevant doses (2.5-10.0 mg/kg intraperitoneally, i.p.) [62,63]. Locomotor sensitization after repeated exposure to drugs of abuse is indicative of plasticity in the reward circuitry that may underlie the transition to addiction.…”

“…Males administered ketamine displayed increased protein expression of ∆fosB, CaMKIIα, and BDNF, this effect was not seen in females. However, males and females administered ketamine displayed increased protein expression of AMPA receptors (GluA1) [62]. Repeated ketamine treatment also induced sustained sex-differentiated neurochemical and molecular effects, as it enhanced hippocampal synapsin protein levels and serotonin turnover in males, but attenuated glutamate and aspartate levels in female mice [60].…”

Effects of a 5-HT1B Receptor Agonist on Locomotion and Reinstatement of Cocaine-Conditioned Place Preference after Abstinence from Repeated Injections in Mice

“…Additionally, the 5-HT 1A/1B R agonist RU24969 dose-dependently increases spontaneous locomotion in wild type mice, but not 5-HT 1B R knockout mice (Saudou et al, 1994 ). CP94253, as well as another 5-HT 1B R agonist CP93129, have been shown to potentiate cocaine-induced locomotion and cocaine sensitization in rats (Przegaliński et al, 2001 , 2002 , 2004 ; Filip et al, 2010 ). Collectively, these findings suggest that 5-HT 1B R stimulation enhances locomotion in rodents given cocaine or with a history of stress.…”