Reinforcing properties of an intermittent, low dose of ketamine in rats: effects of sex and cycle

Abstract

Rationale Repeated intermittent exposure to ketamine has rapid and long-lasting antidepressant effects, but the abuse potential has only been assessed at high doses. Furthermore, while females are more susceptible to depression and more sensitive to ketamine’s antidepressant-like effects, the abuse potential for ketamine in females is unknown. Objectives The objectives of this study are to determine the reinforcing properties of low-dose intermittent ketamine in adult rats of both sexes and determine whether cycling gonadal hormones influence females’ response to ketamine. In male rats, we also aimed to determine whether reinstatement to intermittent ketamine is comparable to intermittent cocaine. Methods Male rats intravenously self-administered cocaine (0.75 mg/kg/infusion) or ketamine (0.1 mg/kg/infusion) once every fourth day, while intact cycling female rats self-administered ketamine only during preidentified stages of their 4-day estrus cycle, when gonadal hormones are either high (proestrus) or low (diestrus). After acquiring self-administration, rats underwent daily extinction training followed by cue-primed and drug-primed reinstatement to assess drug-seeking behavior. Results Diestrus-trained females fail to maintain ketamine self-administration and did not display reinstatement to ketamine-paired cues. Males and proestrus-trained females reinstated to ketamine-paired cues. Ketamine-primed reinstatement was dependent on simultaneous cue presentation. Male rats reinstated to cocaine priming independent of cue presentation. Conclusion These findings indicate that females’s responsivity to this dose of ketamine depends on stage of cycle, as only proestrus-trained females and males respond to ketamine’s reinforcing effects under this treatment paradigm.

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

“…It is possible the observed effect is due to stage of estrous cycle as all females used in the present study were tested and administered ketamine in diestrous 1. A recent study from our lab showed cycle-dependent effects with acquisition of ketamine in a self-administration model, demonstrating that female rats in diestrous 1 do not acquire ketamine self-administration over ten sessions whereas males and proestrous females do (Wright et al , 2016). However, more studies examining cycle-dependent effects on NAc protein expression following ketamine administration are necessary to fully elucidate sex differences in protein expression following repeated ketamine injections.…”

Sex Differences in the Pharmacokinetics of Low-dose Ketamine in Plasma and Brain of Male and Female Rats

“…It is possible that estrous cycle could influence pharmacokinetic parameters of ketamine over repeated administration of a low dose. For example, estrous cycle appears to influence both maintenance of intravenous ketamine self-administration and reinstatement to ketaminepaired cues in rats (Wright et al, 2017). While pharmacokinetic differences between proestrus and diestrus rats are not apparent after a single systemic injection of low-dose ketamine, one cannot exclude the possibility that cycle-dependent reinforcing properties of ketamine following repeated administration (intravenous or otherwise) are influenced by pharmacokinetics.…”

On the safety of repeated ketamine infusions for the treatment of depression: Effects of sex and developmental periods

“… Treatment Regimen Behavioral Response Molecular Change References Male Adult 100 μg per inf i.v. 1x/4 days ↑ FR1 self-administration n/a ( Wright et al, 2017 ) ↑ cue-induced reinstatement 2.5 mg/kg i.p. 1x/2 days no change ↑NAc ΔfosB ( Schoepfer et al, 2017 ) Weekly no change ↑ NAc shell spines ( Strong et al, 2017 ) 5 mg/kg i.p.…”

“… Daily ↑ locomotor sensitization n/a ( Wiley et al, 2008 ) ↑ CPP n/a ( Li et al, 2008 ) 1x/2 days ↑ locomotor sensitization ↑ NAc ΔfosB ( Schoepfer et al, 2017 ) ↑ CPP Female Adult 100 μg per inf i.v. 1x/4 days ↑ FR1 self-administration (proestrous) n/a ( Wright et al, 2017 ) ↑cue-induced reinstatement (proestrous) ↓FR1 self-administration (diestrous) ↓ cue-induced reinstatement (diestrous) 2.5 mg/kg i.p. 1x/2 days no change ↑NAc ΔfosB ( Schoepfer et al, 2017 ) Weekly ↑ locomotor sensitization (diestrous) ↑ NAc shell spines ( Strong et al, 2017 ) 5 mg/kg i.p.…”

“…This differential sensitivity to ketamine in both sexes at the juvenile period could be explained by levels of circulating gonadal hormones. Indeed, estrogen and progesterone are detected in the bloodstream around PND 28, albeit at lower concentrations when compared to adults ( Vetter- O’Hagen and Spear, 2012 ), and given the potential role ovarian hormones play in enhancing ketamine's reinforcing properties in adult rodents ( Wright et al, 2017 ), the same could be true for juvenile rodents. In support of this idea is the fact that the locomotor-activating effects of low-dose ketamine in preadolescent animals (<PND28) was similar between males and females ( McDougall et al, 2017 ).…”