Exploring ketamine's reinforcement, cue-induced reinstatement, and nucleus accumbens cFos activation in male and female long evans rats.

Ketamine (KET), a non-competitive N-methyl-d-aspartate (NMDA) receptor antagonist, has rapid onset of antidepressant effects in Treatment-Resistant Depression patients and repeated infusions are required to sustain its antidepressant properties. However, KET is an addictive drug, and so more preclinical and clinical research is needed to assess the safety of recurring treatments in both sexes. Thus, the aim of this study was to investigate the reinforcing properties of various doses of KET (0-, 0.125-, 0.25-, 0.5 mg/kg/infusion) and assess KET's cue-induced reinstatement and neuronal activation in both sexes of Long Evans rats. Neuronal activation was assessed using the protein expression of the immediate early gene cFos in the nucleus accumbens (Nac), an important brain area implicated in reward, reinforcement and reinstatement to most drug-related cues. Our findings show that KET has reinforcing effects in both male and female rats, albeit exclusively at the highest two doses (0.25 and 0.5 mg/kg/infusion). Furthermore, we noted sex differences, particularly at the highest dose of ketamine, with female rats displaying a higher rate of self-administration. Interestingly, all groups that self-administered KET reinstated to drug-cues. Following drug cue-induced reinstatement test in rats exposed to KET (0.25 mg/kg/infusion) or saline, there was higher cFos protein expression in KET-treated animals compared to saline controls, and higher cFos expression in the core compared to the shell subregions of the Nac. As for reinstatement, there were no notable sex differences reported for cFos expression in the Nac. These findings reveal some sex and dose dependent effects in KET's reinforcing properties and that KET at all doses induced similar reinstatement in both sexes. This study also demonstrated that cues associated with ketamine induce comparable neuronal activation in the Nac of both male and female rats. This work warrants further research into the potential addictive properties of KET, especially when administered at lower doses which are now being used in the clinic for treating various psychopathologies.

Operant novelty seeking predicts cue-induced reinstatement following cocaine but not water reinforcement in male rats.

RATIONALE: An important facet of cocaine addiction is a high propensity to relapse, with increasing research investigating factors that predispose individuals toward uncontrolled drug use and relapse. A personality trait linked to drug addiction is high sensation seeking, i.e., a preference for novel sensations/experiences. In an animal model of sensation seeking, operant novelty seeking predicts the acquisition of drug self-administration. OBJECTIVE: The primary goal of this research was to evaluate the hypothesis that sensitivity to the reinforcing effects of novel sensory stimuli predicts more intensive aspects of drug-taking behaviors, such as relapse. METHODS: Rats were first tested for Operant Novelty Seeking, during which responses resulted in complex visual/auditory stimuli. Next, rats were trained to respond to water/cocaine reinforcers signaled by a cue light. Finally, rats were exposed to extinction in the absence of discrete cues and subsequently tested in a single session of cue-induced reinstatement, during which active responses resulted in cues previously paired with water/cocaine delivery. RESULTS: The present study showed operant responses to produce novel sensory stimuli positively correlate with responding for cocaine during self-administration and during discrete cue-induced reinstatement, but no association with performance during extinction. A different pattern of associations was observed for a natural reward, in this case, water reinforcement. Here, the degree of novelty seeking also correlated with responding to water reinforcement and extinction responding; however, operant novelty seeking did not correlate with responding to water cues during testing of cue-induced reinstatement. Taken together, the incongruence of relationships indicates an underlying difference between natural and drug reinforcers. CONCLUSION: In summary, we found a reinforcer-dependent relationship between operant novelty seeking (i.e., sensation seeking) and responsivity to extinction and discrete cues signaling availability for cocaine (i.e., craving), demonstrating the validity of the operant novelty seeking model to investigate drug seeking and relapse.

A novel role for the actin-binding protein drebrin in regulating opiate addiction.

Persistent transcriptional and morphological events in the nucleus accumbens (NAc) and other brain reward regions contribute to the long-lasting behavioral adaptations that characterize drug addiction. Opiate exposure reduces the density of dendritic spines on medium spiny neurons of the NAc; however, the underlying transcriptional and cellular events mediating this remain unknown. We show that heroin self-administration negatively regulates the actin-binding protein drebrin in the NAc. Using virus-mediated gene transfer, we show that drebrin overexpression in the NAc is sufficient to decrease drug seeking and increase dendritic spine density, whereas drebrin knockdown potentiates these effects. We demonstrate that drebrin is transcriptionally repressed by the histone modifier HDAC2, which is relieved by pharmacological inhibition of histone deacetylases. Importantly, we demonstrate that heroin-induced adaptations occur only in the D1+ subset of medium spiny neurons. These findings establish an essential role for drebrin, and upstream transcriptional regulator HDAC2, in opiate-induced plasticity in the NAc.

Sex-Dependent Ketamine Addiction-Like Behavior Profile Following Exposure to Chronic Mild Stress.

BACKGROUND: Ketamine has rapid antidepressant effects and shows great promise as a novel treatment for depression, but its limitations including its abuse potential are poorly understood. Given that the prevalence of depression is twice as high in women as in men and that depression and substance use disorders are highly comorbid, we hypothesized that a sex-specific responsivity to behavioral assays that characterize addiction-like behavior may arise in rats with prior exposure to chronic stress and therapeutically relevant ketamine. METHODS: Male and female rats that underwent chronic mild stress were treated with four 1.47 mg/kg intravenous ketamine infusions once every fourth day and underwent operant self-administration of 0.5 mg/kg/infusion ketamine. Measures of anhedonia (or lack of pleasure, a signature feature of depression), anxiety-induced neophagia, motivation to obtain ketamine, and craving were assessed using the sucrose intake test, novelty-suppressed feeding test, progressive ratio schedule of reinforcement, and incubation of craving following abstinence, respectively. Finally, dendritic spine density in the nucleus accumbens core was measured. RESULTS: Ketamine infusions reduced anxiety-induced neophagia in both male rats and female rats but had no effect on measures of anhedonia. Female rats with prior exposure to chronic mild stress had greater motivation to obtain ketamine compared to nonstressed female rats, an effect not observed in male rats. Additionally, female rats who received antidepressant ketamine infusions had a higher threshold for displaying ketamine addiction-like behavior than saline-treated female rats as well as increased thin spine density in the nucleus accumbens core. These effects were not observed in male rats. CONCLUSION: This study shows that repeated low-dose ketamine does not increase abuse potential of subsequent ketamine. It also highlights an important female-specific effect of stress to increase ketamine addiction-like behavior, which requires further investigation for clinical populations.